Дисертації: "PTPN14"

1

Hamyeh, Mohamed. "Régulation de l'agressivité tumorale mammaire par la protéine tyrosine phosphatase PTPL1/PTPN13." Thesis, Montpellier, 2016. http://www.theses.fr/2016MONTT015/document.

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Le cancer du sein est un problème majeur de santé public dont l'incidence est en permanente augmentation. La mortalité est le plus souvent due aux métastases. Les études concernant PTPL1, la plus grande des tyrosines phosphatases cytoplasmiques, ont montré que PTPL1 présente les caractéristiques de suppresseur de tumeur. PTPL1 se trouve mutée dans plusieurs types de cancers et son expression est un marqueur de bon pronostique dans les tumeurs mammaires. Mon laboratoire a également montré que PTPL1 participe à l'effet pro-apoptotique des anti-oestrogènes dans les cellules tumorales hormono dépendantes en déphosphorylant IRSl, le substrat d'IGF1-receptor freinant ainsi la voie PI3K/AKT. PTPL1 régule également la croissance, l'invasion et l'adhésion dans les cellules cancéreuses mammaires peu agressives MCF7.Nous avons établi un modèle cellulaire de clones isogéniques capables d'exprimer PTPL1 ou ses mutants d'une manière inductible dans les cellules cancéreuses mammaires invasives MDA-MB-231. D’une part, nous avons montré un impact négatif de l'expression de PTPL1 sur le phénotype invasif de ces cellules. D'une manière intéressante, le mutant catalytiquement inactif a montré un comportement similaire à celui du contrôle de transfection. Ceci montre l'importance de l'activité catalytique de PTPL1 dans l'inhibition du phénotype agressif. Nous testons maintenant in vivo la tumorigenicité des clones chez les souris athymique.D'autre part, nous avons étudié par protéomique comparative (SILAC) la tyrosine phosphorylation globale des protéines cellulaires dans les cellules MCF-7 et MDA-MB-231 exprimant ou non PTPL1. Parmi les protéines identifiées nous retrouvons des acteurs des différentes voies de signalisations connues dans la littérature pour être impactées par PTPL1 , mais de manière remarquable plus du quart des protéines identifiées sont liées aux jonctions cellulaires ou à leur régulation. Nous avons donc étudié l'effet de la phosphatase sur les jonctions cellulaires et montré que la surexpression de PTPL1 favorise la formation d'agrégats cellulaire en culture 3D, augmente la stabilité des contacts cellulaire en vidéo-microscopie, relocalise la desmogléïne aux jonctions cellulaires et induit une réexpression de la E cadhérine aux niveau du contact cellule/cellule dans les cellules MDA-MB-231.Les jonctions et la polarité cellulaires sont très importantes en cancérologie en particulier dans le processus invasif qui est la première étape de la dissémination métastatique donc il serait maintenant important d'identifier les substrats directs de PTPL1 pour élucider la signalisation de PTPL1 vers les jonctions et proposer de nouvelles cibles thérapeutique
The regulation of breast tumor aggressiveness by Protein Tyrosine Phosphatase PTPL1/ PTPN13Breast cancer is a major problem for public health of which the incidence continues to increase. Its mortality is often linked to metastasis formation. Studies on PTPL1, the largest protein tyrosine phosphatase, have shown that it presents the characteristics of a tumor suppressor gene. PTPL1 is mutated in several types of cancers and its expression is associated with good prognostic in prostate and breast cancers. My team has shown that PTPL1 mediates the pro apoptotic effect of anti-estrogen in hormone-sensitive tumor cells by dephosphorylating IRS1, Insulin growth factor-1 receptor substrate, thus blocking PI3K/Akt pathway. In addition, PTPL1 regulates the growth, the invasion, and the adhesion of low aggressive breast tumor cells MCF-7.Our team established an isogenic cellular model capable of expressing PTPL1 or its mutants (phosphatase-dead and substrate-trapping mutants) in an inducible fashion in invasive cells. We showed that functional PTPL1 expression has a negative impact on cell aggressive phenotypes. Interestingly, the phosphatase-dead mutant exhibits the same behavior as the transfection control. This evidences that PTPL1 activity is crucial for the inhibition of aggressiveness. We are currently testing the clones tumorigenicity in athyemic mice.Furthermore, we conducted a comparative proteomic (SILAC) in order to study the global tyrosine phosphatome in MCF-7 and MDA-MB-231 cells with or without PTPL1. Our findings suggest that PTPL1 regulates the phosphorylation of proteins involved in different signaling pathways already described in the literature to be impacted by PTPL1. Remarkably, the quarter of proteins identified belong to cell junction structure or regulation. We then studied the impact of this phosphatase on cell junctions and showed that PTPL1 overexpression enhances cell aggregate formation in 3D culture, increases cell contact stability, relocates desmoglein to the cell junctions, and induces E-cadherin re-expression at the level of cell-cell contacts in MDA-MB-231 cells.Cell junctions and polarity are very important in oncology and particularly in the invasive process which is the first step in the metastatic dissemination. Our ongoing work focuses on identifying direct substrates for PTPL1 in order to elucidate the underlying PTPL1 signal leading to cell junctions and consequently propose a novel therapeutic targets

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2

Dromard, Mathilde. "Rôles et mécanismes d'action de la protéine tyrosine phosphatase PTPL1/ptpn13 dans les cancers mammaires et ovariens." Montpellier 2, 2008. http://www.theses.fr/2008MON20040.

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Des études cliniques récentes suggèrent un rôle anti-oncogénique de la Protéine Tyrosine Phosphatase (PTP) PTPL1/ptpn13. L'analyse de l'effet inhibiteur du 4-hydroxytamoxifène (OH-Tam) sur l'action des facteurs de croissance a permis, dans un premier temps, d'identifier le rôle clé joué par une nouvelle classe d'enzymes, les PTPs, et par la suite plus spécifiquement de PTPL1 dans le contrôle de la prolifération cellulaire. Mon travail de thèse a permis de démontrer d'une part, que PTPL1 inhibe l'activation de la voie de signalisation Insulin Receptor Substrate-1 (IRS-1)/PI3K/Akt induite par l'Insulin like Growth Factor 1 (IGF1) au travers de la déphosphorylation d'IRS-1, et que cette PTP est suffisante pour inhiber l'effet d'IGF1 sur la survie cellulaire. D'autre part, nous avons élucidé les mécanismes par lesquels l'anti-œstrogène, OH-Tam, inhibe via PTPL1 la croissance des cellules cancéreuses mammaires induite par le Nerve Growth Factor (NGF). PTPL1 est en effet capable de déphosphoryler le récepteur du NGF, p140TrkA, nécessaire à l'activation des MAPK (Mitogen Activated Protein Kinase) et à la régulation de la croissance cellulaire. Finalement, nous avons mis en évidence un rôle clé de PTPL1 dans l'inhibition de l'invasion, de la mobilité et de la prolifération des cellules cancéreuses ovariennes, ce qui est en accord avec les résultats de notre étude rétrospective montrant un intérêt pronostique du dosage de PTPL1 dans ce type de tumeur. L'ensemble de ces résultats confirme le rôle anti-oncogénique de cette PTP. La mise en évidence des cibles moléculaires de PTPL1 et la compréhension des mécanismes de régulation de son expression, de sa localisation, et de son activité, devraient permettre d'envisager de nouvelles approches thérapeutiques visant à réguler l'expression ou l'activité de cet anti-oncogène
Recent clinical studies have suggested an anti-oncogenic role for the Protein Tyrosine Phosphatase (PTP) PTPL1/ptpn13. Analysis of the inhibitory effect of 4-hydroxytamoxifen (OH-Tam) on growth factor action has allowed to identify the key role played by a new class of enzymes, PTPs, and more specially PTPL1 on the control of cell proliferation. The first part of my PhD studies, has demonstrated that PTPL1 inhibits activation of the Insulin Receptor Substrate-1 (IRS-1)/PI3K/Akt pathway induced by Insulin like Growth Factor 1 (IGF1), through the dephosphorylation of IRS-1, and that PTPL1 is sufficient to inhibit the IGF1 effect on cell survival and to induce apoptosis. Moreover, we have clarified the mechanisms by which the anti-estrogen OH-Tam inhibits Nerve Growth Factor (NGF)-induced breast cancer cells growth through PTPL1. PTPL1 is able to induce dephosphorylation of the NGF receptor, p140TrkA, which is necessary for activation of the MAPK (Mitogen Activated Protein Kinase) pathway and regulation of cell growth. Finally, in agreement with our retrospective studies showing the prognostic value of PTPL1 expression in ovarian tumors, we have also showed an inhibitory effect of PTPL1 on invasion, mobility and proliferation of ovarian cancer cells. Altogether, these results are consistent with the anti-oncogenic role played by this PTP. The identification of PTPL1 molecular targets and our understanding of the mechanisms that regulate its expression, its location and its activities, should allow consideration of new therapeutic approaches to regulate the expression or activity of this anti-oncogene

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3

Tchankouo, Nguetcheu Stéphane. "Rôle des kinases LAMMER et des phosphatases PTP1B/PTP61F dans la régulation des voies de signalisation médiées par l'insuline." Thesis, Paris 11, 2012. http://www.theses.fr/2012PA11T067/document.

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Le diabète de type 2 et le cancer représentent des problèmes majeurs de santé publique. Une cible thérapeutique importante de ces affections est la protéine tyrosine phosphatase PTP1B. Cette dernière est connue pour réguler la voie de l’insuline en déphosphorylant le récepteur de l’insuline, IR ou le substrat du récepteur de l’insuline, IRS. Cependant lesfonctions de PTP1B, le mécanisme par lequel cette phosphatase est régulée restent très ou pas connus. Deux études ont notamment décrites des effets opposés de l’activité de PTP1B suite à la phosphorylation sur résidu de Ser50 de PTP1B par CLK1/CLK2, des kinases LAMMER d’une part et AKT d’autre part. AKT a aussi été montré de phosphoryler la kinase LAMMER CLK1. Par ailleurs, le rôle de PTP1B dans la régulation de la voie Ras/MAPK et donc dans le cancer est un sujet très controversé. L’objectif premier de ce travail de thèse a été d’analyser, le rôle de Ptp61F (l’orthologue de Drosophile de PTP1B) dans la voie de l’insuline de Drosophile, l’interaction entre la phosphatase et la kinase LAMMER de Drosophile, DOA, le rôle de cette phosphatase dans la voie RAS/MAPK. Pour se faire, nous avons utilisé la puissance génétique de laDrosophile pour générer un mutant du gène Ptp61F qui a été caractérisé et son rôle dans les voies de signalisation a été étudié. Cette étude a montrée que, Ptp61F interagit avec IR comme PTP1B chez les mammifères. Elle montre que Ptp61F régule les acteurs clés de la voie de l’insuline Pi3K/Akt. Elle a également montrée que Ptp61F pouvait réguler les fonctions du gène de la kinase LAMMER de Drosphile, Doa. Elle montre enfin que Ptp61F interagit avec nombreuses composantes de la voie RASMAPK de Drosophile (Egfr, Ras, rl (ERK humain)) en réprimant la fonction de chacun de ces gènes et que Rl serait un substrat direct de PTP61F. Les informations selon lesquelles, Ptp61F interagit avec Akt et le gène de la kinaseLAMMER de Drosophile, Doa ont été utilisées dans la deuxième étude pour montrer le rôle que les kinases LAMMER (notamment CLK2, Cdc-like kinase 2) pouvaient jouer dans la voie de signalisation de l’insuline au niveau moléculaire en utilisant les cellules de neuroblastome humain SH-SY5Y. Il en ressort que la kinase CLK2 joue un rôle importantdans cette voie de signalisation. CLK2 est induit par l’insuline et son expression augmente avec le temps. PTP1B interagit in vitro et in vivo avec CLK2. La surexpression de CLK2 induit la baisse de la phosphorylation de AKT par un mécanisme qui pourrait passer par PTP1B, puisque in vitro, CLK2 phosphoryle PTP1B et ce dernier interagit avec AKT in vivo. C’est le résidu de Ser50 de PTP1B qui est phosphorylé et cette phoshphorylation réprime l’activité de PTP1B in vitro. On n’observe cependant pas AKT capable de phosphoryler PTP1B in vitro suggérant que la phosphorylation de PTP1B par AKT serait dépendante du contexte cellulaire
Type 2 diabetes and cancer represent the major public health problems. One important therapeutic target for these pathologies is the protein tyrosin phosphatase PTP1B. The phosphatase is known to negatively regulates the insulin signaling pathway by dephosphorylating the insulin receptor, IR or the insulin receptor substrate, IRS. However,PTP1B functions and its regulation mechanism remain poorly known. Two studies has notably described opposite effects of PTP1B activity following phosphorylation of its Ser50 residue either by CLK1/CLK2, LAMMER kinases or by AKT. Furthermore, AKT, a main insulin signaling pathway component, has been shown to phosphorylate the LAMMER kinaseCLK1 following insulin stimulation. In addition, the role of PTP1B in the regulation of the RAS/MAPK signaling pathway and hence in cancer is a very controversial subject. The first objective of this work was to analyse, the role of Ptp61F (the Drosophila ortholog of human PTP1B) in the Drosophila insulin pathway, the interaction between the phosphatase and the Drosophila LAMMER kinase gene, Doa, the role of Ptp61F in the RAS/MAPK signaling pathway. To achieve these, we took advantage of the genetic powerful of Drosophila to generate a Ptp61F gene mutant which has been characterized and its role in signaling pathways has been studied. This study showed that Ptp61F interacts with IR like PTP1B in mammals. It shows that Ptp61F regulates key components of insulin signaling pathway Pi3K/Akt. It also shows that Ptp61F is able to regulate the Drosophila LAMMER kinase gene, Doa. Finally, we noted that Ptp61F interacts by inhibiting the activity of severalcomponent of the RAS/MAPK signaling pathway of Drosophila (Egfr, Ras, rl (human ERK)) and conclude that Rl coud be a direct substrate of PTP61F. The data showing that Ptp61F interacts with Akt and the Drosophila LAMMER kinase gene, Doa, were the basis for the second study in order to show the role that the mammal LAMMER kinase CLK2 (Cdc-like kinase 2) could play in the insulin signaling pathway at molecular level using the human neuroblastoma cell line SH-SY5Y. From this second study, we show that CLK2 play an important role in insulin signaling. CLK2 is induced by insulin and its expression increases with time. PTP1B interacts in vivo and in vitro with CLK2. Overexpression of CLK2 impairs AKT phosphorylation by a mechanism which could involved PTP1B, since in vitro, CLK2 phosphorylates PTP1B and the latter interacts withAKT in vivo. It is the Ser50 residue of PTP1B being phosphorylated by CLK2 and this phosphorylation event represses PTP1B activity in vitro. AKT cannot phosphorylates PTP1B in vitro, suggesting that the phosphorylation of PTP1B by AKT could be cellular environment dependant

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4

Cheyssac, Claire. "Etude de deux gènes candidats du DT2 : EIF4A2 : candidat positionnel au locus 3Q27 et PTPN1/PTP1B : cible pharmacologique dans la sensibilité à l'insuline." Lille 2, 2006. http://www.theses.fr/2006LIL2S009.

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Le diabète de type 2 (DT2) représente la forme la plus commune de diabète touchant plus de 170 millions de personnes dans le monde. Les mécanismes physiopathologiques à l'origine de l'hyperglycémie chronique associent des défauts de sécrétion de l'insuline et de son action sur des organes cibles déterminés par des interactions entre des facteurs de risuqe génétiques et environnementaux. Plusieurs gènes responsables de formes monogéniques de diabète ont été identifiés; toutefois, les déterminants génétiques influençant la prédisposition aux formes communes du DT2 sont encore peu connus. Afin d'identifier de nouveaux variants de susceptibilité, nous avons utilisé deux types d'approches: - une analyse d'association familiale de variants de gènes candidats positionnels au locus 3q27 au sein de familles présentant une liaison génétique avec le DT2 apparaissant avant 45 ans; - et l'exploration d'un gène candidat physiologique , PTPN1, par une étude cas-contrôlés dans plusieurs cohortes de sujets diabétiques et obèses. L'étude du locus 3q27 dans les 148 familles françaises à forte agrégation de DT2 (432 sujets diabétiques et 129 sujets normoglycémiques) a permis de confirmer la liaison génétique ave cl'âge d'apparition du diabète. Deux gènes ont été explorés: KNG1 codant pour kininogène, le précurseur de la bradykinine, et EIF4A2, un facteur d'initiation de la synthèse protéique négativement régulé par le glucose dans des cellules -pancréatiques de rat (INS832/13). Un variant (SNP rs266714 C/T), localisé en amont du gène EIF4A2, a montré une association au DT2 et à l'âge de survenue du diabète au sein des familles. Les paires d'atteints porteuses d'au moins un allèle T à risque montrent un lod-score de 5. 24 pouvant expliquer la liaison au DT2. De plus, ce variant explique en partie la liaison génétique avec l'âge de survenue du diabète. Le SNP rs266714 pourrait modifier le niveau d'expression du facteur EIF4A2 qui module la traduction de certains ARN messagers ainsi que le taux de synthèse protéique notamment dans les cellules -pancréatiques. Le gène PTPN1 code pour la protéine tyrosine phosphatase 1B, régulateur négatif des voies de signalisation de l'insuline et de la leptine. Une association au DT2 et à l'obésité modérée est observée pour un variant au locus du gène PTPN1. Chez 736 sujets normoglycémiques non obèses, 2 SNP introniques sont associés à des variations de traits quantitatifs du métabolisme glucido-lipidique : augmentation du HOMA-B et des triglycérides, diminution du HDL-cholestérol suggérant un rôle possible dans la survenue du syndrome métabolique. Ce type d'approche génétique permet d'améliorer nos connaissances des voies de signalisation pouvant être impliquées dans le développement du DT2 et de proposer de nouvelles cibles thérapeutiques
Type 2 diabetes (T2D) is the most common form of diabetes affecting more than 170 million people worldwide. The T2D pathophysiological mechanisms are characterized by defects of insulin secretion and insulin action leading to chronic hyperglycaemia determined by interactions between genetic and environmental risk factors. Although many genes responsible for monogenic forms of diabetes were identified, genetic determinants influencing T2D predisposition are still largely unknown. To identify new susceptibility variants, we used two approaches : - a familial association study of positional candidate gene variants at the 3q27 locus in falilies showing linkage to T2D with onset before 45 years ; and the exploration of a physiological candidate gene, PTPN1, through case-control analyses in different groups of subjects with type 2 diabetes or obesity. The analysis of the 3q27 locus in French families with strong T2D aggregation (432 diabetes subjects and 129 normoglycaemic subjects) confirmed of a genetic linkage with T2D age-of-onset. Two genes were investigated : KNG1, coding for kininogen, the bradykinin precursor, and EIF4A2 coding for the Eukaryotic Translation Initiation Factor 4 alpha 2, a translation initiation factor involved in protein synthesis which is down-regulated by glucose in rat pancreatic beta cells (INS832/13). A variant (rs266714), located upstream of the EIF4A2 gene showed association with T2D and T2D age-of-onset in the families. Affected sib-pairs sharing at least one at risk T allele showed a LOD-score of 5. 24 which could explain the T2D linkage. Moreover, this variant partly explains the age-of-onset linkage. The rs266714 SNP could modify the expression level of the eIF4A2 factor which modulates mRNA translation and protein synthesis rates in pancreatic beta cells. The PTPN1 gene codes for the protein tyrosine phosphatase 1B, a negative regulator of the insulin and leptin signalling pathways. An association with T2D and moderate obesity is observed for a variant at the PTPN1 gene locus. In 736 normoglycaemic non obese subjects, 2 intronic SNPs associate with variations of quantitative traits of glucose and lipid metabolism : increased HOMA-B and triglycerides, decreased HDL-cholesterol, which suggests a possible role in metabolic syndrome. This genetics approach contributes to an improved understanding of the pathways involved in the development of T2D and to propose new therapeutic targets

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5

Sanchez-Blanco, Cristina. "Studies of the protein tyrosine phosphatase PTPN22/Lyp in Ptpn22 deficient mice." Thesis, King's College London (University of London), 2015. http://kclpure.kcl.ac.uk/portal/en/theses/studies-of-the-protein-tyrosine-phosphatase-ptpn22lyp-in-ptpn22-deficient-mice(cbcf6c1c-7d57-4df9-95ef-8696a7856858).html.

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An R620W polymorphism in the haematopoietic protein tyrosine phosphatase PTPN22 increases susceptibility to a number of autoimmune diseases, including rheumatoid arthritis. PTPN22 is a negative regulator of immune cell signalling and its role has been best characterised in T cell receptor (TCR) signal transduction. Functional studies in the mouse are needed to clarify the role of Ptpn22 function. In this PhD project, the Ptpn22 deficient mouse was investigated in the context of chronic inflammatory disease, by investigating its role in T cell activation and downstream effector pathways. Ptpn22-/- mice revealed a modest increase in severity of joint inflammation compared to Ptpn22+/+ and Ptpn22+/- mice in a collagen-induced arthritis (CIA) study. Increased proportions of IFN-γ+ CD4+ T cells, CD4+ effector/memory T cells (CD4+ CD44hi CD62Llo) and regulatory CD4+ T cells (CD4+ CD25+ Foxp3+) were observed in Ptpn22-/- mice compared to Ptpn22+/+ littermates in response to immunisation with type II chicken collagen in complete Freund’s adjuvant. This was accompanied by a decrease in the levels of chicken type II collagen specific IgG1:IgG2c, suggesting an enhanced polarisation to the Th1 lineage in the absence of Ptpn22. Ptpn22+/+ and Ptpn22-/- naïve CD4+ T cells polarise to a Th1 phenotype to a similar extent in vitro in the absence of antigen presentation. However, Ptpn22-/- bone marrow derived dendritic cells were found to polarise CD4+ T cells to a Th1 phenotype in in vitro DC: T cell co-culture experiments utilising transgenic OT-II CD4+ T cells. Ptpn22-/- mice developed more severe inflammatory arthritis than Ptpn22+/+ mice in the K/BxN serum transfer arthritis model. The data presented in this thesis describe a negative regulatory role for Ptpn22 in Th1 differentiation in the CIA model resulting in exacerbated inflammatory arthritis in the Ptpn22 deficient mouse. Evidence suggests a T cell extrinsic influence of Ptpn22 deficiency on the antigen presenting cell in promoting pathways of Th1 differentiation. Furthermore, preliminary findings suggest a role for Ptpn22 in the regulation of IgG1 mediated downstream effector pathways. These results highlight a role for Ptpn22 in negatively regulating multiple pathways in the innate and adaptive immune response, alterations in which could ultimately result in autoimmunity.

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6

Maisonneuve, Pierre. "Etude structurale et fonctionnelle de la phosphatase humaine PTPN4." Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066673/document.

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La fonction des protéines de signalisation est déterminée par la nature des domaines qui les composent. Une meilleure compréhension des voies de signalisation passe par l'étude de ces domaines et de leur régulation. PTPN4 est une tyrosine phosphatase qui joue un rôle anti-apoptotique. Lors de l'infection par une souche atténuée du virus de la rage, sa fonction est perturbée, conduisant à la mort des cellules. Cette perturbation est due à l'interaction du motif de reconnaissance au domaine PDZ (PBM) de la glycoprotéine virale avec le domaine PDZ de PTPN4. Nous avons montré que ce domaine PDZ a un rôle d'inhibiteur allostérique de l'activité catalytique de la phosphatase de PTPN4. Ceci représente la première description de la régulation d'une phosphatase par un domaine PDZ. Cette inhibition est levée lors de la fixation d'un ligand au domaine PDZ, tel que le PBM de la glycoprotéine virale. Notre étude structurale révèle que la fixation d'un PBM perturbe les interactions transitoires entre les deux domaines et rétablit ainsi les propriétés catalytiques de la phosphatase. Nous avons par ailleurs identifié un ligand endogène de PTPN4, la MAP Kinase p38 qui, à travers son interaction avec PTPN4, participerait à la régulation de l'homéostasie cellulaire. La formation du complexe implique le recrutement du PBM de p38 par le domaine PDZ de PTPN4. Ainsi, en plus d'avoir une fonction de régulation du domaine phosphatase, le domaine PDZ permet également le recrutement de partenaires et la présentation de substrats au site actif de la phosphatase de PTPN4. Cette étude contribue ainsi à améliorer notre connaissance du rôle des domaines PDZ dans les voies de signalisation cellulaires
The function of signaling proteins is determined by the nature of the domains from which they are made up. A better understanding of cell signaling pathways will result from the study of these domains and their regulation. PTPN4 is a non-receptor tyrosine phosphatase with an anti-apoptotic function. Upon infection with an attenuated rabies virus, its function is hijacked, which subsequently leads to cell death. This phenotype is arises from the interaction of the PDZ binding motif (PBM) of the viral glycoprotein with the PDZ domain of PTPN4. In this study, we show that this PDZ domain is an allosteric inhibitor of the catalytic activity of the PTPN4 phosphatase domain. This is the first description of the regulation of a phosphatase by a PDZ domain. This inhibition is released by the interaction of a ligand to the PDZ domain, such as the viral glycoprotein PBM. Our structural study revealed that the PBM recognition disrupts the transient inter-domain interactions and restores the complete phosphatase catalytic properties. As well, we identified a PTPN4 endogenous ligand, the MAP Kinase p38, which may participate in the regulation of the cellular homeostatic through its interaction with PTPN4. Thus, in addition to its phosphatase regulatory role, the PDZ domain also allows the recruitment of partners and the introduction of substrates to the PTPN4 phosphatase active site. This study contributes to our understanding of the role played by PDZ domains in cell signaling pathways

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7

Bertola, Débora Romeo. "Estudo do gene PTPN11 nos pacientes afetados pela síndrome de Noonan." Universidade de São Paulo, 2006. http://www.teses.usp.br/teses/disponiveis/5/5141/tde-12042006-110700/.

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INTRODUÇÃO: A síndrome de Noonan é uma doença autossômica dominante caracterizada por baixa estatura, dismorfismos faciais (hipertelorismo ocular, inclinação para baixo das fendas palpebrais, ptose palpebral, palato alto e má-oclusão dentária), pescoço curto e/ou alado, defeitos cardíacos, principalmente a estenose pulmonar valvar, deformidade esternal e criptorquia nos pacientes do sexo masculino. O gene PTPN11, localizado no braço longo do cromossomo 12 (12q24.1), é responsável por aproximadamente 50% dos casos de síndrome de Noonan. OBJETIVO: Detectar a freqüência de mutações no gene PTPN11 em uma amostra de pacientes os quais preenchiam os critérios clínicos para a síndrome de Noonan e síndromes Noonan-like e estabelecer uma correlação genótipo-fenótipo. MÉTODOS: Cinqüenta probandos com síndrome de Noonan, 3 com síndrome de LEOPARD, 3 com síndrome de Noonan-like/lesões múltiplas de células gigantes e 2 com neurofibromatose-Noonan foram incluídos nesse estudo. O estudo molecular foi realizado através da técnica da cromatografia líquida de alta precisão desnaturante e, naqueles com um perfil anormal, a técnica do seqüenciamento do éxon em questão foi concretizada. RESULTADOS: Mutações missense no gene PTPN11 foram identificadas em 21 probandos com síndrome de Noonan (42%), em todos os três pacientes com a síndrome de LEOPARD, em um caso com síndrome de Noonan-like/lesões múltiplas de células gigantes e em um paciente com síndrome da neurofibromatose-Noonan. Este último probando também apresentava uma mutação no gene NF1. A única anomalia que atingiu uma diferença estatisticamente significante quando comparados os grupos de pacientes com e sem mutação foi o grupo de distúrbios hematológicos. Um paciente com síndrome de Noonan que apresentou uma doença mieloproliferativa possuía a mutação T73I. CONCLUSÃO: A síndrome de Noonan é uma doença heterogênea, uma vez que mutações no gene PTPN11 são responsáveis por 42% dos casos. Uma correlação genótipo-fenótipo definitiva não foi estabelecida, mas a mutação T73I parece predispor a distúrbios mieloproliferativos. Com relação às síndromes Noonan-like, o gene PTPN11 é o principal responsável pela síndrome de LEOPARD e também desempenha um papel na síndrome da neurofibromatose-Noonan. A síndrome de Noonan-like/lesões múltiplas de células gigantes, a qual faz parte do espectro da síndrome de Noonan, é também uma doença heterogênea.
INTRODUCTION: Noonan syndrome is an autosomal dominant disorder comprising short stature, facial dysmorphisms (ocular hypertelorism, downslanting palpebral fissures, palpebral ptosis, high arched palate and dental malocclusion), short and/or webbed neck, heart defects, mainly valvar pulmonary stenosis, sternal deformity and cryptorchidism in males. The PTPN11 gene, localized in the long arm of chromosome 12 (12q24.1), is responsible for approximately 50% of the cases. OBJECTIVE: To detect the PTPN11 gene mutation rate in a cohort of clinically well-characterized patients with Noonan and Noonan-like syndromes and to study the genotype-phenotype correlation. METHODS: Fifty probands with Noonan syndrome ascertained according to well-established diagnostic criteria, 3 with LEOPARD syndrome, 3 with Noonan-like/multiple giant cell lesion syndrome and 2 with neurofibromatosis/Noonan were enrolled in this study. Mutational analysis was performed using denaturing high-performance liquid chromatography followed by sequencing of amplicons with an aberrant elution profile. RESULTS: Missense mutations in the PTPN11 gene were identified in 21 probands with Noonan syndrome (42%), in all three patients with LEOPARD syndrome, in one case with Noonan-like/multiple giant cell lesion syndrome and in one with neurofibromatosis-Noonan syndrome. This last patient also showed a NF1 gene mutation. The only anomaly that reached statistical significance when comparing probands with and without mutations was the hematological abnormalities. A Noonan syndrome patient presenting a myeloproliferative disorder showed a T73I mutation. CONCLUSION: Noonan syndrome is a heterogeneous disorder, once PTPN11 gene mutations is responsible for 42% of the cases. A definitive genotype-phenotype correlation is not established, but the T73I mutation seems to predispose to a myeloproliferative disorder. Regarding Noonan-like syndromes, the PTPN11 gene is the main one in LEOPARD syndrome and also plays a role in neurofibromatosis-Noonan syndrome. Noonan-like/multiple giant cell lesion syndrome, part of the spectrum of Noonan syndrome, is also heterogeneous.

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Keren, Boris Verloes Alain. "Syndrome de Noonan et mutations du gène PTPN11 corrélations génotype-phénotype /." Créteil : Université de Paris-Val-de-Marne, 2006. http://doxa.scd.univ-paris12.fr:80/theses/th0247734.pdf.

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Chadwick, Michelle. "Characterization of a Novel Mouse Model for Angiosarcoma in Which Combined Inhibition of mTOR and MEK Results in Tumor Suppression." University of Cincinnati / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1490353768809798.

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Abdessamad, Mahmoud. "Caractérisation moléculaire et fonctionnelle des signalosomes PTEN/MAGI-1b/TRIP6 et PTEN/PTPN13." Paris 7, 2012. http://www.theses.fr/2012PA077048.

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Le suppresseur de tumeurs PTEN est une phosphatase capable de déphosphoryler certains résidus tyrosine, mais également les phosphoinositides produits de la PI3K. Dans son extrémité C- terminale, PTEN comporte un motif d'interaction avec les domaines PDZ. Notre équipe a établi le rôle majeur de l'activité lipide-phosphatase dans la stabilisation des contacts cellulaires et le contrôle de l'invasion. PTEN est recruté vers les jonctions cellulaires E-cadhérine β-caténine, via la molécule à domaines PDZ MAGI-1. Afin d'identifier de nouveaux partenaires de PTEN, nous avons engagé une approche par le système de double hybrides. Cette approche a permis d'identifier TRIP6 et PTPN13. Nous avons montré que TRIP6 induit l'invasion des cellules épithéliales MDCK, via i) la compétition avec les (3-caténines pour lier MAGI-1 et la déstabilisation des complexes jonctionnels, ii) l'activation des voies de signalisations dépendantes de la PI3K et de NFKB (FASEB J 23:916,2009). PTPN13 est une tyrosine phosphatase qui comporte 5 domaines PDZ. Nous avons confirmé l'interaction de PTEN avec le domaine PDZ2 de PTPN13 in vitro et ex vivo. Nous avons montré que PTEN est substrat de PTPN13 in vitro. De même, la surexpression de PTPN13 native, mais pas d'une forme défective dans l'activité phosphatase, induit une diminution de la phosphorylation de PTEN. Cette surexpression n'affecte pas le niveau de phosphorylation de Akt -reflet de l'activité de cette kinase- dans des lignées déficientes en PTEN, mais potentialise les effets inhibiteurs de PTEN sur cet effecteur de la PI3K. Par conséquent, nos résultats démontrent le rôle critique de PTPN13 dans le contrôle de la signalisation dépendante de PTEN
The PTEN tumor suppressor is a multifunctional protein endowed with a phosphatase activity that dephosphorylates not only some phosphotyrosine residues, but also the phosphoinositides generated by PI3K. In its C-terminus, PTEN encodes a PDZ-binding motif. Our Team has demonstrated the critical role of the lipid phosphatase activity of PTEN in stabilizing junctional complexes and in reverting invasiveness. PTEN interacts with cadherin β3-catenin complexes through the PDZ domain containing- protein MAGI-1. To identify new molecular PTEN partners, we applied yeast-two-hybrid assay, and identified TRIP6 and PTPN13. We have demonstrated that TRIP6 induces invasiveness of the MDCK epithelial cells, through i) the competition with (3-catenin for binding to MAGI-1 b and the destabilization of junctional complexes, ii) the activation of the PI3K/ Akt, and NFKB signaling pathways (FASEB J 23:916,2009). PTPN13 is a tyrosine phosphatase with 5 PDZ domains. We have confirmed the interaction of PTEN C-terminus with the 2nd PDZ domain of PTPN13 in vitro and ex vivo. We showed that PTEN is a PTPN13 substrate in vitro. In line with these results, the overexpression of wild-type PTPN13, but not of a mutant deficient in phosphatase activity decreased PTEN phosphorylation. This overexpression did not alter Akt phosphorylation -a reflect of the activity of this kinase- in PTEN deficient cell lines, but potentiated PTEN effects on this downstream target of PI3K. Thus, our results demonstrated the critical role of PTPN13 in controling PTEN signaling pathway

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Xu, Dan. "EFFECTS OF ACTIVATING MUTATIONS IN SHP-2 (PTPN11) PHOSPHATASE ON HEMATOPOIETIC CELL DEVELOPMENT." Case Western Reserve University School of Graduate Studies / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=case1295052361.

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Pratigya, Gautam. "Deciphering the link between PTPN22 and autoimmunity." Thesis, Cardiff University, 2011. http://orca.cf.ac.uk/54471/.

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Recent genetic studies have linked a C to T single nucleotide polymorphism (SNP) in the protein tyrosine phosphatase (PTP) non-receptor type 22 (PTPN22) to several autoimmune diseases (ADs). This changes amino acid at position 620 from an Arginine (R) to a Tryptophan (W) in the protein, Lyp. Lyp is thought to be a negatively regulator of TCR signalling by dephosphorylating Src family kinases Lck and Fyn, and Zap70. However, the cellular and molecular mechanisms of predisposition to ADs by the R620W polymorphism are not yet understood. Several studies have reported the R620W polymorphism as a “gain of function” change resulting in an increase in the PTP activity of Lyp. It has been further hypothesised that the W620 isoform suppresses TCR signalling more potently than the R620 isoform, resulting in the survival of auto-reactive cells that would normally be deleted by negative selection in the thymus. Alternatively, the impact of Lyp W620 on TCR signalling may have an effect on the development and functioning of T regulatory cells. To investigate the effect of the R620W polymorphism in T cells, lentivirus plasmids expressing the R and W isoforms of Lyp were generated and used to introduce the Lyp and wLyp isoforms in leukaemic T cells thereby generating H9 and E6.1 cell lines over- R W expressing the Lyp and Lyp isoforms. Investigation of activation marker expression and cytokine production by these T cell lines post activation showed no differences in CD69 activation marker expression between the RLyp and wLyp expressing T cells or between the R/wLyp expressing and control cells (not expressing exogenous Lyp). However, there was a trend towards a reduction in IL-2 production observed by R/WLyp expressing H9 T cells compared to control cells. In addition, a significant reduction in IL-10 production by R/wLyp expressing H9 T cells compared to control cells was observed. This effect of Lyp on IL-10 production suggests a potential mechanism by which wLyp, if indeed a more active PTP, may predispose to ADs.

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Jariwala, Nidhi. "SND1 mediated downregulation of PTPN23 in HCC." VCU Scholars Compass, 2014. https://scholarscompass.vcu.edu/etd/3648.

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SND1 MEDIATED DOWNREGULATION OF PTPN23 IN HEPATOCELLULAR CARCINOMA By Nidhi Jariwala, MS A thesis submitted in partial fulfillment of the requirements for the degree of Master of Science at Virginia Commonwealth University, 2014. ADVISOR: Dr. Devanand Sarkar Associate Professor, Department of Human and Molecular Genetics Blick Scholar Associate Scientific Director, Cancer Therapeutics VCU Institute of Molecular Medicine Massey Cancer Center ABSTRACT Staphyloccocal nuclease domain containing protein 1 (SND1) is identified as an oncogene in multiple cancers, including hepatocellular carcinoma (HCC). SND1 regulates gene expression at transcriptional as well as post-transcriptional level and mediates molecular pathways that culminate into carcinogenesis. SND1 is a component of RNA-induced silencing complex (RISC) and functions as a nuclease for RNAi-mediated mRNA degradation. On the other hand SND1 also binds to specific mRNAs, increasing their stability and hence expression. The aim of the present study is to identify mRNAs to which SND1 binds and modulates them either by degradation or increasing stability which might facilitate promotion of HCC by SND1. We performed RNA immunoprecipitation followed by RNA sequencing (RIP-Seq) using anti-SND1 antibody and human HCC cell line QGY-7703. More than 350 mRNAs were identified to be interacting with SND1, of which Protein tyrosine phosphatase non-receptor 23 (PTPN23) was of particular interest, since PTPN23 has been identified to be a tumor suppressor and its role in HCC has not been studied. We document that SND1 can bind to PTPN23 mRNA and induce its degradation. There is an inverse correlation between SND1 and PTPN23 levels in human HCC cell lines and PTPN23 level is downregulated in HCC. Our study thus identifies a novel mechanism by which SND1 promotes hepatocarcinogenesis and identifies PTPN23 as a potential tumor suppressor in HCC. Further studies need to be performed to explore the relationship of these two molecules in in vivo models and to develop PTPN23 overexpression as a potential therapeutic approach for HCC.

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Padovani, Carolina Rabello. "Perfil cognitivo de pessoas portadoras da síndrome de Noonan com mutação do gene PTPN11." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/47/47133/tde-21052012-161923/.

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A síndrome de Noonan é uma doença autossômica dominante geneticamente heterogênea. Apesar de relativa alta prevalência, possui poucas informações referentes ao perfil cognitivo de seus portadores. Em literatura atual seus portadores são descritos com moderado prejuízo na cognição social em termos de reconhecimento das emoções e expressão do afeto, além de variável nível de inteligência. Em virtude da raridade de pesquisas na área psicológica acerca desta síndrome e, tomando por base recentes estudos, o presente estudo buscou esclarecer o perfil cognitivo de portadores da síndrome de Noonan decorrente de mutação do gene PTPN11, visando a contribuir para o estabelecimento de seu fenótipo comportamental. Foram estudadas 19 pessoas com a síndrome, de ambos os sexos, diagnosticadas clínica e laboratorialmente. A avaliação psicológica foi realizada por meio das escalas Wechsler de inteligência, pelo teste Figuras Complexas de Rey e pelo Teste Wisconsin de Classificação de Cartas. Os resultados obtidos indicaram uma variação entre inteligência normal a retardo mental leve, além de inflexibilidade mental e resposta não adaptada ao feedback ambiental. A avaliação aferiu presença de prejuízos em categorização e, ainda, falha no planejamento do ato motor (praxia) como responsável pelos escores rebaixados em memória episódica visuo-construtiva gráfica. Estes resultados sugerem a necessidade de ampliação de estudos que correlacionem aspectos cognitivos nas mais variadas patologias genéticas
Noonan syndrome is an autosomal dominant genetically heterogeneous disorder. Although relatively high prevalence, there are few information about the cognitive profile of people with the syndorme. Current literature describes moderately impaired social cognition in terms of emotion recognition and emotion affection, besides a variable level of intelligence. Because of rarely researches about psychological area in this syndrome and, based on recent studies, the present study looked for clarify the cognitive profile of people with Noonan syndrome with mutation in the PTPN11 gene, trying to contribute for the establishment of a phenotypic behavior. 19 persons with the syndrome were studied, both male and female, diagnosticaded clinical and laboratorilly. Psychological assessment was realized by using Wechsler intelligence Scales, Rey Complex Figure Test and Wisconsin Card Sorting Test. The results indicated a variation of normal intelligence to mild mental retardation, besides inflexibility and not adapted responses using environmental feedback. The assessment checked the presence of lacked in categories achieved and, even, fault in planning of motor act (praxis) as responsible for low scores in graphic visuoconstruction episodic memory. These results suggest the necessity of expansion of studies which correlated cognitive aspects in the most variables genetic pathologics

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Fodil, Mostefa. "Etude d'association génétique et analyse de gènes candidats différentiellement exprimés au cours de la polyarthrite rhumatoïde." Thesis, Evry-Val d'Essonne, 2015. http://www.theses.fr/2015EVRY0017/document.

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Nous nous sommes intéressés à l’étude génétique de la PR, maladie auto-immune, chronique et inflammatoire affectant principalement les articulations et entraînant leur destruction. La PR est une pathologie multifactorielle où le système HLA semble être le principal, mais non unique, facteur de prédisposition génétique.Pour la première partie de notre étude, nous nous sommes intéressés à la recherche d’association avec la PR, dans la population Algérienne, pour des polymorphismes de gènes déjà confirmés dans d’autres populations. Cette approche a permis d’établir une preuve solide d’association pour les deux SNPs les plus importants PTPN22rs2476601 et STAT4rs7574865. De plus amples études avec des échantillons élargis et l’inclusion de nouveaux polymorphismes de gènes candidats permettraient d’établir de nouvelles preuves d’association génétique avec la PR dans la population Algérienne.Dans un second temps, nous nous sommes intéressés à l’analyse familiale d’association génétique de polymorphismes de gènes présentant un différentiel d’expression dans la PR. Cette partie de l’étude représente un complément d’information pour la compréhension du fonctionnement de ces gènes et de leur implication dans la PR. Ce travail d’analyse d’association génétique a été complété par l’étude de la relation entre les génotypes des SNPs étudiés et le taux d’expression des gènes considérés.Les polymorphismes d’intérêts mis en évidence au cours de cette thèse représentent des cibles de choix pour l’analyse conjointe de la PR dans les deux populations algérienne et française en vu d’une comparaison ethnique des différents facteurs de prédisposition génétique à la PR
We are interested in genetic study of rheumatoid arthritis “ra”, an autoimmune and chronic inflammatory disease affecting mainly joints and involving their destruction.“ra” is a multi-factor pathology in which the hla region seems to be the main but not unique genetic factor predisposition.for the first part of our study, we are interested in search of association with “ra” in the algerian population for genes polymorphisms already confirmed in other populations. this approach has allowed us establishing an association with solid evidence for the two most important snps ptpn22rs2476601 and stat4rs7574865. further studies with expanded samples and the inclusion of new genes polymorphisms candidates could establish new evidence of genetic association with pr population in algeria.in a second time, we are interested to family association analysis of genetic polymorphism gene having differential expression in pr. this part of the study represents supplementary information for understanding genes these operating and their involvement in pr. this work analysis genetics association was supplemented by the study of relationship between genotypes of snps studied and the rate of gene expression considered.polymorphisms of interest shown during this study represent good targets for a combined analysis of “ra” in both french and algerian populations to establish an ethnic comparison of various factors for genetic predisposition to “ra”

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Ackermann, Nadine [Verfasser], Kai Sven [Gutachter] Erdmann, and Rolf [Gutachter] Heumann. "Biochemische und funktionelle Untersuchung der Multidomänenproteine PTPN13 und OCRL1 / Nadine Ackermann ; Gutachter: Kai Sven Erdmann, Rolf Heumann." Bochum : Ruhr-Universität Bochum, 2013. http://d-nb.info/1129451682/34.

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Ferreira, Lize Vargas. ""Estudo do gene PTPN11 em pacientes com a síndrome de Noonan e crianças com baixa estatura idiopática"." Universidade de São Paulo, 2005. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-02092005-100524/.

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A síndrome de Noonan (SN), caracterizada por baixa estatura, aspectos dismórficos e cardiopatia congênita, foi associada ao gene PTPN11. Estudamos o PTPN11 em pacientes com SN, pais de portadores de mutação e crianças com baixa estatura idiopática (BEI) que apresentam estigmas sugestivos da SN, sem critérios suficientes para o diagnóstico. Encontramos mutações missense em heterozigoze no PTPN11 em 42,3% dos pacientes com SN. Não identificamos alterações nos pais de portadores de mutação no PTPN11 com fenótipo normal tampouco em crianças com BEI. A única diferença estatisticamente significante entre os grupos com e sem mutação foi a resposta em longo prazo ao hGH, melhor no grupo sem mutação
Noonan syndrome (NS), characterized by short stature, dysmorphic facial and thoracic features and congenital heart disease, was associated to PTPN11 gene. We studied the PTPN11 in patients with NS, parents of mutation-positive NS patients and idiopathic short stature children with signs related to NS without fulfilling the diagnostic criteria. We found missense mutations in 42.3% of the NS group. Parents of NS mutation-positive patients did not present mutations, nor did children with short stature. The only statistically significant difference between groups with and without mutations was response to long term use of hGH, better on the mutation-negative group

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Lefevre, D., N. Cranley, and Ø. Holmeide. "PTPV1 and PTPV2 Translation in FTI Systems." International Foundation for Telemetering, 2013. http://hdl.handle.net/10150/579686.

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ITC/USA 2013 Conference Proceedings / The Forty-Ninth Annual International Telemetering Conference and Technical Exhibition / October 21-24, 2013 / Bally's Hotel & Convention Center, Las Vegas, NV
A Flight Test Instrumentation (FTI) system may consist of equipment that either supports PTPv1 (IEEE 1588 Std 2002) or PTPv2 (IEEE 1588 Std 2008). The challenge in such time distributed system is the poor compatibility between the two PTP protocol versions. This paper describes how to combine the PTP versions in the same network with minimum or no manual configuration.

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Babault, Nicolas. "Etude structurale du domaine PDZ de PTPN4, une cible pour le déclenchement de la mort neuronale." Paris 6, 2011. http://www.theses.fr/2011PA066211.

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Brasil, Amanda Salem. "Estudo dos genes PTPN11 e KRAS em pacientes afetados pela síndrome de Noonan e pelas síndromes Noonan-like." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/5/5141/tde-25022010-140048/.

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INTRODUÇÃO: a síndrome de Noonan apresenta herança autossômica dominante e é considerada uma doença relativamente frequente na população, com uma incidência estimada entre 1/1000 e 1/2500 nascidos vivos. Dentre os seus acometimentos destacam-se: dismorfismos faciais, baixa estatura, alterações cardíacas e criptorquia. A síndrome de Noonan é muito confundida com as síndromes Noonan-like devido à sobreposição dos achados clínicos. Estas, mais raras que a síndrome de Noonan, incluem as síndromes de LEOPARD, neurofibromatose-Noonan, cardiofaciocutânea e Costello. Atualmente sabe-se que tanto a síndrome de Noonan como as síndromes Noonan-like envolvem mutações em genes pertencentes à via de sinalização RAS-MAPK. Na síndrome de Noonan, pelo menos quatro genes desta via são responsáveis pelo fenótipo: PTPN11, SOS1, RAF1 e KRAS. Mutações no gene PTPN11, o primeiro gene descrito em associação com a síndrome, são encontradas em aproximadamente 40% dos casos. O segundo gene descrito, o gene KRAS, é responsável por cerca de 2% dos casos que não apresentam mutações no gene PTPN11. Mutações no gene KRAS estão presentes em pacientes com síndrome de Noonan com retardo mental e/ou atraso no desenvolvimento mais acentuados e em pacientes com a síndrome cardiofaciocutânea cujo envolvimento ectodérmico é mais sutil. OBJETIVO: devido à recente associação do gene KRAS com a síndrome de Noonan e outras síndromes Noonan-like é importante: (1) testar a frequência de mutação neste gene em pacientes que apresentam ou não mutações no gene PTPN11 e (2) tentar estabelecer uma correlação genótipo-fenótipo mais precisa, o que permitirá a realização de um aconselhamento genético mais adequado. MÉTODOS: foram avaliados 95 probandos com síndrome de Noonan e 30 com síndromes Noonan-like. O estudo molecular foi realizado através da reação em cadeia de polimerase, seguida das reações de purificação e sequenciamento bidirecional. RESULTADOS: foram encontradas mutações no gene PTPN11 em 20/46 (43%) pacientes com síndrome de Noonan, duas delas não descritas anteriormente. Relacionando o quadro clínico dos pacientes com síndrome de Noonan deste estudo, com e sem mutação no gene PTPN11, nota-se que os pacientes com mutação apresentam incidência significativamente maior de baixa estatura, de estenose pulmonar valvar e menor frequência de miocardiopatia hipertrófica. Uma mutação no gene KRAS foi encontrada em um paciente com síndrome de Costello, mutação esta ainda não relatada. Alterações gênicas em mais de um gene da via RAS-MAPK foram observadas em dois pacientes, sendo que uma delas em cada paciente não predizia um efeito fenotípico importante. Foram também encontrados três polimorfismos no gene KRAS, porém com mesma frequência no grupo controle. A fim de verificar a influência destes polimorfismos, as principais características da síndrome de Noonan foram relacionadas entre os pacientes com esta síndrome que apresentavam mutação no gene PTPN11 e comparadas quanto à presença ou ausência desses polimorfismos. Nenhuma diferença estatisticamente significante foi encontrada. CONCLUSÃO: Pacientes com síndrome de Noonan e mutações no gene PTPN11 apresentaram uma maior incidência de baixa estatura e de estenose pulmonar valvar e uma menor incidência de miocardiopatia hipertrófica. O gene KRAS, até então relacionado às síndromes de Noonan e cardiofaciocutânea, mostrou-se também responsável pela síndrome de Costello. Tanto as alterações gênicas consideradas não patogênicas como os polimorfismos encontrados no gene KRAS parecem não ter uma grande influência sobre a variabilidade fenotípica na síndrome de Noonan. Contudo, não é possível afastar totalmente que estas alterações apresentem um efeito sutil e que, em conjunto com outras variações genéticas e/ou ambientais, tenham um efeito modulador
INTRODUCTION: Noonan syndrome shows autosomal dominant inheritance, and is a relatively frequent disease in the population, with an estimated incidence between 1/1000 and 1/2500 live births. The main clinical features are: facial dysmorphisms, short stature, cryptorchidism and cardiac abnormalities. The differential diagnosis between Noonan syndrome and Noonan-like syndromes is not always easy, due to the overlap of the their clinicla findings. The Noonan-like syndromes, more rare that the Noonan syndrome, include the LEOPARD syndrome, neurofibromatosis-Noonan, cardiofaciocutaneous and Costello. Currently it is known that Noonan syndrome and Noonan-like syndromes involve mutations in genes belonging to the RAS-MAPK signaling pathway. In Noonan syndrome, at least four genes of this pathway are responsible for the phenotype: PTPN11, SOS1, RAF1 and KRAS. Mutations in PTPN11, the first gene described in association with this syndrome, are found in approximately 40% of cases. The second gene described, the KRAS gene, is responsible for about 2% of the cases that dont have mutations in the PTPN11 gene. Mutations in the KRAS gene are present in patients with Noonan syndrome with mental retardation and/or developmental delay more pronounced and in patients with cardiofaciocutaneous syndrome whose ectodermal involvement is more subtle. OBJECTIVE: Due to the recent association of the KRAS gene with Noonan and Noonan-like syndromes is important: (1) to test the frequency of mutation in this gene in patients with or without mutations in PTPN11 and (2) to estabilish a more precise genotype-phenotype correlation, allowing the realization of a more appropriate genetic counseling. METHODS: 95 probands with Noonan syndrome and 30 with Noonan-like syndromes were evaluated. The molecular analysis was performed by the polymerase chain reaction, followed by purification and bidirectional sequencing. RESULTS: PTPN11 gene mutation was found in 20/46 (43%) patients with Noonan syndrome, two of them not previously described. By correlating the clinical features of patients with Noonan syndrome in this study, with or without mutations in the PTPN11 gene, it was noted that patients with mutations have significantly higher incidence of short stature, pulmonary stenosis and lower incidence of hypertrophic cardiomyopathy. Mutations in KRAS gene were found in two patients a patient with Noonan syndrome ant the other with Costello syndrome. Gene alterations in more than one gene at the RASMAPK patway were observed in two patients, but one of the mutations in each patient didnt predict a significant phenotypic effect. Were also foud three polymorphisms in the KRAS gene, but with the same frequency in the control group. To check the influence of these polymorphisms, the main features of Noonan syndrome were related among patients with this syndrome who had mutations in the PTPN11 gene and compared of the presence or absence of these polymorphisms. No statistically significant difference was found. CONCLUSION: Patients with Noonan syndrome and PTPN11 gene mutation had a higher incidence of short stature and pulmonary valve stenosis and a lower incidence of hypertrophic cardiomyopathy. The KRAS gene, previously related to Noonan and cardiofaciocutaneous syndrome, was also responsible for Costello syndrome. Gene alterations considered as nonpathogenic and polymorphisms found in the KRAS gene seem to have a not great influence on the phenotypic variability in Noonan syndrome. However, it is not possible to completely rule out that these changes have a subtle effect and that, together with other genetic variations and/or environmental factors, may have a modulating effect

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Zheng, Peilin [Verfasser], and Stephan [Akademischer Betreuer] Kissler. "Ptpn22 silencing in the NOD model of type 1 diabetes indicates the human susceptibility allele of PTPN22 is a gain-of-function variant / Peilin Zheng. Betreuer: Stephan Kissler." Würzburg : Universitätsbibliothek der Universität Würzburg, 2012. http://d-nb.info/1028327145/34.

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Sood, Shatakshi. "Role of protein Tyrosine Phosphatase PTPN22 in T cell signalling and autoimmunity." Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/10490.

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Signals via the T cell receptor (TCR) are critical for the development of T cells in the thymus, maintenance of a self-tolerant peripheral T cell repertoire and the activation of T cells in secondary lymphoid organs. A dynamic balance between tyrosine phosphorylation and dephosphorylation is essential for the maintenance of homeostasis and proper regulation of the immune system. The cytoplasmic phosphatase, PTPN22 (protein tyrosine phosphatase non-receptor type 22) is involved in negative modulation of signal transduction through the TCR and plays a central role in regulating lymphocyte homeostasis. Genome wide association studies reveal that point mutations in PTPN22 confer an increased risk of developing multiple autoimmune diseases in humans. The precise function of PTPN22 and how mutations contribute to autoimmunity is controversial. Loss-of-function mutations in PTPN22 are associated with elevated T effector cell expansion and autoreactive B cells in both humans and mice. A thorough dissection of the molecular involvement of PTPN22 and its allelic variant R619W is important to delineate its role in autoimmunity, to this end we utilised the Ptpn22-/- mice generated in our laboratory. In order to address whether R619W allelic variant is a gain- or loss-of-function mutation, we expressed both PTPN22WT and PTPN22R619W constructs in primary activated Ptpn22-/- T lymphocytes using lentiviral transduction. Surprisingly expression of either wild type or variant phosphatase showed no affect on cytokine production. Preliminary results from bone marrow chimeras generated by retroviral expression of PTPN22WT and PTPN22R619W in Ptpn22 deficient mice showed reduced T cell activation compared to Ptpn22-/- T cells. PTPN22WT appeared to be more suppressive of T cell responses than variant PTPN22R619W. Consistent with studies conducted in comparable knock-in mouse models, our data point to the variant PTPN22R619W as being a partial loss of function allele. To elucidate the mechanism of PTPN22 action in context of an autoimmune disease, we investigated the effect of Ptpn22 deficiency on the phenotype of SKG mice. The SKG mouse harbours a point mutation (W163C) within the carboxyl terminal SH2- domain of ZAP-70, which results in decreased TCR signalling and impaired thymocyte development with defective positive and negative selection. These mice are prone to developing CD4+ T cell mediated autoimmune arthritis that closely resembles rheumatoid arthritis in humans. We found that thymus differentiation was partially restored in SKG Ptpn22-/- thymocytes and Ptpn22 deficiency enhanced TCR mediated signalling in SKG Ptpn22-/- thymocytes relative to SKG thymocytes. Consistent with increased signalling observed in the thymocytes, there was improved in vitro proliferation and IL-2 production of CD4+ T lymphocytes from SKG Ptpn22-/- mice compared to SKG mice. By contrast to SKG mice, SKG Ptpn22-/- mice developed less severe mannan-induced arthritis and showed decreased proportions of Th17 and higher numbers of regulatory T cells. These results show that removal of PTPN22 can compensate, at least partially, for the deficient ZAP-70 activity in the SKG mouse, thus linking PTPN22 and ZAP-70 to the same signalling pathway. This study advances our understanding of how manipulating TCR signals impacts on downstream T cell functions, suggesting PTPN22 may be a valuable target for the treatment of autoimmune diseases. Further studies to determine physiological role of the phosphatase and its disease-associated variants could provide insight into mechanism of immune activation, tolerance and autoimmunity.

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Naß, Alexandra [Verfasser]. "Investigations on Key Principles of PTP1B Selectivity / Alexandra Naß." Berlin : Freie Universität Berlin, 2018. http://d-nb.info/1176708279/34.

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Ribeiro, Alexsandra Christianne Malaquias de Moura. "Avaliação do padrão de crescimento na síndrome de Noonan em pacientes com mutações identificadas nos genes PTPN11, SOS1, RAF1 e KRAS." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-17062011-160529/.

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A Síndrome de Noonan (SN) é caracterizada por baixa estatura proporcionada de início pós-natal, dismorfismos faciais, cardiopatia congênita e deformidade torácica. A frequência da SN é estimada entre 1:1000 e 1:2500 nascidos vivos, com distribuição semelhante em ambos os sexos. A herança é autossômica dominante com penetrância completa, porém a maioria dos casos é esporádica. Até o momento, mutações em genes da via RAS-MAPK (PTPN11, KRAS, SOS1, RAF1, MEK1, NRAS e SHOC2) foram identificadas em aproximadamente 70% dos pacientes. Uma das principais características fenotípicas da SN é a baixa estatura pós-natal, embora o mecanismo fisiopatológico do déficit de crescimento nesta síndrome ainda não esteja totalmente esclarecido. Estudos que avaliaram o padrão de crescimento linear em crianças com SN foram realizados anteriormente ao conhecimento do diagnóstico molecular dessa síndrome. No presente estudo, avaliamos a frequência de mutação nos genes PTPN11, SOS1, RAF1 e KRAS em 152 pacientes com SN e o padrão de crescimento linear (altura) e ponderal [índice de massa corpórea (IMC)] dos pacientes com mutação identificada. No total, mutações nos genes relacionados foram encontradas em 99 pacientes (65%) do nosso estudo, com predominância do gene PTPN11 (47%), seguido do SOS1 (9%), RAF1 (7%) e KRAS (3%). Foram construídas curvas específicas para SN de Altura e IMC para idade e sexo utilizando o método LMS. Os pacientes com SN apresentaram crescimento pré-natal preservado, porém o comprometimento do crescimento pós-natal foi observado desde o primeiro ano de vida, atingindo uma altura final de -2,5 e -2,2 desvios-padrão da média para população brasileira em homens e mulheres, respectivamente. O prejuízo da altura foi maior nos pacientes com mutação no gene RAF1 em comparação com os genes PTPN11 e SOS1. O IMC dos pacientes com SN apresentou queda de 1 desvio-padrão em relação à média da população brasileira normal. O comprometimento do IMC foi menor nos pacientes carreadores de mutação no RAF1. Pacientes com mutação nos genes PTPN11 e SOS1 apresentaram maior frequência de estenose de valva pulmonar, enquanto a miocardiopatia hipertrófica foi mais frequente nos pacientes com mutação no gene RAF1. A variabilidade fenotípica observada nos pacientes com mutação no PTPN11 não pode ser explicada pelo grau que estas mutações influenciam a atividade tirosina fosfatase da SHP-2 nem pela presença de polimorfismos no gene KRAS. Com a análise dos éxons 3, 8 e 13 do PTPN11, seguido dos éxons 6 e 10 do SOS1 e éxon 7 do RAF1 identificamos 86% dos pacientes carreadores de mutações nos genes relacionados, propondo uma forma mais eficiente de avaliação molecular na SN. Acreditamos que a variabilidade fenotípica presente nessa síndrome esteja diretamente ligada aos diferentes papéis exercidos pelas proteínas que participam da via RAS/MAPK. Entretanto, mais estudos em relação à via RAS/MAPK serão necessários para esclarecer as questões relacionadas ao crescimento e outras características fenotípicas da SN
Noonan Syndrome (NS) is characterized by distinctive facial features, short stature and congenital heart defects. The estimated prevalence is 1:1000 to 1:2500 live births, affecting equally both sexes. It is an autosomal dominant disorder with complete penetrance, but most cases are sporadic. To date, mutations in the RAS/MAPK pathway genes (PTPN11, KRAS, SOS1, RAF1, MEK1, NRAS and SHOC2) were identified in approximately 70% of patients. One of the cardinal signs of NS is proportional postnatal short stature although the physiopathological mechanism of growth impairment remains unclear. The current knowledge about the natural history of growth associated with NS was described before molecular diagnosis era. In this study, we performed PTPN11, SOS1, RAF1, and KRAS mutation analysis in a cohort of 152 NS patients and studied the natural linear (height) and ponderal growth [body mass index (BMI)] of NS patients with related mutations. Mutations in NS-causative genes were found in 99 patients (65%) of our cohort. The most common mutated gene was PTPN11 (47%), followed by SOS1 (9%), RAF1 (7%) and KRAS (3%). Sex-specific percentile curves for height and BMI were constructed using the LMS method. NS patients had birth weight and length within normal ranges but the postnatal growth impairment was observed during the first year of life, reaching a final height of -2.3 and -2.2 standard deviations from the mean for Brazilian healthy men and women, respectively. Postnatal growth impairment was higher in RAF1 mutation patients than in patients with SOS1 and PTPN11 mutations. BMI values in NS patients were lower in comparison with normal Brazilian population. BMI values were higher in patients with RAF1 mutations than in patients with other genotypes. Patients with mutations in PTPN11 and SOS1 genes were more likely to have pulmonary valve stenosis, whereas hypertrophic cardiomyopathy was more common in patients with mutations in the gene RAF1. The intensity of constitutive tyrosine phosphatase activity of SHP-2 due to PTPN11 mutations, as well as the presence of polymorphisms in KRAS gene did not influence the phenotype of NS patients with mutation in PTPN11 gene. Analysis of exons 3, 8 and 13 of PTPN11 gene, followed by exons 6 and 10 of SOS1 gene and exon 7of RAF1 gene identified 86% of patients harboring mutations in related genes, suggesting a more efficient evaluation of NS molecular diagnosis. We believe that the phenotypic variability in this syndrome is directly linked to the different roles played by proteins that participate in RAS/MAPK pathway. However, further studies in RAS/MAPK pathway are needed to clarify issues related to growth and other phenotypic characteristics of SN

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Burn, Garth Lawrence. "PTPN22/Lyp : a novel regulator of integrin signalling and function in T lymphocytes." Thesis, King's College London (University of London), 2015. https://kclpure.kcl.ac.uk/portal/en/theses/ptpn22lyp-a-novel-regulator-of-integrin-signalling-and-function-in-t-lymphocytes(126c4e96-15a5-4c11-89b1-f21a6310098e).html.

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Integrins are large heterodimeric surface receptors that, when engaged, are able to transduce information from the extracellular environment leading to a diverse set of cellular programmes including migratory responses. Despite a wealth of literature describing how integrins on T cells are activated such that they can bind to their ligand, the nature and regulation of the signal transduced via the integrin cytoplasmic tails once the integrin engages its counter-ligand is not yet clear. Here, we report that in primary human and mouse T cells, PTPN22, a cytoplasmic protein tyrosine phosphatase expressed only in immune cells, negatively regulates signal transduction downstream of LFA-1 engagement. Loss of PTPN22/Lyp expression enhances integrin-mediated adhesion and migration in vitro and in vivo, while overexpression of wild type Lyp-R620 decreased migration. The catalytic activity of PTPN22 was required in order to regulate T cell migration. Co-immunoprecipitation experiments demonstrated that PTPN22 associated with Lck, ZAP-70, Vav and LFA-1 in migrating T blasts. In performing shear flow experiments and biophysical investigations, human individuals homozygous for the disease associated R620W mutation functionally recapitulated the phenotype of PTPN22 knockout mouse cells in that they were more adherent and demonstrated hyperphosphorylation of signalling intermediates downstream of LFA-1 engagement. Super resolution microscopy revealed that in non-signalling T cells, PTPN22 formed large clusters that appeared to de-cluster following LFA-1 engagement. Suprisingly, the R620W mutation did not appear to impact clustering, but instead lead to less Lyp monomers being retained at the membrane outside of clusters in signalling T cells. A correlate between less Lyp monomers and increased LFA-1 clustering at the leading edge of migrating T cells is demonstrated, with an inverse relationship existing between number of Lyp monomers present at the plasma membrane and LFA-1 clustering. These studies place PTPN22 as a novel negative regulator downstream of LFA-1 signalling, with a disease predisposing R620W mutation lending itself to a loss-of-function allele that might impact the development of autoimmune disease through dysregulation of integrin function.

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Johnson, Kevin. "PTP1B regulation of the transcription factor Stat5 in breast cancer." Connect to Electronic Thesis (CONTENTdm), 2009. http://worldcat.org/oclc/454241197/viewonline.

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Bray, Cara. "Using CRISPR to determine the effects of mutations of PTPN22 in human T cells." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31418.

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The haematopoietic phosphatase PTPN22 is a key regulator in balancing immune responses between self-reactivity and tolerance. PTPN22 downregulates T cell signaling and harbors the non-HLA genetic variation most strongly associated with autoimmune disease in humans, the single nucleotide polymorphism R620W. The effect of this mutation is currently controversial due to confounding results in mouse and human models. The polymorphism is linked to increased susceptibility to autoimmunity in both human and mouse models, although the latter does depend on genetic background. However, mouse data clearly shows that the polymorphism has a loss-of-function effect on T cell signalling, whereas studies in human models largely demonstrate a gain-of-function effect for R620W. A confounding issue in human studies is that they depend on comparison of T cells from distinct individuals, on protein over-expression, or on RNA interference, techniques for which it is difficult to control for genetic and environmental variables, changes in stoichiometry, and off-target effects or incomplete knockdown, respectively. We aimed to create isogenic human cell lines with mutations in PTPN22 at the genomic level to alleviate the complications inherent in analysing human data. In addition to autoimmune pathogenesis, we are interested in the role of PTPN22 in a cancer setting. Because PTPN22 has a strong suppressive effect on T cell responses to weak affinity antigen, which encompass most tumour antigens, we postulated that knocking out PTPN22 may better enable T cells to kill tumour cells. Furthermore, we have shown that PTPN22 knockout (KO) leads to increased IL-2 expression in mouse T cells, and that this effect is protective against TGF-β mediated suppression, a common driver of T cell inhibition in the tumour microenvironment. T cell transfer experiments in mice showed that PTPN22 KO T cells are indeed more effective at reducing tumour size. Based on these findings, we aim to determine whether PTPN22 KO in human cells confers a similar effect on signaling. To investigate the effects of PTPN22 KO on human T cell signaling, we used CRISPR gene-editing to target PTPN22 in a Jurkat cell line. By combining this technique with lentiviral transduction of a specific T cell receptor, we generated human cell lines which are genetically identical, save for specific alterations to PTPN22, and which can be stimulated with strong or weak cognate antigen. We found that PTPN22 KO Jurkat cells develop an enhanced activation phenotype upon stimulation, including increased IL-2 expression. Additionally, PTPN22 KO Jurkat cells show enhanced Erk signalling following stimulation with weak affinity antigen, but this difference is lost as stimulus strength increases. CRISPR technology has presented the opportunity to create novel models of PTPN22 signalling in the context of human T cell lines. The data from these lines suggests that, unlike the R620W mutation, complete loss of PTPN22 has a comparable effect in human and mouse T cells. In conjunction with our previous findings, these results suggest that knocking out PTPN22 may lead to signalling alterations that improve adoptive T cell cancer therapy.

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Delile, Eugénie. "Impact de la délétion totale et endothéliale de PTP1B sur la dysfonction cardiovasculaire et l'insulino-résistance dans un modèle de sepsis sévère expérimental." Thesis, Normandie, 2017. http://www.theses.fr/2017NORMR011/document.

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L’hyperglycémie et l’insulino-résistance constituent les altérations métaboliques des patients septiques associées à un pronostic défavorable, à une augmentation des dysfonctions cardiovasculaires et à une augmentation de la mortalité. Si plusieurs études démontrent quel’insulinothérapie à forte dose diminue la mortalité et prévient la dysfonction multi-organes, elle est souvent controversée car responsable d’hypoglycémies délétères. La Protéine Tyrosine Phosphatase1B (PTP1B) est un régulateur négatif de la voie de signalisation dépendante de l’insuline et de la voie de production du NO.L’idée développée dans le laboratoire est que l’inhibition de la PTP1B pourrait constituer une cible thérapeutique potentielle dans le sepsis en améliorant la sensibilité à l’insuline et ainsi les conséquences sur la fonction endothéliale et cardiaque. Bien qu’il ait été montré que la délétion génétique en PTP1B diminue la dysfonction cardiovasculaire lors du sepsis, les effets de cette délétion sur le métabolisme glucidique dans l’amélioration de la dysfonction cardiovasculaire restent méconnus et constituent l’objectif de notre travail.Dans un modèle de sepsis induit par Ligature et Perforation Caecale, nous avons pu mettre en évidence que la délétion génétique totale de PTP1B limite l’insulino-résistance induite par le sepsis,améliore la voie de signalisation dépendante de l’AMPK et la translocation des GLUT-4 et diminue l’inflammation. Ces effets s’accompagnent d’une diminution de la dysfonction endothéliale induite parle sepsis et améliore la production de NO. La délétion génétique endothéliale de PTP1B permet quant à elle une amélioration significative de la fonction endothéliale et de la sensibilité à l’insuline et au glucose.Ces travaux ont donc permis de mettre en évidence l’effet bénéfique de la délétion génétique en PTP1B dans le sepsis par amélioration de la sensibilité à l’insuline et des conséquences sur la fonction endothéliale et cardiaque
Hyperglycemia and insulin resistance are septic metabolic alterations associated with poorprognosis, increased cardiovascular dysfunction and mortality. Several studies have demonstrated thathigh-dose insulin therapy reduces mortality and prevents multi-organ dysfunction but is controversialbecause it is often associated with deleterious hypoglycemia. Protein Tyrosine Phosphatase 1B (PTP1B)is a negative regulator of both insulin signaling and NO production.The concept developed in our laboratory is that PTP1B inhibition could be a potentialtherapeutic target in sepsis by improving both insulin sensitivity and these consequences onendothelial and cardiac function. PTP1B genetic deletion has been shown to decrease cardiovasculardysfunction in sepsis but the effects of this deletion on carbohydrate metabolism in the improvementof cardiovascular dysfunction remain unknown and constitute the objective of our work.In a sepsis model induced by Ligature and Caecal Perforation, we have demonstrated that thetotal PTP1B genetic deletion limits insulin resistance induced by sepsis, improves the AMPK signalingpathway, the GLUT-4 translocation and reduces inflammation. These effects are followed by decreasedendothelial dysfunction induced by sepsis and improves NO production. The endothelial PTP1B geneticdeletion, significantly improves endothelial function, insulin and glucose sensitivity.This work demonstrate the beneficial effect of the PTP1B genetic deletion in the sepsis byimprovement of the insulin sensibility and these consequences on endothelial and cardiac function

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Kokkonen, Heidi. "Pathogenetic factors of importance for the development and progression of rheumatoid arthritis." Doctoral thesis, Umeå universitet, Institutionen för folkhälsa och klinisk medicin, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-54003.

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Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by joint inflammation eventually leading to the destruction of cartilage and bone. The aetiopathogenesis is not completely understood, but previous studies have shown that the disease is multifactorial with genetic, environmental and hormonal factors involved. Immune cells, e.g., T- and B-cells, and macrophages, migrate into the joints, with increased expression of numerous soluble factors such as cytokines, chemokines and adhesion molecules functionally active both locally and systemically. Analyses of blood samples from the Medical Biobank in Umeå from individuals before the onset of symptoms of joint disease showed that anti-citrullinated protein/peptide antibodies (ACPA) preceded the development of disease by years and this finding has been confirmed by other studies. The aim of this thesis was to identify signs of activation of the immune system analysed as up-regulation of pro- and anti-inflammatory cytokines, sero-positivity for autoantibodies, and genetic factors identified as relevant for the development and disease progression of RA. The concentrations of 30 cytokines and chemokines were measured in blood samples from individuals before the onset of symptoms, and when diagnosed with RA, together with population-based matched controls using a multiplex system. The predictive value of different isotypes (IgG, IgA, and IgM) of ACPA and rheumatoid factor (RF) before onset of symptoms and different types of ACPA (e.g., mutated citrullinated vimentin, MCV) were analysed for disease development and progression in patients with early RA and controls from Northern Sweden. These factors were related to the genetic markers, HLA- shared epitope (SE) alleles and the 1858C/T polymorphism of the protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene. In paper I, it was shown that in individuals who later developed RA (i.e., pre-patients) the levels of several cytokines and related factors that represent the adaptive immune system (Th1, Th2, and T regulatory cell related factors) were significantly elevated compared with controls, whereas, after the onset of disease the involvement of the immune system was more general and widespread. In paper II, the presence of different isotypes (IgM, IgA and IgG) of ACPA in pre-patients, patients and controls was evaluated showing that both the IgG and IgA isotype predicted the onset of RA by years with the IgG isotype having the highest predictive value. In paper III, the association of the 1858T variant of PTPN22 with RA was confirmed. Furthermore, the association was restricted to autoantibody positive disease and this variant was correlated with an earlier age for disease onset. In paper IV, anti-MCV antibodies were identified as being associated with a more severe disease course of RA, measured by disease activity score, erythrocyte sedimentation rate, and swollen joint count over time compared with anti-CCP2, anti-CCP3, and anti-CCP3.1 antibodies. In conclusion, individuals who later developed RA had increased concentrations of inflammatory markers reflecting an activation of the immune system years before the clinical symptoms of the disease developed. Also, the presence of ACPA of IgG and IgA isotype prior to disease onset predicted the development of RA. The PTPN22 1858T variant was associated with sero-positive RA and anti-MCV antibodies were associated with a higher inflammatory activity compared with anti-CCP2, -CCP3 and -CCP3.1 antibodies. These findings together present a possibility to better predict the development and progression of RA.

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Hébert, Chatelain Etienne. "Impact des phosphorylations sur tyrosine sur le métabolisme mitochondrial : régulation et impacts fonctionnels des phosphorylations induites par la Src kinase." Thesis, Bordeaux 2, 2011. http://www.theses.fr/2011BOR21830/document.

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La mitochondrie est une organelle très importante vu son implication dans plusieurs processus cellulaires. Elle produit notamment la majeure partie de l'énergie qui est consommée par la cellule, grâce aux processus d'oxydation phosphorylante (OXPHOS). La phosphorylation des enzymes impliquées dans les OXPHOS apparait comme une voie de régulation importante de la production énergétique. L'objectif de ce thèse était donc de comprendre comment les phosphorylations, et plus particulièrement, les phosphorylations sur tyrosine induites par la Src kinase influencent les OXPHOS. Il a donc été démontré qu'il existe, à l'intérieur des mitochondries, des voies de régulation de ces processus de phosphorylation induits par la Src kinase. Ces processus pouvant induire la phosphorylation de plusieurs enzymes mitochondriales, notamment plusieurs sous-unités des complexes du système des électrons et ainsi, grandement influencer les OXPHOS. Il a aussi été démontré que la Src kinase semble aussi présente dans les mitochondries de cellules cancéreuses, induisant la phosphorylation d'une sous-unité de la NADH-oxidoréductase et une augmentation du métabolisme énergétique mitochondrial. Cette régulation des OXPHOS dans les cellules cancéreuses par la Src kinase pourrait participer à l'établissement du phénotype hautement prolifératif de ces cellules
Mitochondria are implicated in several key cellular processes. They are producing most part of the energy that is consumed by the cell via oxidative phosphorylation processes (OXPHOS). Phosphorylation of different components implicated in OXPHOS are known to constitute an important regulation pathway of energetic production. The objective of this thesis was to understand how tyrosine phosphorylation induced by the Src kinase could influence OXPHOS. First, it was shown that Src kinase mediated phosphorylation can be regulated directly in mitochondria, inducing phosphorylation of several mitochondrial proteins and different effects on OXPHOS. I also demonstrated that Src kinase is also present in mitochondria of cancer cells where it can lead to phosphorylation of NADH-oxidoreductase. This phosphorylation site is associated with increase of OXPHOS which could be implicated in the establishment of global phenotype of cancer cells

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Couture, Pascal. "Role of a PTP1B Pathway in the Neuropsychiatric Expression of a Mouse Maternal Immune Activation Model." Thesis, Université d'Ottawa / University of Ottawa, 2019. http://hdl.handle.net/10393/38891.

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Activation of the immune system in gestating mothers has been identified as an important environmental risk factor for neuropsychiatric disorders. Maternal immune activation (MIA) animal models have been used to explore how the maternal immune system may cause expression of pathophysiology in offspring. Protein tyrosine phosphatase (PTP1B) is recruited during inflammation and its regulatory proteins are modulated in MIA. Disrupted regulation of PTP1B has been linked to mental disorders such as Rett Syndrome and anxiety. We asked if ablating neuronal PTP1B could protect from the expression of some neuropsychiatric phenotypes that appear in MIA models. In our MIA model induced with poly I:C injection at gestational day 9.5, we observed increased locomotion and sensorimotor gating and reduced anxiety in 3-month-old male offspring while females showed decreased sensorimotor gating. These effects were not replicated in PTP1B KO mice indicating a role of PTP1B in affecting locomotion and anxiety level in MIA. This model promotes a more balanced understanding of MIA and introduces PTP1B as a player in MIA-induced behaviour changes.

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32

Wagner, Johanna. "Die Rolle von IL12B- und PTPN2-Polymorphismen bei der Pathogenese chronisch entzündlicher Darmerkrankungen." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-174373.

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33

Castro, Dopico Xaquin. "A PTPN22 gene-to-phenotype study ; and, The evaluation of IL-2 immunotherapy for type 1 diabetes." Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.707951.

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Chiarreotto-Ropelle, Eloize Cristina 1978. "Caracterização da atividade da PTP1B em hipotálamo de roedores obesos submetidos ao exercício físico." [s.n.], 2013. http://repositorio.unicamp.br/jspui/handle/REPOSIP/244471.

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Orientador: José Rodrigo Pauli
Dissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Aplicadas
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Resumo: A ingestão alimentar e o gasto energético são minuciosamente regulados por neurônios específicos localizados no hipotálamo. O funcionamento adequado desta complexa rede neuronal é determinante para a manutenção da homeostase energética em mamíferos. No entanto, a inflamação hipotalâmica está associada com a resistência à insulina e leptina, obesidade e hiperfagia. Neste contexto, proteína tirosina fosfatase 1B (PTP1B) hipotalâmica surgiu como a fosfatase chave responsável pela resistência central à insulina e à leptina. O objetivo do atual estudo foi avaliar o efeito do exercício físico agudo sobre a expressão da PTP1P hipotalâmica em roedores obesos. Nossos resultados demonstraram que o exercício físico reduziu a inflamação e os níveis proteicos e a atividade da PTP1B no hipotálamo de animais obesos. O exercício físico reduziu a interação entre a PTP1B com proteínas envolvidas na via de transmissão do sinal da insulina (IRbeta e IRS1) e da leptina (Jak2), melhorando os sinais anorexigênicos mediados por esses hormônios. De forma interessante, o efeito anti-inflamatório e o efeito inibitório sobre a PTP1B mediados pelo exercício ocorreu de forma dependente da Interleucina-6 (IL-6), uma vez que o exercício não reduziu a inflamação e os níveis proteicos PTP1B após a inibição específica da IL-6 hipotalâmica em animais obesos. Por outro lado, a administração intracerebroventricular (ICV) do IL-6 recombinante reproduziu os efeitos do exercício, melhorando a ação da insulina e leptina hipotálamo, reduzindo a sinalização inflamatória e atividade PTP1B em ratos obesos em repouso. Coletivamente, o nossos resultados demonstraram que o exercício físico restaurou a sinalização de insulina e da leptina no hipotálamo de animais obesos, pelo menos em parte, pela redução da expressão e atividade da PTP1B hipotalâmica, sendo esse efeito decorrente da resposta anti-inflamatória mediada, e também dependente, de IL-6
Abstract: The food intake and energy expenditure are regulated by specific neurons in the hypothalamus. The proper functioning of this complex neuronal network is crucial to the maintenance of energy homeostasis in mammals. However, hypothalamic inflammation is associated with insulin and leptin resistance, hyperphagia and obesity. In this scenario, hypothalamic protein tyrosine phosphatase 1B (PTP1B) has emerged as the key phosphatase induced by inflammation responsible for the central insulin and leptin resistance. The aim of this study was evaluate the effects of exercise on PTP1B activity in the hypothalamus of obese rodents. Here, we demonstrated that acute exercise reduced inflammation and PTP1B protein level/activity in the hypothalamus of obese rodents. Exercise disrupted the interaction between PTP1B with proteins involved in the early steps of insulin (IRbeta and IRS1) and leptin (Jak2) signaling, increased the anorexigenic effects of insulin and leptin in obese rats. Interestingly, the anti-inflammatory action and the reduction of PTP1B activity mediated by exercise occurred in an Interleukin-6 (IL-6)-dependent manner, because exercise failed to reduce inflammation and PTP1B protein level after the disruption of hypothalamic-specific IL-6 action in obese rats. Conversely, intracerebroventricular (ICV) administration of recombinant IL-6 reproduced the effects of exercise, improving hypothalamic insulin and leptin action by reducing the inflammatory signaling and PTP1B activity in obese rats at rest. Taken together, our study reports that physical exercise restores insulin and leptin signaling, at least in part, by reducing hypothalamic PTP1B protein level through the central anti-inflammatory response mediate by IL-6
Mestrado
Metabolismo e Biologia Molecular
Mestra em Ciências da Nutrição e do Esporte e Metabolismo

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Veenstra, Cynthia. "The receptor tyrosine kinase Met and the protein tyrosine phosphatase PTPN2 in breast cancer." Doctoral thesis, Linköpings universitet, Avdelningen för kliniska vetenskaper, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-135047.

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Breast cancer is the most common form of cancer in women worldwide and the second leading cause of cancer death. It is a heterogeneous disease and is subdivided into different subtypes, all with different treatment responses and survival outcomes. Luminal breast cancers are characterised by the expression of oestrogen receptor and generally have a good prognosis. More aggressive tumours are marked by the presence of growth stimulating receptor tyrosine kinase HER2 (HER2-like breast cancer) or the absence of oestrogen receptor, progesterone receptor, and HER2 (triple-negative breast cancer,TNBC). The latter is the most aggressive form and is difficult to treat due to lack of treatment targets. This thesis aimed to explore possible prognostic and predictive biomarkers in different subtypes and study their role in breast cancer. To this aid, breast cancer tumours of pre- and post-menopausal patients enrolled in two cohorts were analysed for gene copy numbers and expression of proteins involved in cell proliferation. Gene copy numbers of receptor tyrosine kinases MET and EGFR, Met’s ligand HGF, and protein tyrosine phosphatase PTPN2 were determined by droplet digital PCR or quantitative PCR in both cohorts. Met, phosphorylated Met (pMet), HGF, and PTPN2 protein expression levels were analysed with immunohistochemical staining in the pre-menopausal cohort. Moreover,the role of the aforementioned proteins was investigated in breast cancer cell lines. Amplification of MET, HGF, and EGFR in breast tissues was found to be low (5-8%). These three genes, all located on chromosome 7, were found to be strongly correlated with eachother and to be associated with shortened distant recurrence-free survival. High protein expression of Met, pMet, and HGF was found in 33%, 53%, and 49% of the breast tumours. MET and EGFR were found to be more often amplified in TNBC disease, correlating with worse survival. Moreover, stromal expression of HGF was associated with shorter survival in TNBC. EGF stimulation in TNBC cell line MDA-MB-468 led to inhibited cell proliferation and migration. Partial knockdown of EGFR caused TNBC cells to proliferate and migrate more upon EGF treatment, mirroring EGFR inhibitor resistance. Knockdown of Met had in part the opposite effects, indicating that Met inhibitors might be useful in the treatment of TNBC. The increase in proliferation and migration upon EGFR depletion could be counteracted with simultaneous knockdown of EGFR and Met, indicating that dual inhibition of these proteins might be a future treatment option in TNBC. Copy loss of PTPN2 was reported in 15% of the cases in both pre- and post-menopausal cohorts. Low cytoplasmic PTPN2 protein expression was found in half of the cases. Loss of PTPN2 gene or protein was associated with a shorter distant recurrence-free survival in Luminal A and HER2-positive tumours, not in TNBC, suggesting a subtype-related prognostic value of PTPN2. Subtype relevance of PTPN2 was further implied by in vitro analyses. Whereas PTPN2 knockdown had no observed effect on TNBC cell lines, knockdown in the Luminal A cell line MCF7 inhibited Met phosphorylation and promoted phosphorylation of Akt, a key regulator of cellular proliferation and survival. The cell growth and survival regulating RAS/MAPK pathway remained unaffected. Knockdown in the HER2-positive cell line SKBR3 led to increased Met phosphorylation and decreased RAS/MAPK-related Erk phosphorylation as well as EGF-mediated transcription factor STAT3 phosphorylation. These results indicate that the role of PTPN2 in breast cancer is subtype-related and needs to be further investigated for future treatment options.

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Lopes, Antonio Luiz Ribeiro Boechat. "Influencia de polimorfismos dos genes TNF e PTPN22 sobre a artrite reumatoide e a tuberculose no Amazonas, Brasil." Universidade Federal do Amazonas, 2010. http://tede.ufam.edu.br/handle/tede/4302.

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Rheumatoid Arthritis (RA) is a autoimmune disease that affects 1% of worldwide population and promotes polyarthritis and joint destruction with work disability. About 60% of the risk factors of RA are related to genetic characteristics of individuals. The functional polymorphisms of the TNF gene -308 G/A andPTPN22 1858 C/T were associated with RA in several studies.The aim of this study was to investigate the influence of the TNF 308 G/A polymorphism in the promoter region of the tumor necrosis factor- gene and PTPN22 1858 C/T on rheumatoid arthritisand tuberculosis patients from the Brazilian Amazon. A total of 545 individuals 205 healthy controls without arthritis and 132 individuals suffering from rheumatoid arthritis and 208 tuberculosis patients  were genotyped for these polymorphisms using a methodology based on PCR-RFLP. Rheumatoid factor, age more than 60 years old and more than 10 disease years, was found to be risk factors for systemic disease (p=0,0001). The frequency of the A allele (TNF2) in rheumatoid arthritis sufferers was not found to be significantly higher than in the controls (p=0.671; OR=1.16; confidence interval=0.59 – 2.25). However, using a logistic regression model when the patients were stratified according to whether the manifestations were preponderantly articular or systemic, there was a strong association between the TNF2 allele and the systemic disease (p=0.001; OR=4.75; confidence interval=1.82 – 12.40) as well as the use of anti-TNF immunotherapy (p=0.021; OR 2.93; confidence interval=1.15 –7.46). On the other hand, PTPN22 1858T allele was not associated with systemicdisease (p=0,071; OR=3,17; confidence interval=0.83 – 11.73), but we found association between this allele and biologic anti-TNF immunotherapy (p=0,021; OR=4.39; confidence interval=1.08 – 17.86). Moreover, there was found no association between PTPN22 15858 C/T and rheumatoid arthritis nor tuberculosis. These results suggest that the TNF2 allele is associated with the more serious forms of the disease in individuals from the Brazilian Amazon but not with a risk for developing RA.
A Artrite Reumatoide (AR) é uma doença autoimune que afeta 1% da população geral, promovendo poliartrite e destruição articular com variados graus de incapacidade. Cerca de 60% dos fatores de risco da AR são relacionados a caracteres genéticos do indivíduo. Os polimorfismos funcionais dos genes TNF -308 G/A e PTPN22 1858 C/T foram associados à AR e à Tuberculose em diversos estudos. O objetivo deste estudo foi analisar a influência do polimorfismo da região promotora do gene do Fator de Necrose Tumoral-α, TNF -308 G/A e do gene PTPN22 1858 C/T na Artrite Reumatoide (AR) e na Tuberculose pulmonar em indivíduos procedentes do Amazonas. Para isso, foram genotipados, pela técnica baseada em PCR-RFLP para o polimorfismo TNF 308 G/A (TNF2) e PTPN22 1858T, 545 indivíduos sendo 205 controles sem Artrite, 208 pacientes com Tuberculose e 132 portadores de AR. Não foi observado aumento da frequência dos alelosTNF2ouPTPN22 1858T em portadores de Artrite Reumatoide e Tuberculose em comparação aos controles (p=0,218; p=0,376, respectivamente). Foram identificados como fatores preditivos para manifestações sistêmicas da Artrite Reumatoide: o Fator Reumatoide positivo, a idade maior que 60 anos e o tempo de doença (p=0001).Quando os dados foram estratificados segundo as formas predominantemente articulares ou sistêmicas, o alelo TNF2 esteve fortemente associado às formas sistêmicas (p=0,001; OR=4,75; Intervalo de confiança = 1,82 – 12,40), além de estar associado ao uso de imunobiológicos Anti-TNF (p=0,021; OR=2,93; Intervalo de confiança=1,15 – 7,49). O alelo PTPN22 1858T também está associado ao uso de imunobiológicos (p=0,021; OR= 4,39; Intervalo de Confiança=1,08 – 17,86), mas não está relacionado às formas sistêmicas (p=0,071; OR = 3,17; Intervalo de Confiança = 0,83 – 11,73). Entretanto, o polimorfismo de PTPN22 1858 C/T não foi associado à Artrite Reumatoide ou à Tuberculose Pulmonar. Estes resultados sugerem que o alelo TNF2 está associado às formas mais graves da AR em indivíduos do Amazonas, mas não ao risco de desenvolver Artrite Reumatoide.

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Santaniemi, M. (Merja). "Genetic and epidemiological studies on the role of adiponectin and PTP1B in the metabolic syndrome." Doctoral thesis, University of Oulu, 2010. http://urn.fi/urn:isbn:9789514261855.

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Abstract The metabolic syndrome is a cluster of components predisposing to type 2 diabetes and cardiovascular disease. Abdominal obesity and insulin resistance seem to be central in the metabolic syndrome, although no unifying pathophysiological mechanism is available. The aim of this thesis was to determine out how the variation in PTP1B and adiponectin gene as well as variations in the plasma adiponectin concentration contribute to the risk of obesity related diseases. PTP1B is a negative regulator of insulin signalling and therefore considered a candidate gene for type 2 diabetes. In the first study, it was found that three PTP1B polymorphisms studied have not strong impact on type 2 diabetes. However, one SNP may be slightly protective against type 2 diabetes, since it was more frequent in the healthy group compared to group of patients with type 2 diabetes. Another SNP was associated with body mass index (BMI). The combination of certain alleles of PTP1B and LEPR (leptin receptor) genes was also associated to BMI. Adiponectin is an adipocytokine expressed in adipose tissue. It has insulin sensitizing effects in liver and muscle and it has also beneficial effects on cardiovascular health. In the second study, the contribution of adiponectin genotypes with obesity-related phenotypes was studied. In Caucasians, the carriers of rare allele of Tyr111His polymorphism were more insulin resistant and at a higher risk of developing type 2 diabetes. In African-Americans, other polymorphisms were associated with BMI and lipids. Thus, the effects of polymorphisms on obesity related phenotypes seemed to be different between ethnic groups. Plasma adiponectin levels were measured from different study groups. In the third study, it was found out that low plasma adiponectin levels associated with different components of the metabolic syndrome and there was a trend towards reductions in adiponectin with an increasing number of components. Fourth study indicated that baseline low adiponectin level associated with a more than 2-fold risk for developing impaired glucose tolerance or type 2 diabetes in the follow-up study of normoglycemic middle-aged Finnish subjects. In the fifth study, plasma adiponectin levels were measured from postmenopausal women receiving estrogen replacement therapy. We observed a reduction in adiponectin levels in women having peroral estradiol which could be part of the "early harm" profile on cardiovascular risk factors of the peroral estrogen replacement therapy detected in clinical trials. These studies further strengthen the role of plasma adiponectin in the obesity related diseases and bring new information of polymorphisms in the adiponectin and PTP1B genes in different populations
Tiivistelmä Metabolinen oireyhtymä on kertymä tekijöitä, jotka altistavat tyypin 2 diabetekselle ja sydän- ja verisuonitaudeille. Keskivartalolihavuus ja insuliiniresistenssi, eli insuliinin heikentynyt teho, vaikuttavat olevan keskeisiä metabolisessa oireyhtymässä. Kuitenkaan taustalla olevaa syntymekanismia ei täysin tunneta. Väitöskirjatyön tavoitteena oli tutkia PTP1B- ja adiponektiinigeenin muuntelun sekä plasman adiponektiinitason yhteyttä metaboliseen oireyhtymään, sen osatekijöihin ja seurauksiin. PTP1B on insuliinin toimintaa soluissa estävä molekyyli. Ensimmäisessä tutkimuksessa havaittiin että kolme tutkittua PTP1B-geenin nukleotidimuutosta eivät ole vahvasti yhteydessä tyypin 2 diabetekseen. Eräs nukleotidimuutos saattaisi olla lievästi suojaava tyypin 2 diabetesta vastaan, sillä se oli yleisempi terveillä kuin tyypin 2 diabetesta sairastavilla. PTP1B:n ja leptiinireseptorigeenin eräiden alleelien yhdistelmä oli yhteydessä painoindeksiin. Adiponektiini on rasvakudoksen erittämä hormoni, jolla on suotuisia, insuliinin vaikutusta edesauttavia vaikutuksia elimistössä sekä edullisia vaikutuksia verenkiertoelimistössä. Toisessa työssä havaittiin että Amerikan valkoihoisilla, joilla oli eräs harvinainen adiponektiinigeenin alleeli (Tyr111His), oli heikompi insuliinin teho kuin henkilöillä joilla ei ollut kyseistä muutosta. Tämä alleeli oli yleisempi suomalaisilla tyypin 2 diabetesta sairastavilla kuin terveillä, mikä saattaa tarkoittaa että se liittyy suurentuneeseen riskiin tyypin 2 diabetekselle. Afroamerikkalaisilla taas toiset nukleotidimuutokset olivat yhteydessä lihavuuteen ja plasman rasva-arvoihin. Adiponektiinin pitoisuutta plasmassa mitattiin erilaisissa aineistoissa. Kolmannessa tutkimuksessa havaittiin, että matala pitoisuus oli yhteydessä metabolisen oireyhtymän eri osatekijöihin ja pitoisuus oli sitä matalampi, mitä enemmän osatekijöitä henkilöllä on. Neljännessä tutkimuksessa havaittiin että matala plasman adiponektiinipitoisuus oli yhteydessä suurentuneeseen riskiin saada huonontunut glukoosin sietokyky tai tyypin 2 diabetes tulevaisuudessa. Viidennessä tutkimuksessa adiponektiinitaso määritettiin naisilta jotka olivat ohittaneet vaihdevuodet ja saivat estrogeenikorvaushoitoa. Havaittiin että plasman adiponektiinitaso laski niillä naisilla, jotka saivat korvaushoitoa suun kautta. Tämä saattaisi osittain selittää suun kautta annettavan estrogeenikorvaushoidon epäedullista vaikutusta sydän ja -verisuonitautien riskitekijöihin. Tutkimus vahvistaa edelleen adiponektiinin merkitystä lihavuuteen liittyvissä sairauksissa ja tuo uutta tietoa adiponektiini- ja PTP1B-geenien muuntelun merkityksestä eri väestöissä

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Genera, Mariano. "Structural and functional study of the human phosphatase PTPN3 and its interaction with oncogenic viruses." Electronic Thesis or Diss., Sorbonne université, 2019. http://www.theses.fr/2019SORUS112.

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PTPN3 est une protéine humaine contenant un domaine PDZ avec un rôle soit de suppresseur de tumeur soit de promoteur de tumeur dans de nombreux cancers. Cependant, sa fonction dans la signalisation cellulaire reste encore floue. Fait intéressant, les papillomavirus humains (HPV) génitaux à haut risque de types 16 et 18 et le virus de l'hépatite B (HBV) ciblent le domaine PDZ de PTPN3 (PTPN3-PDZ) par le biais de motifs de reconnaissance au domaine PDZ (PBMs) dans l’oncoprotéine E6 et la protéine de capside HBc de HPV et HBV respectivement. Nous avons étudié les interactions entre le PTPN3-PDZ et ses ligands cellulaires et viraux. Nous avons étudié les propriétés structurales et fonctionnelles du PTPN3-PDZ et les principaux déterminants structuraux de la reconnaissance des PBMs en combinant des expériences de biophysique, de RMN et de diffraction aux rayons X. Nous nous sommes ensuite intéressés à la protéine de capside HBc de HBV. En criblant une bibliothèque contenant l’ensemble des domaines PDZ des protéines humaines, nous avons identifié 28 partenaires cellulaires potentiels interagissant avec le PBM de HBc. Nous avons confirmé que PTPN3 pouvait interagir avec le PBM de HBc au sein d’une capside virale et nous avons montré que les PBMs viraux interagissaient avec PTPN3-PDZ avec des affinités similaires aux ligands endogènes de PTPN3. En utilisant des hépatocytes infectés par HBV, nous avons observé que la surexpression de PTPN3 avait des effets multiples sur l’infection. Enfin, nous avons étudié l’interactome de PTPN3-PDZ afin de mieux comprendre le rôle de PTPN3 dans la signalisation cellulaire et les effets perturbateurs de HBV sur celle-ci
The human protein tyrosine phosphatase non-receptor type 3 (PTPN3) is a PDZ (PSD-95/Dlg/ZO-1) domain-containing phosphatase with a tumor-suppressive or a tumor-promoting role in many cancers, although its role in cell signalling is still unclear. Interestingly, the high-risk genital human papillomavirus (HPV) types 16 and 18 and the hepatitis B virus (HBV) target the PDZ domain of PTPN3 through PDZ-binding motifs (PBMs) in their E6 and HBc proteins. Here, I report a detailed study of the interactions between the PDZ domain of PTPN3 and its cellular and viral ligands. First, we combined biophysical, NMR and X-ray experiments to investigate the structural and functional properties of the PDZ domain of PTPN3 and its interaction with the E6 PBM. We then extended our structural study of PTPN3-PDZ to other cellular and viral partners, and gained insights into the main structural determinants of recognition of PBMs. We then focused on the HBV HBc protein. We screened a library of human PDZ-containing proteins for HBc binders and identified 28 cellular HBc-interacting partners, most of which are involved in cell polarity. We confirmed that PTPN3 can bind the HBc PBM in the context of the viral capsid, and we showed that viral PBMs interact with PTPN3-PDZ with similar affinities to endogenous PTPN3 ligands. Using HBV-infected hepatocytes we observed that overexpression of PTPN3 has multiple effects on HBV infection. Finally, we investigated the interactome of PTPN3-PDZ to gain insights into the role of this protein in cell signalling and the disruptive effects of HBV

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Moise, Gwendolyn. "Investigations into Factors Affecting the WPD-Loop in the Protein Tyrosine Phosphatases YopH and PTP1B." DigitalCommons@USU, 2018. https://digitalcommons.usu.edu/etd/7226.

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The research in this dissertation documents connections between the primary amino acid sequence of proteins, the dynamics of proteins, and their catalytic function. This research project studied two proteins called protein-tyrosine phosphatases (PTPs): the human enzyme PTP1B, and the bacterial enzyme YopH. PTP1B is a human enzyme that down regulates the insulin receptor on the outer cellular membrane, and causes the insulin receptor to be less responsive to insulin. A deeper knowledge of how PTP1B is different from other human PTPs might be useful in designing drugs to increase insulin sensitivity in diabetics. Yersinia Pestis is the bacteria that caused the Black Plague, and YopH is an essential for virulence factor that helps Yersinia Pestis to escape the human immune response. Using these proteins, the primary sequence of amino acids in a small but critical loop region was altered and the effect on the catalytic efficiency was measured. This research shows how some residues are key to the catalytic efficiency of PTPs while others could be changed with little to no effect on the catalytic efficiency. A deeper understanding of the difference between key residues and structural residues may allow future scientists to create designer enzymes and perhaps design pharmaceuticals that mediate enzyme activity by affecting their protein dynamics.

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40

Kuga, Gabriel Keine [UNESP]. "Efeitos biomoleculares do exercício físico sobre a disfunção na via de sinalização da insulina em hipocampo de ratos envelhecidos." Universidade Estadual Paulista (UNESP), 2018. http://hdl.handle.net/11449/155987.

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A insulina e o fator neurotrófico derivado do cérebro (BDNF) no hipocampo promovem a plasticidade sináptica e a formação da memória no hipocampo. Por outro lado, o envelhecimento está relacionado ao declínio cognitivo e é o principal fator de risco para a doença de Alzheimer (DA). No entanto, a comunidade científica tem feito grande esforço para elucidar os mecanismos moleculares responsáveis pela patogênese da DA que são disparados pelo envelhecimento. A Proteina Tirosina Fosfatase 1B (PTP1B) está relacionada a vários processos deletérios nos neurônios e pode ser alvo promissor para novas terapias, e também regulada pelo exercício físico. Neste contexto, nosso estudo teve como objetivo investigar as alterações relacionadas com o envelhecimento sobre o conteúdo de PTP1B, sinalização da insulina e conteúdo de β-amilóide no hipocampo de ratos de meia-idade, bem como o possível efeito terapêutico do exercício físico. Ratos Wistar jovens (3 meses de idade) e de meia-idade (sedentários e exercitados) (17 meses de idade) foram submetidos ao teste do Labirinto Aquático de Morris (MWM), ao teste de tolerância à glicose e à análise molecular do tecido hipocampal através da técnica de Western Blot. Os dados foram analisados através da Análise de Variância (ANOVA) one-way com nível de significância estabelecido abaixo de 0,05. Os ratos realizaram protocolo de exercício físico de natação durante 5 dias consecutivos, com 2 horas de duração por dia. Através dos resultados, verificou-se que o envelhecimento resultou em aumento do peso corporal e intolerância à glicose, bem como diminuiu o processo de aprendizagem no MWM. Observou-se também que os ratos de meia-idade têm níveis mais altos de PTP1B, e isso está relacionado a menor fosforilação de Substrato do Receptor de Insulina-1 (IRS-1), Proteína Kinase B (Akt), Glicogênio Sintase Kinase β (GSK3β), e Receptor Tirosina Kinase Beta (TrkB). Além disso, o processo de envelhecimento aumentou o conteúdo β-amilóide no hipocampo. Por outro lado, o exercício físico foi eficiente em melhorar a tolerância à glicose e o desempenho no MWM, bem como em restaurar a fosforilação da Akt e reduzir o conteúdo de β-amilóide. Em conclusão, este estudo fornece novas evidências de que o conteúdo de PTP1B no hipocampo está aumentada com o envelhecimento e isto está relacionado com alterações cognitivas, e, por outro lado, o exercício físico atenua esse processo em ratos envelhecidos.
The insulin and Brain-Derived Neurotrophic Factor (BDNF) signaling in the hippocampus promote synaptic plasticity and memory formation. On the other hand, aging is related to the cognitive decline and is the main risk factor for Alzheimer’s Disease (DA). Nevertheless, a great effort has been made by the scientific community to elucidate the molecular mechanism of aging-related DA pathogenesis. The Protein-Tyrosine Phosphatase 1B (PTP1B) is related to several deleterious processes in neurons and emerges as a promising target for new therapies, like as physical exercise. In this context, our study aims to investigate the age-related changes in hippocampal PTP1B content, insulin signaling, β-amyloid content in the hippocampus of middle-aged rats, and the possible therapeutic effect of exercise. Young (3 months-old) and Middle-aged (17 months-old) Wistar rats were submitted to Morris-water maze (MWM) test, glucose tolerance test, and to molecular analysis in the hippocampus. The rats performed a 2-hour swim physical exercise protocol for 5 consecutive days. Aging resulted in increased body weight, and glucose intolerance and decreases learning process in MWM. Interestingly, the Middle-Aged rats have higher levels of PTPB, and this is related to lower phosphorylation of Insulin Receptor Substrate-1 (IRS-1), Protein Kinase B (Akt), Glycogen Syntase Kinase β (GSK3β), and Tyrosine Kinase Receptor Beta (TrkB). Also, the aging process increased β-amyloid content in the hippocampus. On the other hand, the physical exercise was efficient to improve glucose tolerance and MWM performance, as well as to restore Akt phosphorylation and reduce β-amyloid content. In conclusion, this study provides new evidence that PTP1B content in the hippocampus is increased with aging and this is related to cognitive alterations, and physical exercise can attenuate this process in middle-aged rats.

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41

Michou, Laëtitia. "Approches génétiques de la polyarthrite rhumatoïde." Paris 5, 2007. http://www.theses.fr/2007PA05P603.

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L’objectif de ce travail était de rechercher des facteurs génétiques de la polyarthrite rhumatoïde (PR) en utilisant différentes approches génétiques cliniques et moléculaires. L’approche de génétique clinique de ce travail a permis de mettre en évidence une agrégation familiale de la PR et des maladies auto-immunes (MAI), et de montrer que certaines caractéristiques du cas index (âge de début de la PR et sexe) étaient associées à une augmentation du risque de PR et/ou MAI chez les apparentés. Il semblait exister une influence de l’auto-immunité personnelle et/ou familiale sur les résultats des analyses de liaison, qui nécessite probablement des échantillons de plus grande taille pour être mise en évidence. La modélisation par la méthode MASC de la composante HLA dans la PR avait jusqu’à présent toujours rejeté un modèle dans lequel un épitope partagé (EP) unique expliquerait la susceptibilité à la maladie. Une nouvelle classification basée sur de la présence ou non de la séquence RAA en position 72 à 74, mais modulé par l’acide aminé en position 71 et par l’acide aminé en position 70 a été proposée et a permis de ne pas rejeter l’hypothèse de l’EP. Cette nouvelle classification a été répliquée dans un échantillon indépendant. L’approche gènes candidats a permis de sélectionner 187 gènes sur les 1577 gènes de fonction connue au sein des 19 régions chromosomiques suggérées par le criblage fin du génome. Une analyse de liaison/association sur un échantillon franco-européen de 465 familles trio a confirmé qu’il existait bien une liaison entre le polymorphisme PTPN22-1858T et la PR, en plus de l’association rapportée dans de nombreuses publications dans la population caucasienne. En revanche, l’étude d’association du gène BlyS et du gène CRLR, tous deux situés dans des régions chromosomiques suggérées par l’analyse de liaison et excellents gènes candidats par leur fonction, n’étaient pas associés à la PR dans un échantillon de 100 familles trio. Enfin, la recherche d’interaction gène-environnement dans les formes familiales de PR a permis de montrer qu’il existait de plus une interaction entre le tabac, les anti-CCP et le HLA-DRB1*0401, suggérant un rôle particulier de cet allèle au sein de l’EP, dans cette interaction
The aim of this work was to search for rheumatoid arthritis (RA) genetic factors using different clinical and molecular genetic approaches. The clinical genetic approach of this work led to exhibit familial aggregation of RA and autoimmune diseases (AID), and to show that some characteristics of the index case (RA age of onset and sex) were associated to an increased risk of RA and/or AID in the relatives. There seemed to be an influence of personal and/or familial autoimmunity on the results of linkage analysis, which probably needs to be studied on larger samples. The modelisation by MASC method of the HLA component in RA has up to now rejected the model in which a unique shared epitope (SE) should explain the disease susceptibility. A new classification based on the presence or not of the RAA motif at position 72 to 74, but modulated by the aminoacid at position 71 and the aminoacid at position 70 was proposed and allowed not to reject the SE hypothesis. This new classification was replicated in an independent sample. The candidate genes approach allowed to select 187 genes among the 1577 genes of known function in the 19 chromosomal regions suggested by the dense genome-wide scan. A linkage/association on a French and European sample of 465 trio families provided a linkage proof between the PTPN22-1858T polymorphism and RA, in the addition of the association reported in numerous publications in the Caucasian population. However, the association study of BlyS and CRLR genes, both located in suggested chromosomal regions by linkage analysis and good candidate genes by their function, were not associated with RA in a sample of 100 trio families. Finally, the search for gene-environment interaction in familial forms of RA led to show an interaction between tobacco, anti-CCP and the HLA-DRB1*0401, underlining a particular role of this allele among SE in this interaction

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42

Bayley, Rachel. "Altered leukocyte signalling thresholds in rheumatoid arthritis through changes in the function of the protein tyrosine phosphatase PTPN22/LYP." Thesis, University of Birmingham, 2014. http://etheses.bham.ac.uk//id/eprint/5060/.

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Rheumatoid arthritis (RA) results from complex interactions between genetic and environmental risk factors. Two examples of these are the genetic variant PTPN22 R620W, a disease-associated form of the protein tyrosine phosphatase (PTP) Lyp and cigarette smoking (CS). Epidemiological studies have identified interactions between R620W and CS, but the biological mechanisms behind these interactions are unclear. Lyp is expressed by all leukocytes and changes in leukocyte function are implicated in the pathogenesis of RA. Thus the aim of this study was to characterise the effects of R620W and CS on leukocyte signalling, to determine possible mechanisms by which these factors could interact to promote the development of RA. An assay to measure the specific activity of the Lyp phosphatase was developed. Healthy controls and RA patients were recruited and genotyped for the PTPN22 R620W variant. Following determination of genotype, neutrophils and CD4+ T cells were isolated and cell function assessed following cigarette smoke extract (CSE) treatment. R620W in T lymphocytes increased Lyp phosphatase activity, decreased Lyp substrate phosphorylation and increased production of the pro-inflammatory cytokines IFN-γ and TNF-α. CSE treatment decreased T cell receptor signalling which was characterised by decreased PTP activity, decreased calcium (Ca2+) flux and decreased cytokine production. R620W in neutrophils was associated with increased neutrophil activation and functions including Ca2+ flux, reactive oxygen species production and migration. Overall these data suggest that R620W may facilitate RA development and persistence by promoting the generation of inflammatory T cells and by enhancing neutrophil activation and migration. CS may promote further signalling dysfunction by oxidising the proteins controlling leukocyte signalling. These separate pathways leading to altered Lyp function may act additively or synergistically to promote the immune disturbances which underpin the development of RA.

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43

Hanna, Nadine. "Maladies héréditaires liées à une dérégulation de la voie Ras-MAPK : Conséquences des mutations de PTPN11 associées au syndrome LEOPARD et étude des corrélations génotype/phénotype dans les syndromes NCFC." Paris 5, 2008. http://www.theses.fr/2008PA05T023.

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Les syndromes Neuro-Cardio-Facio-Cutanés (NCFC) regroupent quatre syndromes polymalformatifs apparentés : les syndromes de Noonan (NS), LEOPARD (LS), Cardio-Facio-Cutané (CFC) et Costello (CS). La découverte de mutations de PTPNll codant la phosphatase SHP-2 dans le NS a été la clef de l'implication de nombreux acteurs de la voie Ras-MAPK dans les syndromes NCFG. Alors que les mutants de SHP-2 associés au NS montrent une activité phosphatasique augmentée in vitro, nous avons montré que les mutants LS présentent une activité phosphatasique basale effondrée entraînant in cellulo une augmentation de l'interaction Gabl/PI3K. D'autre part, nous avons réalisé une étude des corrélations génotype/phénotype sur une grande cohorte de patients présentant un syndrome NCFC. Chacune des mutations des gènes de la voie Ras-MAPK, par ses conséquences fonctionnelles et par le niveau de la voie touché, détermine une symptomatologie particulière qui s'inscrit dans le spectre phénotypique de ces syndromes
Neuro-Cardio-Facio-Cutaneous (NCFC) syndromes groups four clinically related developmental disorders: Noonan (NS), LEOPARD (LS), Cardio-Facio-Cutaneous (CFC) and Costello (CS) syndromes. Discovery of PTPNll mutations, coding the phosphatase SHP-2, in NS was the key of the identification of mutations of numerous actors of the Ras-MAPK pathway in the NCFC syndromes. Whereas NS mutations enhance SHP-2 in vitro catalytic activity, we showed that activity of LS mutants is decreased and promote in cellulo Gabl/PI3K binding. How these apparently opposite behaviours of SHP-2 mutants lead to clinically overlapped syndromes still remain to be explained. On the other hand, we performed a genotype/phenotype correlation study in a large NCFC patients cohort. Each of the mutations affecting the Ras-MAPK pathway, by its functional consequences and by the level of the pathway affected, determines a particular symptomatology demonstrating a phenotypic continuum between the clinical entities

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44

Goëb, Vincent. "Identification de marqueurs diagnostiques de la polyarthrite rhumatoïde par une double approche génétique et protéomique." Rouen, 2008. http://www.theses.fr/2008ROUES032.

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L’intérêt des allèles 196R de TNFRII, 1858T de PTPN22 et HLA portant l’épitope partagé (HLA-SE) pour le diagnostic de la polyarthrite rhumatoïde (PR) a été évalué. Les allèles 196R de TNFRII et HLA-SE sont associés au diagnostic, mais leur étude dans une cohorte de patients atteints de rhumatisme inflammatoire débutant (cohorte VerA) n’optimise pas celle des autoanticorps anti-peptides citrullinés et/ou du facteur rhumatoïde, qui permettent à eux-seuls de prédire la survenue d’une PR après 2 ans d’évolution chez 68% des patients de la cohorte. Afin d’améliorer la sensibilité des tests diagnostiques utilisant les marqueurs autoimmuns, nous avons utilisé l’outil protéomique (électrophorèse bi-dimensionnelle d’extraits protéiques de cellules HL-60, spectrométrie de masse MALDI-TOF) qui a permis l’identification d’enzymes de la voie glycolytique et de protéines chaperonnes, pour certaines citrullinées, comme étant de nouveaux autoantigènes ciblés par la réponse autoimmune précoce de la PR
The interest of TNFRII 196R, PTPN22 1858T and HLA-shared epitope alleles (HLA-SE) for rheumatoid arthritis (RA) diagnosis was assessed. TNFRII 196R and HLA-SE alleles are associated with RA diagnosis but their study, in a cohort of patients with very early arthritis (VerA cohort) does not improve those of antibodies against citrullinated proteins and/or rheumatoid factors which led to predict RA outcome in 68% of VerA cohort after 2 years of follow-up. In order to improve the sensitivity of the autoimmune diagnosis markers, we used proteomic tools (two-dimensional electrophoresis with protein extract from HL-60 and MALDI-TOF mass spectrometry), which allowed is to highlight several citrullinated enzymes of the glycolytic pathway and molecular chaperonins as new early autoentigens

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45

Lin, Wai Wai. "TRAF3 regulates B cell survival and IL-6 receptor signaling." Diss., University of Iowa, 2015. https://ir.uiowa.edu/etd/1678.

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Tumor-necrosis factor (TNF)-receptor (R) associated factor 3 (TRAF3) is an important adaptor protein that plays a variety of context-dependent regulatory roles in all types of immune cells. In B cells, TRAF3 mediates signaling downstream of CD40, B cell activating factor (BAFF)-R, and toll-like receptors (TLR)s to restrain B cell survival and function. Downstream of CD40 and BAFF-R, TRAF3 negatively regulates NF-κB2 activation through NF-κB inducing kinase (NIK) stabilization. NF-κB2 activation is important for B cell-homeostatic survival. However, the constitutively active NF-κB2 in other TRAF3 deficient immune cell types does not lead to increased cell survival. More importantly, loss-of-function mutations of the TRAF3 gene are found at relatively high frequencies in B cell malignancies such as multiple myeloma and B cell lymphoma. Therefore, TRAF3 plays a critical and unique role in B cells to restrain cell survival and differentiation that contributes to B cell malignancies. In this study, we aim to identify TRAF3 modulated survival pathways that contribute to homeostatic B-cell survival and B-cell differentiation. We found that TRAF3 degradation was not sufficient or necessary to induce NF-κB2 activation. We also showed that TRAF3 degradation is dependent on association with TRAF2 and cytoplasmic tail of CD40 or BAFF-R. TRAF3 regulation of NIK is important for mature B cell development; however, NIK only partially contributes to TRAF3-mediated B cell survival. TRAF3 also regulates the protein level of proviral integrations of Moloney virus (Pim2), a pro-survival serine/threonine protein kinase encoded by the Pim2 gene, to restrain B cell survival; this regulation can operate independently of the NF-κB2 pathway. Furthermore, we showed that TRAF3 negatively regulates IL-6R signaling, a pathway that contributes to expansion of the plasma cell compartment and to the pathogenesis of multiple myeloma, a plasma cell malignancy. We found that TRAF3 facilitates recruitment of PTPN22, a tyrosine phosphatase, to associate with Jak1 following IL-6 binding to the IL-6R complex. This regulation by TRAF3 restrains plasma cell differentiation, and also provides the first demonstration that PTPN22 regulates cytokine receptor signaling. Collectively, these findings highlight the importance of TRAF3 in the regulation of B cell-specific survival and differentiation pathways. This information could be exploited for more precise and effective therapeutic choices in treatment of B cell malignancies with TRAF3 deficiencies.

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46

Edouard, Thomas. "Impact sur la signalisation cellulaire des mutations de la tyrosine phosphatase Shp2 associées aux syndromes de Noonan et LEOPARD." Toulouse 3, 2009. http://thesesups.ups-tlse.fr/849/.

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"Le syndrome de Noonan (SN) est une maladie génétique autosomique dominante relativement fréquente (environ 1/2000), caractérisée par l'association d'une dysmorphie faciale, d'un retard statural et d'une cardiopathie. Le syndrome LEOPARD (SL) est une maladie génétique plus rare, phénotypiquement très proche du SN, s'en distinguant essentiellement par l'existence d'une surdité et d'anomalies cutanées. Ces deux syndromes appartiennent à la famille des syndromes " Neuro-Cardio-Facio-Cutanés ", un groupe de maladies du développement en rapport avec des mutations germinales de gènes codant pour des molécules impliquées dans la voie Ras/Mitogen Activated Protein Kinase (MAPK). Au moins 50% des patients SN et plus de 80% des patients SL ont des mutations germinales du gène PTPN11, codant pour la tyrosine phosphatase Shp2. Les études biochimiques ont montré que les mutations de PTPN11 ont des effets opposés sur l'activité de la phosphatase, gain de fonction dans le SN et perte de fonction dans le SL. Comment des mutations aux effets opposés peuvent être à l'origine de phénotypes similaires est à ce jour incompris. Ce travail nous a permis d'observer, qu'en réponse à l'EGF, la voie PI3K/Akt est hyperactivée dans les cellules de patients SL comparées à celles des patients SN ou des contrôles. Cet effet dominant positif des mutants SL de Shp2 est du à une diminution de la déphosphorylation des sites de liaison de PI3K sur Gab1, augmentant ainsi l'association PI3K/Gab1 et l'activation de la voie PI3K/Akt. Nous avons également observés dans les cellules de patients SL que cette hyperactivation de PI3K/Akt entraîne une augmentation de l'inactivation de GSK3-beta et par conséquent une régulation positive des marqueurs d'hypertrophie cardiaque. Ces données suggèrent que l'hyperactivation de PI3K/Akt pourrait participer à l'hypertrophie cardiaque souvent observée dans le SL. "
Noonan syndrome (NS) is a relatively frequent (about 1/2000 births) autosomal dominant disease primarily characterized by facial dysmorphism, heart defects and short stature. LEOPARD syndrome (LS) is a rarer but related disorder that associates, roughly, NS symptoms with deafness and cutaneous abnormalities. Both NS and LS belong to the family of "neuro-cardio-facial-cutaneous" (NCFC) syndromes, a group of developmental disorders, which display different combinations of the above-mentioned symptoms with mental retardation and tumor predisposition. At least 80% of LS and 50% of NS patients carry germline missense mutations in PTPN11, the gene encoding Shp2. Shp2 is a widely expressed protein tyrosine phosphatase (PTP) that contains Src homology 2 (SH2) domains and promotes Ras-MAPK activation through different molecular mechanisms. Biochemical studies have shown that NS mutations are located at contact points between the catalytic and the SH2 domains and therefore disrupt Shp2 autoinhibitory conformation, stimulating Shp2 catalytic activity (gain-of-function mutations). Conversely, LS mutations are confined within the catalytic domain and repress Shp2 activity. Although genetic studies provided essential advances, how PTPN11 mutations cause the diseases' symptoms remains an open question. We assessed whether LS mutations could influence PI3K activation. To this aim we generated primary and immortalized fibroblast cell lines from LS patient and healthy controls and showed that, in response to EGF stimulation, PI3K/Akt was upregulated in LS cells. This deregulation was due to impaired dephosphorylation of Gab1 PI3K-binding sites by LS mutants. Furthermore, LS mutant promoted PI3K-dependent upregulation of hypertrophy genes in cardiomyocytes, suggesting that this deregulation is involved in LS pathophysiology

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47

Miraldi, Emily R. (Emily Rae). "Bridging the gap between protein-tyrosine phosphorylation networks, metabolism and physiology in liver-specific PTP1b deletion mice." Thesis, Massachusetts Institute of Technology, 2012. http://hdl.handle.net/1721.1/72824.

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Thesis (Ph. D.)--Massachusetts Institute of Technology, Computational and Systems Biology Program, 2012.
Cataloged from PDF version of thesis.
Includes bibliographical references.
Metabolic syndrome describes a complex set of obesity-related disorders that enhance diabetes, cardiovascular, and mortality risk. Studies of liver-specific protein-tyrosine phosphatase lb (PTPlb) deletion mice (L-PTPlb-/-) suggests that hepatic PTPlb inhibition would mitigate metabolic syndrome progression through amelioration of hepatic insulin resistance, endoplasmic reticulum stress, and whole-body lipid metabolism. However, the network alterations underlying these phenotypes are poorly understood. Mass spectrometry was used to quantitatively discover protein phosphotyrosine network changes in L-PTP lb-/- mice relative to control mice under both normal and high-fat diet conditions. A phosphosite set enrichment analysis was developed to identify numerous pathways exhibiting PTPlb- and diet-dependent phosphotyrosine regulation. Detection of PTP lb-dependent phosphotyrosine sites on lipid metabolic proteins initiated global lipidomics characterization of corresponding liver samples and revealed altered fatty acid and triglyceride metabolism in L-PTPlb-/- mice. Multivariate modeling techniques were developed to infer molecular dependencies between phosphosites and lipid metabolic changes, resulting in quantitatively predictive phenotypic models.
by Emily R. Miraldi.
Ph.D.

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48

Owen, Carl. "The role of adipocyte and liver protein tyrosine phosphatase 1B (PTP1B) in glucose homeostasis and insulin sensitivity." Thesis, University of Aberdeen, 2013. http://digitool.abdn.ac.uk:80/webclient/DeliveryManager?pid=203411.

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Hirata, Aparecida Emiko. "Modulação da associação IR/PTP1B na transmissão do sinal da insulina em modelos animais de resistencia insulinica." [s.n.], 2002. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311229.

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Orientador : Mario Jose Abdalla Saad
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciencias Medicas
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Resumo: A PTP18 atua como efetor negativo do receptor da insulina, desfosforilando o receptor e o IRS-1 e parece estar correlacionada com a sensibilidade à insulina e desenvolvimento da obesidade. No presente estudo avaliamos a associação do receptor da insulina com a PTP18 sobre a regulação da transmissão do sinal da insulina em animais obesos MSG, animais submetidos a jejum por 72h e animais tratados agudamente com adrenalina....Observação: O resumo, na integra, podera ser visualizado no texto completo da tese digital
Abstract: Insulin is the most potent anabolic hormone known and is essential for appropriate tissue development, growth, and maintenance of whole-body glucose homeostasis. Insulin signaling is initiated by binding of insulin to the insulin receptor (IR), stimulating its tyrosine kinase activity, which, in tum triggers downstream signaling events. These include tyrosil phosphorylation of IR substrates 1 and 2 (IRS-1, IRS-2) that activate other adapter molecules such as PI3-K, PDK1 and Akt, which combined actions mediate the biological effects of insulin....Note: The complete abstract is available with the full electronic digital thesis or dissertations
Doutorado
Doutor em Clínica Médica

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50

Richan, Teisha. "Conservative Tryptophan Mutations in Protein Tyrosine Phosphatase PTP1B and its Effect on Catalytic Rate and Chemical Reaction." DigitalCommons@USU, 2017. https://digitalcommons.usu.edu/etd/5584.

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Protein-tyrosine phosphatases (PTPs) catalyze the hydrolysis of phosphorylated tyrosines by a 2-step mechanism involving nucleophilic attack by cysteine and general acid catalysis by aspartic acid. In most PTPs the aspartic acid resides on a flexible protein loop, consisting of about a dozen residues, called the WPD loop. PTP catalysis rates span several orders of magnitude, and differences in WPD loop dynamics have recently been show to correlate with the rate of enzymatic catalysis. The rate of WPD loop motion could possibly be related to a widely conserved tryptophan residue on the WPD loop. Therefore, point mutants were made in PTP1B (a human PTP) to the conserved tryptophan residue and their effects on catalytic rate and chemical reaction were studied. The results of these studies are presented in this thesis.

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Дисертації з теми "PTPN14"

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