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1
Iron, Albert. "L'acide DL-amino-1-(parahydroxyphényl)-2-éthylphosphonique, analogue phosphonique de la tyrosine : quelques propriétés physicochimiques et métaboliques." Bordeaux 2, 1989. http://www.theses.fr/1989BOR2E001.
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Nadeau, Robert J. "Sprouty Regulation of Tyrosine Kinase Signal Transduction is Governed by Tyrosine Phosphorylation: A Functional Role for Sprouty2 N- and C- Terminal Tyrosines." Fogler Library, University of Maine, 2006. http://www.library.umaine.edu/theses/pdf/NadeauRJ2006.pdf.
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Lee, Joseph Moon-Hee 1967. "Characterization of tyrosine phosphorylation in the protein tyrosine phosphatase CD45." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=37758.
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The enzymatic activity of the protein tyrosine phosphatase, CD45 has been demonstrated to play an absolutely required role in the regulation of Src family protein tyrosine kinases in T lymphocytes. CD45 function during early events of antigen receptor signaling has been well established, however, the role of CD45 during later stages of T cell activation is only beginning to emerge. Transient tyrosine phosphorylation of CD45 has previously been demonstrated. We show this phosphorylation can be sustained through treatment of a T cell hybridoma cell line with the PTPase inhibitor, pervanadate. Tyrosine phosphorylation of CD45 is significantly increased in the presence of an activated form of Lck. Tyrosine phosphorylated CD45 is correlated with the association of a subset of signaling molecules containing SH2 domains. These molecules include p56Lck, p59Fyn, rasGAP, Grb2 and Csk. Although CD45 becomes abundantly tyrosine phosphorylated upon pervanadate treatment, no other SH2-containing molecules that we had tested demonstrated association with CD45. The interaction between CD45 and Grb2 in particular was found to be dependent upon CD45 tyrosine phosphorylation and mediated through the SH2 domain of Grb2. Interestingly, both Grb2 and a close homolog, Grap are able to bind CD45 in in vitro binding assays. Grap does not, however, associate with CD45 in vivo as was observed for Grb2.CD45 contains two Grb2 consensus binding sequences. Deletion of both results in a greatly diminished capacity for CD45- Grb2 association. However, interaction between the two is not completely abolished and appears to result from an unconventional peptide sequence as observed by 2-dimensional phosphopeptide mapping studies. In the process of mapping the phosphotyrosine sequences required for CD45-Grb2 interaction, many tyrosine-phosphorylated peptides have been identified and assigned to tyrosine residues in CD45.
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Lu, Wei. "Regulation of protein tyrosine phosphatase SHP-2 by tyrosine phosphorylation." Available to US Hopkins community, 2002. http://wwwlib.umi.com/dissertations/dlnow/3080719.
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Chen, Shirley Chun-Jyue. "The regulation and function of protein tyrosine phosphatase alpha (PTPα) tyrosine phosphorylation." Thesis, University of British Columbia, 2007. http://hdl.handle.net/2429/31583.
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Protein tyrosine phosphatase alpha (PTPα) is a ubiquitously expressed receptor protein tyrosine phosphatase that functions as an early upstream regulator in the integrin signaling pathway. The integrins, by interacting with extracellular matrix components, regulate cell growth, migration, and survival, and are functionally linked to multiple aspects of cancer biology such as invasion and metastasis. PTPα plays a major role in the integrin signaling cascade by activating Src family kinases (SFKs), which are required for the full activation of the central signaling molecule focal adhesion kinase (FAK). The importance of PTPα in integrin signaling is demonstrated by defects observed in integrin-mediated cytoskeletal rearrangement and focal adhesion formation in PTPα-deficient fibroblasts. PTPα contains a tyrosine phosphorylation site, Tyr-789, located in the intracellular C-terminal tail. Tyr-789 phosphorylation is shown to not affect PTPα catalytic activity, but allows binding of Src and the adaptor protein Grb2. Little is known about the regulation and function of PTPα Tyr-789 phosphorylation. Recent work from our laboratory has discovered that PTPα Tyr-789 phosphorylation is positively regulated upon integrin engagement and is functionally required for integrin-induced cytoskeletal reorganization events, suggesting the importance of the phospho-Tyr-789 motif in PTPα-mediated signaling events. In a search for other regulators of PTPα Tyr-789 phosphorylation, IGF-1, and potentially aFGF, LPA, and PMA, were found to positively regulate PTPα Tyr-789 phosphorylation. These inductions occurred in a Src/Fyn/Yes-independent manner, indicating an involvement of likely non-SFK cellular kinases distinct from those involved in integrin-induced PTPα phosphorylation. Although PTPα Tyr-789 phosphorylation mediates integrin-induced cytoskeletal remodeling, this phosphorylation event did not appear to act upstream of the Rho family of small GTPases that are key regulators of cellular actin structures. To further understand the precise action of PTPα Tyr-789 phosphorylation in integrin (and other) signaling pathway, the interaction between the PTPα phospho-Tyr-789 motif and other cellular proteins was investigated. Integrin-induced PTPα Tyr-789 phosphorylation was accompanied by increased Grb2 recruitment to phospho-PTPα which provides for a mechanism by which Grb2-interacting signaling proteins are recruited to PTPα to mediate downstream integrin signaling events. In addition, several proteins representing potential PTPα phospho-Y789 interacting proteins were isolated by (phospho)peptide affinity purification. The identification of these proteins and validation of their interactions with PTPα may reveal the precise signaling role of PTPα Tyr-789 phosphorylation.Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate
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Hardwick, James S. "Regulation of the Lck tyrosine protein kinase by oxidant-induced tyrosine phosphorylation /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1997. http://wwwlib.umi.com/cr/ucsd/fullcit?p9814544.
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Fustier, Caroline. "Tyrosinase nanocapsules for the lowering of systemic tyrosine for the treatment of melanoma." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=18429.
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This study describes the preparation and characterization of biodegradable nano-artificial cells containing the enzyme tyrosinase. The rationale for doing this is that this may have potential implication for the treatment of melanoma, a fatal skin tumour that is tyrosine-dependent. A poly (ethylene glycol)- poly (lactic acid) block-copolymer has been prepared and characterized. A method for the preparation of the tyrosinase nanocapsules has been designed. The physical properties and the membrane properties of the nanocapsules have been characterized. The electron microscopy images show round and unaggregated nanocapsules. The average size of these nanocapsules can be controlled by modifying the stirring speed. Studies on the enzymatic properties show that tyrosinase can be nanoencapsulated without being inactivated. Nanoencapsulated tyrosinase is stable for several weeks when stored at 4ºC. Nanoencapsulation greatly increases the stability of tyrosinase at 37ºC. In vivo studies show that one intravenous injection of tyrosinase nanocapsules can effectively and quickly decrease the systemic tyrosine level to very low levels.Cette thèse décrit la préparation et la caractérisation de nano-cellules artificielles biodégradables contenant l'enzyme tyrosinase. La raison de cette étude est la possibilité d'application au traitement du mélanome, un cancer de la peau mortel. Un copolymère de polyethylène glycol et d'acide polylactique a été préparé et caractérisé. Une méthode pour la préparation des nanocapsules de tyrosinase a été mise au point. Les propriétés physiques des nanocapsules ainsi que les propriétés de leur membrane ont été étudiées. Les images prises à l'aide de microscopes à électrons montrent des nanocapsules rondes et qui ne s'agrègent pas. La taille moyenne des nanocapsules peut être contrôlée en modifiant la vitesse de l'agitateur magnétique lors de leur préparation. L'étude de l'activité enzymatique montre que la tyrosinase peut être nano-encapsulée sans être inactivée. La tyrosinase dans les nanocapsules est stable pendant plusieurs semaines à 4ºC. La nano-encapsulation augmente fortement la stabilité de la tyrosinase à 37ºC. Les expériences in vivo montrent que les niveaux de tyrosine circulant peuvent être réduits efficacement et rapidement avec une injection intraveineuse de ces nanocapsules contenant de l'enzyme tyrosinase. fr
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Sun, Guobin. "The role of protein tyrosine phosphatase alpha tyrosine 789 phosphorylation in integrin signaling." Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/43924.
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Focal adhesions (FA) form interfaces between the extracellular matrix and the cytoskeleton to regulate cell responses such as cell proliferation, survival, and migration. The functions and dynamic interactions of many of the ~180 molecules in this integrin-initiated FA complex network are far from fully understood. Among these is the receptor-like protein tyrosine phosphatase PTPα. In addition to the integrin-proximal action of PTPα to catalyze activation of Src family kinases, subsequent phosphorylation of PTPα at its C-terminal Tyr789 site is essential and acts in an unknown manner to promote cell spreading and migration. We used reconstitution assays in PTPα-null cells to identify and distinguish integrin signaling events that were PTPα-dependent and PTPα-Tyr789-dependent. Results show that PTPα-Tyr789 mediates the localization of PTPα and the scaffolding protein Cas to FAs where Cas interacts with and gets phosphorylated by Src to initiate Cas/Crk-Rac/Cdc42-PAK signaling. Linking these events, this study identifies the Cas-binding protein BCAR3 as a molecular connector of PTPα and Cas, with phosphoTyr789-PTPα interacting with the BCAR3 SH2 domain to recruit BCAR3-Cas to newly forming adhesion sites. These findings identify phospho-Tyr789-PTPα as the first cellular ligand for the SH2 domain of BCAR3, and reveal a role of PTPα in integrin-induced adhesion complex assembly that enables Src-mediated activation of the pivotal function of Cas in cell migration. Furthermore I extended this study into a cancer cell model by showing that the disruption of this PTPα-BCAR3-Cas-Src signaling module inhibits the invasive motility in a rhabdomyosarcoma cell line. In summary, my results in this thesis elucidate the molecular mechanism underlying the PTPα-Tyr789-dependent cell spreading and migration, and support that the PTPα-BCAR3-Cas complex is a critical regulator of cell migration as well as cancer cell invasion and metastasis.
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Mehere, Prajwalini V. "Towards the Characterization of Enzymes Involved in the Metabolism of Tyrosine and Tyrosine Derivatives." Diss., Virginia Tech, 2010. http://hdl.handle.net/10919/77289.
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Tyrosine is involved in many biological processes including protein synthesis. This dissertation is focused on two different aspects: tyrosine catabolism and tyrosine derivative metabolism. Tyrosine undergoes degradation via tyrosine aminotransferase (TAT). Deficiency of TAT leads to some disease conditions or tyrosinemia type II. TAT has been characterized in several species, including humans. Mouse tyrosine aminotransferase was used as a model protein for the tyrosine catabolism portion of this study. Characterization of TAT included its expression in a bacterial expression system, purification using various chromatographic techniques, crystallization under different conditions, and its kinetic analysis, and molecular dynamics simulations. Based on sequence, structure, and kinetic data we have shown that mouse TAT behaves like human TAT. Our crystallization studies added new insights into the mechanism of TAT by shedding light on involvement of a disulfide bond in the regulation of mTAT. Molecular dynamics analysis provided perspective on the differences (preferences) in the substrate specificities of mouse and Trypanosome cruzi TAT.
Tyrosine is a precursor of several key neurotransmitters. These neurotransmitters must be regulated in order to function properly. The hypothetical N-acetyltransferases from Aedes aegypti were used as model proteins for investigation of tyrosine derivative metabolism. We found nine potential arylalkylamine N-acetyltransferase (AANAT) genes in Ae. aegypti. Phylogenetic analysis suggests that these Ae. aegypti AANATs (AeAANATs) can be further divided into three clusters. Phylogenetic analysis suggests that insect AANATs may have different functions as compared with the mammalian AANATs, for which function is specific to circadian rhythm regulation. PCR amplification indicates that eight of the nine putative AeAANATs are expressed in the mosquito. Expression of the eight putative AeAANATs and substrate screening of their recombinant proteins against dopamine, octopamine, tyramine, epinephrine, tryptamine, 5-hydroxytryptamine, and methoxytryptamine established that five of the eight putative AeAANATs are true AANATs.
The discontinuous expression profiles of AeAANAT genes were studied in detail. Six of the AeAANATs were expressed in the head before and after blood feeding, suggesting their potential role in neurotransmission inactivation. Down-regulation of these genes after blood feeding suggests that blood feeding or factors related to blood feeding impact on the regulation of these genes. Kinetic studies determined that two AeAANAT proteins are highly efficient in mediating the acetylation of dopamine and 5-hydroxytryptamine. Substrate analysis of AeAANATs supports the notion that acetylation of arylalkylamines is vital to the biology of mosquito species, and that these genes emerged in response to specific pressures related to necessities for biogenic amine acetylation.Ph. D.
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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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Grangeasse, Christophe. "Phosphorylation des protéines bactériennes au niveau de la tyrosine : étude des activités protéine-tyrosine kinase et phosphotyrosine-protéine phosphatase chez Acinetobacter johnsonii." Lyon 1, 1998. http://www.theses.fr/1998LYO10061.
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Nous avons demontre l'existence d'une modification post-traductionnelle des proteines par phosphorylation chez la bacterie acinetobacter johnsonii. Cette modification concerne principalement une proteine de 82 kilodaltons, localisee dans la membrane interne de la cellule bacterienne, que nous avons purifiee a homogeneite. Nous avons montre que cette proteine, appelee ptk pour prokaryotic protein-tyrosine kinase, est capable de s'autophosphoryler au niveau de plusieurs residus de tyrosine. Le gene correspondant, ptk, a ete clone et totalement sequence. L'analyse theorique de la sequence de la proteine ptk a revele differents motifs caracteristiques des proteine-kinases et des homologies avec plusieurs proteines bacteriennes intervenant dans la biosynthese des polysaccharides de surface. Par ailleurs, le sequencage du genome d'a. Johnsonii en amont du gene ptk a permis de caracteriser un second gene, appelee ptp, codant pour une proteine homologue de certaines phosphotyrosine-proteine phosphatases. Nous avons ainsi mis en evidence deux genes successifs, localises au sein d'un meme operon, qui codent pour deux enzymes d'activites opposees : une proteine-tyrosine kinase et une phosphotyrosine-proteine phosphatase. Cette observation nous a conduits a etudier le caractere reversible de la reaction de phosphorylation et le role regulateur que peut jouer cette modification dans la physiologie de la cellule. A cet effet, les deux proteines ont ete surproduites par genie genetique et purifiees. L'activite phosphotyrosine-proteine phosphatase de la proteine ptp a ete caracterisee sur un plan biochimique et la proteine ptk s'est averee etre le substrat endogene de la proteine ptp. Une organisation genomique similaire a ete retrouvee chez differentes especes bacteriennes, au sein d'operons tous impliques dans la synthese de polysaccharides de surface. Or, ces glycocomposes sont connus pour etre des facteurs de virulence des bacteries pathogenes. A partir de la, une relation possible entre la phosphorylation des proteines et la pathogenicite des bacteries a ete envisagee.
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Ripani, Meri <1977>. "p300/CBP tyrosine phosphorylation in response to dna damage activated by c-Abl tyrosine kinase." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2010. http://amsdottorato.unibo.it/2276/1/Ripani_Meri_tesi.pdf.
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The nuclear signaling that is triggered in response to DNA damage entails the recruitment and assembly of repair proteins and the induction of genes involved in the activation of cell cycle checkpoint, apoptosis or senescence. The extensive changes in chromatin structure underlying these processes suggest that chromatin-modifying enzymes could be relevant targets of DNA damage-activated signaling. The acetyltransferases p300 and CBP participate in DNA damage-activated responses, including local histone hyperacetylation, cell cycle regulation, and co-activation of DNA damage activated proteins, such as p53, p73 and BRCA1. However, the link between DNA damage and p300/CBP activation has not been identified.We have detected p300 tyrosine phosphorylation in response to DNA damage. We show that the DNA damage-activated cAbl tyrosine kinase enters the nuclei of cells exposed to genotoxic agents and phosphorylates p300 on a tyrosine residue within the bromodomain that is conserved in p300, CBP and many other bromodomain-containing proteins. Antibodies against tyrosine phosphorylated p300/CBP show a DNA damage-inducible nuclear staining, suggesting that p300 tyrosine phosphorylation is an event linking DNA damage and chromatin modifications.
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Ripani, Meri <1977>. "p300/CBP tyrosine phosphorylation in response to dna damage activated by c-Abl tyrosine kinase." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2010. http://amsdottorato.unibo.it/2276/.
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The nuclear signaling that is triggered in response to DNA damage entails the recruitment and assembly of repair proteins and the induction of genes involved in the activation of cell cycle checkpoint, apoptosis or senescence. The extensive changes in chromatin structure underlying these processes suggest that chromatin-modifying enzymes could be relevant targets of DNA damage-activated signaling. The acetyltransferases p300 and CBP participate in DNA damage-activated responses, including local histone hyperacetylation, cell cycle regulation, and co-activation of DNA damage activated proteins, such as p53, p73 and BRCA1. However, the link between DNA damage and p300/CBP activation has not been identified.We have detected p300 tyrosine phosphorylation in response to DNA damage. We show that the DNA damage-activated cAbl tyrosine kinase enters the nuclei of cells exposed to genotoxic agents and phosphorylates p300 on a tyrosine residue within the bromodomain that is conserved in p300, CBP and many other bromodomain-containing proteins. Antibodies against tyrosine phosphorylated p300/CBP show a DNA damage-inducible nuclear staining, suggesting that p300 tyrosine phosphorylation is an event linking DNA damage and chromatin modifications.
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Yu, Binglan 1971. "Polyhemoglobin-tyrosinase and artificial cells microencapsulated tyrosinase for the removal of systemic tyrosine : a potential novel therapy for melanoma." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=38534.
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Artificial cells microencapsulation have a number of potential areas of application. Studies showed that lowering of tyrosine level could inhibit the growth of melanoma. However, at present there is no practical method to lower the tyrosine level in humans. We have therefore devised novel methods as follows. (1) Microencapsulation of tyrosinase for the removal of systemic tyrosine by oral administration. Characterization, optimization, and feasibility studies were carried out to test the therapeutic potentials. In temperature and pH studies, the encapsulated tyrosinase maintained higher enzyme activity than the free enzyme in solution. The in vivo studies showed that daily oral administration of encapsulated tyrosinase by itself for about 3--5 days could lower the body tyrosine level. (2) A novel polyhemoglobin-tyrosinase preparation for intravenous injection can rapidly lower the body tyrosine level after one intravenous injection. In this form, the enzyme is covered by hemoglobin molecules and therefore has less immunological properties. Furthermore, polyhemoglobin is an oxygen carrier and being in a solution, it can more readily reach the narrower capillaries of the melanoma cancer cells than red blood cells and can therefore bring more oxygen for radiation therapy. Our in vitro studies showed that this novel polyhemoglobin-tyrosinase preparation inhibited the growth of melanoma cells in culture. (3) A combination of two intravenous injections of polyhemoglobin-tyrosinase with 3 times a day oral administration of encapsulated tyrosinase could immediately lower the body tyrosine and maintained this low level as long as the oral administration was continued.
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Robertson, Sears Heather C. 1975. "The receptor tyrosine phosphatase Ptp69D and the receptor tyrosine kinase Pvr in Drosophila nervous system development." Thesis, Massachusetts Institute of Technology, 2004. http://hdl.handle.net/1721.1/32254.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2004.Includes bibliographical references.
Cell migration and axon guidance are highly similar processes important for the development of the nervous system. Both processes involve the transduction of signals across the membrane, resulting in changes in the cytoskeleton. I have examined the roles of two receptors that are involved in axon guidance and cell migration in Drosophila. Ptp69D is a receptor tyrosine phosphatase required for axon guidance in the developing embryo and for layer-specific axon targeting in the developing visual system. Using a dominant-negative form of Ptp69D, I have identified several genes with which Ptp69D genetically interacts in photoreceptor axon targeting. Removing a single dose of the cytoplasmic tyrosine kinases Src64 or Abl or the repulsive axon guidance receptor robo enhanced the Ptp69D dominant-negative phenotype. In mammalian systems, Src plays a key role in the regulation of cell adhesion, and Abl is a known regulator of actin cytoskeletal dynamics. Removing a single dose of the EGF receptor or Ras85D suppressed the Ptp69D dominant negative phenotype. Interestingly, the cytoplasmic tyrosine kinase PR2 binds Ptp69D, and the C. elegans homolog of PR2 has been found to suppress the Egfr/Ras pathway. Other evidence suggests that the Egfr/Ras pathway may be required for axon outgrowth. In addition to PR2, I also identified the receptor tyrosine kinase Pvr in a biochemical screen for proteins that bind Ptp69D. I generated mutants in Pvr by gene disruption and EMS mutagenesis. These mutants have disruptions in the embryonic central nervous system, including mispositioning of axon tracts and the glia that wrap them. However, these defects are not inherent to the CNS.
(cont.) Rather, they result from a failure of hemocytes to migrate out of the head and engulf dead cells in the CNS. To identify proteins that signal downstream of Pvr in cell migration, I used a yeast two-hybrid screen to identify 15 proteins that bind the intracellular domain of kinase-active Pvr. One of these proteins, drk, is required for Pvr-dependent Erk MAP kinase activation. None has defects in hemocyte migration when disrupted by RNA interference. Whether these proteins have redundant functions or function downstream of Pvr in other systems remains to be determined.
by Heather C. Robertson Sears.
Ph.D.
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Lebel, France. "Évaluation de trois tests de dépistage de porteurs et recherche d'un effet fondateur dans la tyrosinemie héréditaire de type 1 au Saguenay-Lac-St-Jean /." Thèse, Québec : Université Laval, 1992. http://theses.uqac.ca.
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Mémoire (M.Sc.)-- Université du Québec à Chicoutimi, 1992.Ce mémoire a été réalisé à l'UQAC dans le cadre du programme de maîtrise en médecine expérimentale (génétique) extensionné de l'Université Laval à l'UQAC. CaQCU Bibliogr.: f. [1-5]. Document électronique également accessible en format PDF. CaQCU
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Inamdar, Vaishali Vijay. "FUNCTIONAL PROTEIN TYROSINE PHOSPHATASES IN PLATELETS." Diss., Temple University Libraries, 2017. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/473257.
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Biomedical SciencesPh.D.
Platelets are small anucleate cells in blood that are derived from megakaryocytes and their primary function is to prevent bleeding. Upon vascular injury, the sub-endothelial collagen gets exposed to which platelets bind and aggregate eventually forming a platelet plug. There are several receptors on platelet surface that can be divided into two broad categories; the immune-receptor tyrosine-based activation motif (ITAM) and the G protein-coupled receptors (GPCRs). The role of several protein tyrosine kinases (PTKs) downstream of ITAM and GPCRs has been extensively studied. However, the role of protein tyrosine phosphatases (PTPs) have been under-investigated in platelets. PTPs are important for dephosphorylating and activating or inactivating the protein. Proteomics studies show presence of 10 receptor like and 10 cytoplasmic phosphatases in platelets. To date, only five non-transmembrane PTPs (NTPTPs), PTP-1B, Shp1, Shp2, LMW-PTP, MEG2-PTP and a one receptor- like PTP (RPTP), CD148,
Temple University--Theses
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Melhado, Ian Granville. "Characterization of protein-tyrosine-phosphatase E." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0020/NQ46390.pdf.
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Bäckesjö, Carl-Magnus. "Molecular biology of Bruton's tyrosine kinase /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-693-6.
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Mertins, Philipp. "Investigations of protein tyrosine phosphatase functions." kostenfrei, 2008. http://mediatum2.ub.tum.de/doc/631437/631437.pdf.
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Pannifer, Andrew. "Structural studies on protein tyrosine phosphatases." Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390536.
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Page, Timothy C. M. "Mechanism based inhibitors of tyrosine kinases." Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.260163.
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Iqbal, Azhar. "Towards understanding the photochemistry of tyrosine." Thesis, University of Warwick, 2010. http://wrap.warwick.ac.uk/3735/.
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The H-atom detachment driven through the 1πσ* states of biological chromophores containing an X-H bond (where X = N or O) upon UV absorption is ubiquitous in nature. Understanding the role of this dissociative state in the chromophores and their respective amino acids following UV excitation would enable a step change towards establishing a better understanding of the mechanisms of photostability of larger peptides in the gas-phase. The work presented in this thesis focuses on the H-atom elimination of phenol and indole, the chromophores of the amino acids tyrosine and tryptophan, respectively. The H-atom elimination has also been carried out in tyrosine and its sub-units p-ethylphenol and tyramine upon excitation at 200 nm. In all these systems the O-H bond fission on the phenol ring results in a range of H-atoms kinetic energy release. Using a combination of femtosecond pump-probe spectroscopy, time-offlight mass spectroscopy (TOF-MS) and velocity map ion imaging (VMI) reveals that H-atom elimination in all these systems occurs on an ultrafast timescale (~200 fs) for both fast and slow H-atoms. This casts considerable doubt over the previously assigned statistical origin of the slow H-atoms and suggests direct pathways to their formation. The H-atom kinetic energy spectrum in tyrosine also implies that H-atom elimination is occurring through the same coordinate i.e. O-H bond as exhibited by it’s phenol chromophore, thus confirming the active participation of the 1πσ* states from the chromophore of the amino acid to the amino acid itself. These findings are of great importance enabling one to compare these results with existing calculations on the chromophores which often model the system in an isolated environment. These results also provide ground work for more complex calculation to be carried out, in particular on the amino acids and the di/tri peptides.
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Gaspar, Hubert Baburaj. "Molecular studies on Bruton's tyrosine kinase." Thesis, University College London (University of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.322123.
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Cory, Giles Oliver Cholmondeley. "Molecular interactions of Bruton's tyrosine kinase." Thesis, University College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264935.
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Sørum, Christopher. "Synthesis of new tyrosine kinase inhibitors." Thesis, Norges teknisk-naturvitenskapelige universitet, Institutt for kjemi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:no:ntnu:diva-6863.
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Topall, Guy. "Etudes biochimiques et pharmacologiques de la tyrosine et d'agents affectant son métabolisme." Paris 5, 1988. http://www.theses.fr/1988PA05P612.
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Gervais, François G. "Regulation of lymphocyte-specific tyrosine protein kinase p56[superscript]l[superscript]c[superscript]k by tyrosine phosphorylation." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0023/NQ29945.pdf.
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Hatahet, Laith. "Regulation of lymphocyte specific protein tyrosine kinase, Lck, by tyrosine phosphorylation : evaluation of the tail-bite model." Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=78375.
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Several studies show that the catalytic function of the Src-family protein kinase Lck is repressed by phosphorylation of a conserved carboxyl-terminal residue (Y505). This phosphorylation allows the molecule to bind to its SH2 domain rendering the protein in an inactive state, a proposed model called the tail-bite mechanism. However, previous findings demonstrated that the activity of Lck from several T cell lines lacking CD45, which is the phosphatase known to dephosphorylate Y505, was significantly elevated. Herein, we are evaluating the tail bite mechanism model by examining the major regulatory sites of Lck, Y394 and Y505, in several T cell lines and assessing the catalytic function of Lck tail mutants on its substrates in JCaM1 cells in vivo . Utilizing phospho-specific antibodies, we provide evidence that Lck from activated T cells is phosphorylated both at Y394 and Y505.
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Faure, Camille. "Régulation de la localisation et de l'activation de la tyrosine kinase Pyk2 (Proline-rich tyrosine kinase 2)." Paris 6, 2010. http://www.theses.fr/2009PA066736.
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Proline-rich tyrosine kinase 2 (Pyk2) est une tyrosine kinase non récépteur de 110-kDa deappartenant à la famille de focal adhesion kinase (FAK). Elle a été initialement caractérisée comme une enzyme cytoplasmique. Elle est, régulée par autophosphorylation (sur la tyrosine 402) en réponse à l’des augmentations de la concentration de Ca2+calcium libre cytosolique. L’autophosphorylation de Pyk2 est cruciale pour son activation puisqu’elle permet le recrutement des membres de la famille de Src, conduisant à l’ac’tivation de nombreuses voies de signalisation. Pyk2 existe sous deux isoformes produites par épissage alternatif, une isoforme enrichie dans le système nerveux contenant l’exon alternatif et une forme spécifique des cellules hématopoïétiques, dans laquelle cet exon est absent. Le laboratoire s’intéresse à l’isoforme de Pyk2 abondante dans les neurones qui joue un rôle important dans l’induction de la plasticité synaptique dans l’hippocampe. Au cours de ma thèseN, nous nous sommes intéressés à la régulation de l’activation et de la localisation de Pyk2 en réponse à la dépolarisation membranaire. Nous avons montré observé dans différents modèles, que des augmentations de Ca2+ induisent indépendamment l’activation et la relocalisation de Pyk2 dans le noyau en impliquant la calcineurine, probablement en amont de ces évènements. Nous avons la dépolarisation de la membrane induisait une accumulation nucléaire rapide et transitoire de Pyk2. Nous avons montré que cette relocalisation de Pyk2 dans le noyau était calcium-dépendante, mais indépendante de son autophosphorylation, de son activité kinase et du recrutement des kinases de la famille de Src. En revanche, nous avons démontré qu’en réponse à la dépolarisation, l’autophosphorylation et la localisation subcellulaire de Pyk2 sont régulées par une protéine sérine/thréonine phosphatase, la calcineurine. Afin de caractériser le mécanisme moléculaire permettant la régulation de la localisation de Pyk2, nous avons recherché les séquences responsables de son trafic nucléo/cytoplasmique. Nous avons utilisé une stratégie de délétion qui nous a permis d’isoléer une région de Pyk2, localisée entre les domaines kinase et FAT, nécessaire à lsa localisation cytoplasmique de Pyk2 contenantdans les cellules non stimulées. Nous avons démontré la présence d’ une séquence d’export nucléaire qui dans cette région, comprenant les résidus hydrophobes Leu-735, Phe-739, Val-741. Au cours de ces expériences, nous avons observé que cette région mimait en partie la régulation de la localisation de Pyk2 induite par la dépolarisation membranaire suggérant que l’accessibilité de ces séquences d’export et/ou d’import nucléaire est régulée au cours de la stimulation pour permettre la translocation nucléaire de Pyk2. De manière intéressante, la séquence d’export nucléaire que nous avons caractérisée appartient en partie à l’exon alternatif et n’est pas fonctionnelle dans l’isoforme spécifique des cellules hématopoïétiques révélant. Ces données suggèrent que cet épissage alternatif traduirait une spécificité tissulaire de lala régulation de sla localisation de Pyk2 mise en évidence par la dépolarisation membranaire. Nous avons également pu observéer une accumulation nucléaire de Pyk2 dans d’autres modèles, ainsi qu’ in vivo, suggérant l’existence des fonctions nucléaires de Pyk2 différentes de ses fonctions cytoplasmiques connues. L’ensemble de ces résultats permet de révéler que des augmentations de calcium induites par la dépolarisation membranaire induisent indépendamment l’activation de Pyk2 et sa re-localisation dans le noyau. Ces deux phénomènes impliquent la calcineurine, qui agit probablement en amont de ces évènements. D’autre part, la localisation cytoplasmique de l’isoforme neuronale de Pyk2 est assurée par une séquence d’export nucléaire située au niveau du site d’épissage alternatif, permettant d’appréhender les bases d’une spécificité neuronale Tyrosine kinase
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Lynch, Deborah Frances. "The role of tyrosine, serine and threonine phosphorylation in the regulation of the insulin receptor tyrosine kinase activity." Thesis, University of Bristol, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.282141.
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Ezumi, Yasuharu. "Differntial regulation of protein-tyrosine phosphatases by integrin α_β_3 through cytoskeletal reorganization and tyrosine phosphorylation in human platelets." Kyoto University, 1997. http://hdl.handle.net/2433/202159.
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Beslu, Nathalie. "Etude des interactions et de ses conséquences fonctionnelles, des substrats (PI3K, GRB2) du récepteur hématopoîétique à activité tyrosine kinase : flt3." Aix-Marseille 2, 1998. http://www.theses.fr/1998AIX22052.
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Le recepteur flt3 est un recepteur hematopoietique a activite tyrosine kinase de classe iii. L'interaction de ce type de recepteur avec leur ligand induit leur homodimerisation, et conduit a leur transphosphorylation sur les residus tyrosine. Ces residus une fois phosphoryles interagissent specifiquement avec les domaines sh2 de proteines cytoplasmiques, conduisant a la transduction du signal. Nous avons dans un premier temps, entrepris de muter ces residus tyrosine pour identifier les sites d'interaction de certains substrats avec flt3. Cela nous a permis de montrer que la sous-unite p#8#5 de la pi3'kinase interagit avec le residu y958 du recepteur, que les residus tyrosine 769 et 958 sont les sites d'interaction de la molecule adaptatrice grb2. Dans un deuxieme temps, nous avons etudie les consequences fonctionnelles de ces mutations en introduisant ces recepteurs mutes, par infection retrovirale, dans des populations cellulaires telles que : des fibroblastes, une lignee pro-lymphocytaire b et des cellules primaires mastocytaires. Nous avons montre que la perte d'interaction de la pi3k avec flt3 n'a pas d'effet sur l'internalisation du recepteur, ni sur le pouvoir mitogenique et transformant de ce dernier. De meme, la perte d'interaction de flt3 avec la proteine adaptatrice grb2 (mutations 769 et 958) n'a pas d'effet sur le pouvoir mitogenique du recepteur. En revanche, le pouvoir transformant de flt3 est tres fortement reduit. Cette inhibition est correlee a la perte de l'induction de l'activite mapkinase a long terme. Toutefois, l'inhibition de l'interaction de grb2 avec sos (activateur de la voie ras/mapk) a l'aide d'une drogue, n'a pas d'effet sur le pouvoir transformant de flt3 et restitue la capacite transformante du recepteur mute sur les 2 residus y769 et 958. L'interaction de grb2 avec le recepteur flt3 ne semble donc pas essentielle au pouvoir transformant de ce dernier. D'autres voies de transduction induites a partir de ces memes sites pourraient etre responsables de cette fonction.
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Le-Tien, Hoang Kim. "Regulation of protein tyrosine phosphatases by glucose." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0023/MQ50436.pdf.
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Jones, P. F. "Cloning and expression of tyrosine kinase genes." Thesis, University of Oxford, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.382626.
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Marshall, Stuart J. "GPIb-mediated tyrosine phosphorylation in human platelets." Thesis, University of Oxford, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275467.
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Boys, Sarah K. "Tyrosine derivatives and their anti-cancer applications." Thesis, University of Edinburgh, 2012. http://hdl.handle.net/1842/6243.
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The incorporation of a propargyl group to a natural product target allows for a streamlined approach to the investigation of structure activity relationships (SARs) and target identification in forward chemical genetics programmes using a ‘click’-based approach. To this end, an efficient synthesis of O-propargylated tyrosine derivatives was designed, and these have been used in the construction of peptide motifs both (a) derived from phage display libraries and (b) found in natural products. The L-tyrosine derivative Y* (compound I, X=H, R=H) was incorporated into a peptide sequence, PTTIYY, which is known to prevent the inhibition of p53 by the AG-2 protein. Y* has been included as both the terminal and the internal tyrosine in the peptide sequence. ELISA assays were carried out to determine how the binding of PTTIYY* and PTTIY*Y to AG-2 compared to that of the un-marked PTTIYY sequence. The results of these assays allowed new conclusions to be drawn regarding the important binding features of the peptide and possible sites for further optimisation of the AG-2 binding properties of this peptide through ‘click’ functionalisation of the modified tyrosine. The binding of the peptides incorporating Y* was also assessed using MCF-7 breast cancer cell lysate, known to contain the AG-2 protein. These results confirmed those seen for the purified AG-2 ELISA. The related bromo-D-tyrosine derivative (compound I, X=Br, R=Me) has been prepared and employed towards the synthesis of a bisebromoamide derivative. Bisebromoamide is a newly discovered polypeptide, and a promising anti-cancer agent. The bisebromoamide derivative contains a thiazole unit (Tzl), two N-methylated amino acids, and an oxopropyl pyrrolidine (Opp) moiety, which is unique to bisebromoamide in natural products. The activity of this bisebromoamide derivative will be investigated via ‘click’-based affinity chromatography using a new supported linker recently developed within the Hulme group.
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Cooper, Margaret S. "Anti-cancer peptides containing modified tyrosine residues." Thesis, University of Nottingham, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246193.
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Lannigan, Alison Kerr. "Tyrosine kinase growth factors in gastric cancer." Thesis, University of Glasgow, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394975.
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Achison, Marcus. "Collagen-induced tyrosine phosphorylation in human platelets." Thesis, University of Cambridge, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624884.
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Vavricka, Christopher John. "Mass Spectrometric Analysis of Tyrosine Metabolic Enzymes." Diss., Virginia Tech, 2009. http://hdl.handle.net/10919/28585.
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The metabolism of tyrosine is essential for many critical biochemical events including catecholamine synthesis, melanogenesis and insect cuticle sclerotization. These pathways are highly regulated in both insects and mammals by many well-characterized enzymes including dopa decarboxylase and tyrosine hydroxylase. On the other hand, there are still many enzymes involved in these processes that we know very little about. Dopachrome tautomerase (DCT), dopachrome conversion enzyme (DCE) and α-methyldopa resistant protein (AMD) fall into the category of the less characterized enzymes.
Dopachrome is a pivotal intermediate in melanogenesis. Mammalian DCT and insect DCE both use dopachrome as a substrate. DCE catalyzes a decarboxylative structural rearrangement of dopachrome to 5,6-dihydroxyindole (DHI), whereas DCT mediates the isomerization/tautomerization of dopachrome to 5,6-dihydroxyindole-2-carboxylic acid (DHICA). DHI is oxidized easily, leading to the production of melanin, as well as reactive oxygen species (ROS). DHICA is less reactive, relative to DHI, and consequently produces less toxic byproducts during melanogenesis; therefore DCT plays an important role in detoxification of DHI and ROS.
Purification and MS analysis of DCE and DCT determined that N-glycosylation is a primary post-translational modification. Q-TOF mass spectrometry was used to determine N-glycosylation patterns from Aedes aegypti DCE and MALDI-TOF/TOF was used to determine multiple glycosylation sites in DCT. N-glycosylation is critical for the folding and trafficking of secreted proteins in the endomembrane system. The analysis of glycosylation sites in DCE and DCT therefore is essential toward achieving a comprehensive understanding of their structure and function.
Like DCT, AMD also plays a protective role. The AMD protein was originally identified in Drosophila mutants hypersensitive to α-methyldopa, an inhibitor of dopa decarboxylase (DDC). Production of dopamine by DDC is critical for developing insects because dopamine conjugates are used as crosslinking agents for cuticle sclerotization. Although there has been much discussion into the function of AMD, what exactly this protein does has been unknown. AMD shares 48% sequence identity with DDC, however we have found that AMD is an enzyme, which possesses a different catalytic activity. GC-MS analysis of AMD enzymatic reaction components revealed that AMD catalyzes the oxidative decarboxylation of L-DOPA to DOPAL, and also the oxidative decarboxlation of α-methyldopa to 3,4-dihydroxyphenylacetone.
In summary, multiple N-glycosylation sites were characterized in DCT and DCE, furthermore a new protein function has been demonstrated for AMD. These experiments were performed using classical biochemistry techniques in combination with mass spectrometry.Ph. D.
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Zhai, Yujing. "Specificty and Inhibition of Protein Tyrosine Phosphatases." The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1429223068.
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Carvalho, Sara da Costa Cabral Pires. "Receptor Tyrosine Kinases interactions in human cancers." Master's thesis, Universidade de Aveiro, 2009. http://hdl.handle.net/10773/838.
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Mestrado em Biologia Molecular e CelularObjectivos: Os receptores tirosina cinase MET, ErbB-2 e EGFR foram identificados como tendo um papel importante no desenvolvimento e progressão de cancro. O objectivo deste estudo foi determinar a expressão e procurar interacções dos receptores MET, ErbB-2 e EGFR em linhas celulares de carcinomas de tiróide e mama, e em tumores mamários. Métodos: Neste estudo a expressão e interacções dos receptores MET, ErbB-2 e EGFR foi determinada em duas linhas celulares de carcinoma da tiróide (TPC-1 e 8505C) e em duas linhas celulares de carcinomas da mama (MDAMB- 231 e SkBr3). A expressão de MET foi também estudada, por Imunohistoquímica, numa serie de 219 carcinomas invasivos da mama, em microarrays, com um acompanhamento dos pacientes de 13 anos. Resultados: Observámos que MET, ErbB-2 e EGFR são expressos em todas as linhas de tiróide e mama, e observámos também interacções entre MET e ErbB-2. Na série de tumores mamários a expressão de MET foi significativamente relacionada com factores de prognóstico bem estabelecidos como ErbB-2, receptor de estrogénio, grau histológico e subtipos moleculares, sendo também significativamente associada com a diminuição da sobrevida das pacientes. Por análise multivariada MET demonstrou ter um valor prognóstico independente. Conclusões: O nosso estudo sugere que a comunicação entre MET e ErbB-2 pode ter um importante impacto clínico-patológico e que merece uma futura investigação, nomeadamente ao nível do desenvolvimento de novas terapêuticas. ABSTRACT: Aims: Receptor tyrosine kinases (RTKs) MET, ErbB-2 and EGFR have been identified to play an important role in cancer development and progression. Our aim was to determine MET, ErbB-2 and EGFR expression and search for their interactions in thyroid and breast carcinoma-derived cell lines and human breast tumours. Methods: We have studied the RTKs expression and interactions in two thyroid carcinoma-derived cell lines (TPC-1 and 8505C) and in two breast carcinomaderived cell lines (MDA-MB-231 and SkBr3). We have also studied, by Immunohistochemistry, MET expression on a series of 219 invasive breast carcinomas with 13-year disease follow, using tissue-microarray. Results: We observed that MET, ErbB2 and EGFR were expressed in both thyroid and breast cell lines, and we found physical interactions between MET and ErbB2. In the series of breast tumours, MET expression was significative correlated with established prognostic factors such ErbB-2, oestrogen receptor (ER), grade and subtype, and was also significatively associated with poor clinical outcome of the patients. By multivariate analysis MET showed to have an independent prognostic value. Conclusions: Our study suggests that the cross-communication between MET, and ErbB-2 may have clinicopathological impact and deserves further analysis namely in the design of novel combined therapeutic approaches.
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Halloran, Stephen Mitchell. "Regulation of tyrosine hydroxylase by protein phosphorylation /." For electronic version search Digital dissertations database. Restricted to UC campuses. Access is free to UC campus dissertations, 2003. http://uclibs.org/PID/11984.
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Kim, Yohan. "Tau associates with protein tyrosine phosphatase SHP2." Diss., University of Iowa, 2017. https://ir.uiowa.edu/etd/5535.
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The microtubule-associated protein tau normally functions to bind to and stabilize microtubules. However, evidence now indicates that tau may also play a critical role in signaling pathways linked to neuronal development and neurodegeneration. The tau association with numerous signaling proteins such as tyrosine kinases, adaptor proteins, and scaffold proteins support this hypothesis. Phospho-Y18 tau was previously found in Alzheimer’s disease (AD) brain. Interestingly, this phosphorylation appeared to be regulated during neurodegeneration possibly by a tyrosine phosphatase(s). Identifying a candidate phosphatase, our lab found the association between tau and SHP2 in a neuronal cell line and dephosphorylation of phospho-Y18 by protein tyrosine phosphatase SHP2 in vitro. Since both tau and SHP2 play a critical role in NGF-induced signaling pathway, these findings raised the possibility that the tau-SHP2 association has a role in NGF signaling.
The aim of this dissertation research is to characterize the tau-SHP2 association and its role in neuronal signaling. Here, we provide evidence that tau phosphorylation is not required for SHP2 association but significantly enhances the interaction. The SHP2 binding region of tau napped to residues 256-273, which contain the microtubule binding repeat 1 of tau. Using in situ proximity ligation assay (PLA), we also showed the presence of endogenous tau-SHP2 and tau-activated SHP2 complexes in neuronal cells. The number of complexes was increased in the cells in response to NGF. Our PLA data also showed the localization of these complexes to actin ruffles. In NGF signaling, we showed that phosphorylation at T231 of tau was necessary for the increase in tau-SHP2 association. Lastly, we provide evidence that tau-SHP2 complexes are present in mouse primary neuronal cultures and mouse brain sections. Together, these findings show a role for tau phosphorylation in SHP2 binding and a potential role for tau-SHP2 interaction in neuronal signal transduction. Based on our findings, we speculate that there is a role for tau-SHP2 association during early brain development and in neurodegenerative disease.
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Kuczek, Elizabeth Salome. "High-glycine/tyrosine keratin genes of wool." Title page, contents and summary only, 1985. http://web4.library.adelaide.edu.au/theses/09PH/09phk95.pdf.
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BESTETTI, STEFANO. "AQP8, a redoxtat controlling tyrosine kinase signalling." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2017. http://hdl.handle.net/10281/170789.
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AQP8-mediated H2O2 transport allows efficient amplification of tyrosine kinase signalling, therefore influencing pathways frequently dysregulated under tumour progression. Besides, control of H2O2 cell permeability impacts life-death cell decisions in response to stress. Despite the important consequences of AQP8 gating, the precise biochemical modification that inhibits H2O2 transport still remains to be identified. We show here that the mechanism of regulation implies sulphydration of AQP8. Addition of an exogenous H2S donor (NaHS) is sufficient to block H2O2 entry and dampen EGF receptor signalling, bypassing stress. Moreover, cells expressing non-inhibitable AQP8 mutant (e.g. C53S) are able to transport H2O2 also upon H2S treatment. Stress-induced blockade of transport requires cystathionine-beta-synthase, a key enzyme in the transulphuration pathway. These findings identify a novel circuit modulating the strength and duration of key signalling pathways based on AQP8 regulation by sulphydration.AQP8-mediated H2O2 transport allows efficient amplification of tyrosine kinase signalling, therefore influencing pathways frequently dysregulated under tumour progression. Besides, control of H2O2 cell permeability impacts life-death cell decisions in response to stress. Despite the important consequences of AQP8 gating, the precise biochemical modification that inhibits H2O2 transport still remains to be identified. We show here that the mechanism of regulation implies sulphydration of AQP8. Addition of an exogenous H2S donor (NaHS) is sufficient to block H2O2 entry and dampen EGF receptor signalling, bypassing stress. Moreover, cells expressing non-inhibitable AQP8 mutant (e.g. C53S) are able to transport H2O2 also upon H2S treatment. Stress-induced blockade of transport requires cystathionine-beta-synthase, a key enzyme in the transulphuration pathway. These findings identify a novel circuit modulating the strength and duration of key signalling pathways based on AQP8 regulation by sulphydration.
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Andersson, Jeanette. "Finns det något värde i att mäta Peptide tyrosine tyrosine, Glucose-dependent insulinotropic polypeptide och Oxyntomodulin postprandialt vid måltidsstudier?" Thesis, Linnéuniversitetet, Institutionen för kemi och biomedicin (KOB), 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:lnu:diva-45009.
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Övervikt och fetma sprider sig likt en epidemi över världen. Omkring 1,9 miljarder vuxna varöverviktiga år 2014 och av dessa klassificerades 600 miljoner som feta. Forskning kring fetmas uppkomst och nya former av behandlingsalternativ pågår. En viktig faktor för uppkomst av övervikt är aptitreglering, där t.ex. Peptide tyrosine tyrosine (PYY), Oxyntomodulin (OXM) och Glucosedependent insulinotropic polypeptide (GIP) har betydelse. En litteraturstudie genomfördes där totalt nio originalartiklar från PubMed utvärderades. Syftet var att undersöka om det finns något värde i att mäta dessa hormon postprandialt. Finns det någon skillnad mellan normalviktiga, överviktiga och obesa och finns det någon skillnad mellan individer med typ 2-diabetes mellitus (T2DM) och friska individer? Finns det någon pålitlig analysmetod? Samtliga studier var måltidsstudier där olika näringsämnens påverkan på den postprandiala responsen undersöktes. Peptide tyrosine tyrosine ochGlucose-dependent insulinotropic polypeptide mättes i sex resp. fem av artiklarna och OXM mättes ien artikel. Protein, fett och kolhydrater ger en postprandial respons på PYY och GIP. Responsen av PYY var starkast efter stimuli från fett och protein. Fett tycks ge starkast respons på GIP. Fastevärden av PYY och GIP var inte olika hos normalviktiga och överviktiga i de studier som undersöktes. Det fanns en signifikant skillnad (p=0,01) mellan normalviktiga och överviktiga tonårsflickor av den postprandiala utsöndringen av PYY efter fettrik måltid, där de obesa flickorna hade lägre procentuell ändring jämfört med de normalviktiga. Pålitliga analysmetoder vid koncentrationsbestämning av dessa tre hormon i plasma är Radioimmunoassay (RIA) och Enzyme-linked immunosorbent assay (ELISA).
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Franck, Dominic. "Radiofluorinated cyclobutyl group for increased metabolic stability using tyrosine derivatives as model system." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2012. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-99003.
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The metabolic stability of these tracers is, in addition to its affinity and selectivity, an important factor for a successful disease diagnosis. PET tracers and all other drugs are subject to biotransformation which can form metabolites as a part of the inactivation or detoxification process of the human body. These metabolites may result in a higher background which has a detrimental influence on the PET image quality or can even make imaging impossible. The aim of this work was to investigate whether [18F]fluorocyclobutyl rings can be introduced into biologically active small molecules to improve metabolic stability of the PET tracer while maintaining or improving the binding affinity and lipophilicity. To test this hypothesis, the tyrosine model compound, O-(3-[18F]fluorocyclobutyl)-L-tyrosine (L-3-[18F]FCBT), was chosen to be investigated. Precursors for the indirect and direct radiolabeling as well as the non-radioactive L- and D-3-FCBT were successfully synthesized. The radiolabeled of L-3-[18F]FCBT were produced via the indirect and direct method in sufficient yield and activity for the biological evaluation.
In the biological characterization, L-3-[18F]FCBT showed good tumor uptake in human lung carcinoma cell lines (A549) and was able to be blocked by both non-radioactive L-3-FCBT and non-radioactive FET. In the biodistribution study, the tracer demonstrated tumor uptake and high metabolic stability due to non accumulation of activity in bone. These results were consistent with the animal-PET imaging where L-3-[18F]FCBT showed good tumor uptake and no accumulation of activity in the bone. The D-isomer in comparison with the L-isomer was found to give lower tumor uptake and very low accumulation in the pancreas. The in vitro stability of the L-3[18F]FCBT in human and rat plasma was excellent over 120 minutes. In vivo stability in mice showed very little metabolites and L-3-[18F]FCBT is considered to be stable in vivo.
These results have shown that the new [18F]fluorocyclobutyl group has the potential for the preparation of metabolically stable radiotracers and the application looks very promising.
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Lermet, Anne. "Synthèse d'inhibiteurs de la protéine à activité tyrosine kinase c-kit de type sauvage et muté." Lyon 1, 2006. http://www.theses.fr/2006LYO10026.
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