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1
Barbera, Stefano. "The C-type lectin CD93 in physiological and pathological angiogenesis." Doctoral thesis, Università di Siena, 2022. http://hdl.handle.net/11365/1193440.
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Formation of blood vessels is required for development, growth and healing. Although quiescent, endothelial
cells (ECs) store a potent proliferative and invasive potential that, upon the appropriate stimuli, is unleashed
and gives rise to neovascularization phenomena.
Disease progression of cancer and neovascular age-related macular degeneration (nAMD) strongly depends
on angiogenesis. In cancer, tumor cells are able to stimulate ECs to become angiogenic and form new blood
vessels that allow them to fulfill their tendency to grow and escape the site of the primary tumor. In nAMD,
instead, inflammation and drusen deposition induce a strong damage to the retinal pigment epithelium
(RPE), which in response to the damage triggers abnormal vessel formation that directly causes disease
progression and consequent vision loss. In light of the role that angiogenesis plays in these diseases,
targeting blood vessels with anti-angiogenic drugs has always been an appealing concept. However, due to
the partial failure of anti-angiogenic therapies in the treatment of such diseases, it has become crucial to find
alternative strategies that rely on targeting new molecules in a way to show great efficacy with minimal toxic
effects.
CD93 is a transmembrane glycoprotein that has been shown to have a prevalent role in controlling EC
function, such as cell adhesion and migration. In this work, we investigated the molecular pathways behind
the function of CD93 as regulator of EC adhesion and migration, showing that CD93 regulates actin
dynamics via the small GTPases Rac1, Cdc42 and RhoA in a signaling axis triggered by its phosphorylation
and interaction with Cbl phosphorylated on tyrosine 774. We also gained insights on the functional transport
of CD93 during adhesion and migration, demonstrating that it is regulated by both its cytoplasmic domain
and the Rab5C-
2
Seo, Wooseok. "Functional analysis of murine CD43 shedding : a role for the CD43 cytoplasmic tail in nuclear signalling." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/629.
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CD43, a representative of the leukocyte mucin family proteins, is a transmembrane protein highly expressed on most lymphohemopoietic cells and is believed to play a role in the regulation of leukocyte activation and/or migration. CD43 was shown to be proteolytically shed from human cells and high concentrations of soluble CD43 have been found in human plasma. The biological significance of CD43 shedding however remains enigmatic.
To study the functional significance of CD43 shedding, we initiated our study by investigating whether CD43 shedding also occurs in the murine system and confirmed using flow cytometry, Western blot and ELISA techniques that murine CD43 is cleaved from the cell surface as is observed in the human system. To examine the biological significance of CD43 shedding, we designed and constructed non-sheddable forms of murine CD43. Ectopic expression of non-sheddable CD43 molecules in primary CD43 deficient bone marrow cells showed that these CD43 mutants have serious negative impacts on cell viability, revealing CD43 shedding as an essential process and implying that the CD43 mutants interfered with intracellular signaling processes. Our data support the hypothesis that CD43 ectodomain shedding is a requirement for release of the cytoplasmic domain and its translocation to the nucleus. In support of our hypothesis, we confirmed that the CD43 cytoplasmic domain is localized in the nucleus and is modified by SUMO (small ubiquitin-like modifier) peptides. In an attempt to determine the functional significance of CD43 nuclear translocation and SUMO modification, we examined nuclei from hemopoietic cells more closely and observed that the CD43 cytoplasmic tail is localized in a subnuclear structure called promyelocytic nuclear bodies, which control many nuclear functions including apoptosis. Consistent with this observation we find that leukocytes from CD43 deficient mice have an increased apoptotic response upon growth factor withdrawal. We conclude that nuclear translocation of the CD43 cytoplasmic tail serves to control the apoptotic response in leukocytes and that CD43 functions as an anti-apoptotic molecule.
3
Greaves, Sarah Jennifer. "Analysis of cd9b in CXCR4b signalling." Thesis, University of Sheffield, 2016. http://etheses.whiterose.ac.uk/13921/.
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CXCR4b, CXCR7b and their ligand, CXCL12a, are essential for the migration of the posterior lateral line primordium (pLLP) and primordial germ cells (PGCs) in zebrafish (Dambly-Chaudière et al. 2007, Boldajipour et al. 2008). A number of tetraspanins have been shown to affect CXCR4-mediated processes through regulating CXCR4 trafficking or downstream signalling (Yoshida et al. 2008, Li et al. 2011, Leung et al. 2011). Based upon these results we set out to identify candidate tetraspanins that may play a similar role in CXCR4b signalling during pLLP and PGC migration. CD9b, one of the zebrafish homologs of human CD9, was identified as a good candidate gene. Morpholino knock down of cd9b, using either a translation-blocking or splice-site blocking morpholino, resulted in reduced neuromast deposition and abnormal structure of the posterior lateral line. However, morpholinos often have nonspecific effects and so two CD9b knockout lines were created using TALENs. Surprisingly CD9b homozygous mutants showed normal lateral line structure. Preliminary results suggest that the phenotype differences between CD9b morphants and mutants may be due to residual functionality in the wildtype N-terminal of CD9b, upstream of the mutation site, in CD9b mutants. As well as assessment of PGC and pLLP migration, CD9b mutants were also assessed for fertility defects. Significantly reduced numbers of pups are born to CD9 knockout mice. This is due to a requirement of CD9 on the egg membrane for efficient sperm-egg fusion in the CD9-/- female mice (Kaji et al. 2000, Le Naour et al. 2000, Miyado et al. 2000). CD9b -/- zebrafish also appear to have fertility defects. Fewer eggs were laid by CD9b -/- zebrafish pairs and of the eggs laid, a lower percentage were fertilised.
4
Brosig, Susann. "Signaltransduktion von CD97 in humanen Fibrosarkomzellen." Doctoral thesis, Universitätsbibliothek Leipzig, 2015. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-164004.
Full textAbstract:
CD97 gehört zur Familie der Adhäsions-G-Protein gekoppelten Rezeptoren (aGPCR), die aus einem langen extrazellulären N-terminalen Fragment (NTF) und einem nicht-kovalent gekoppelten C-terminalen Fragment (CTF) mit der sieben-transmembranären (TM7) Region und dem intrazellulären Teil bestehen. CD97 wird in malignen Tumoren exprimiert. In der humanen Fibrosarkomzelllinie HT1080 steigert die stabile Überexpression von CD97 die ungerichtete zweidimensionale (2D) Migration einzelner Zellen. Eine Verkürzung von CD97 im CTF auf zwei transmembranäre (TM2) Domänen führt zu einer Suppression der 2D-Migration im Vergleich zu stabil mock-transfektierten HT1080 Kontrollzellen. Wahrscheinlich supprimiert CD97/TM2 die endogene CD97-Wirkung. Unbekannt ist, welche Signalwege durch CD97-Überexpression in HT1080 reguliert werden und welche Signalwege für die Migrationssteigerung von HT1080 verantwortlich sind. Die Klärung dieser Signalwege ist Gegenstand der vorliegenden Arbeit.
Die Phosphorylierung von Proteinkinasen ist eine posttranslationale Modifikation zur Regulation der Kinaseaktivität mit nachfolgender Aktivierung oder Inaktivierung eines Signalweges. Daher sind Expression und Phosphorylierung der Proteinkinasen zur Identifikation regulierter Signalwege interessant. Dazu wurden in Lysaten von CD97/TM7, CD97/TM2 und mock-transfektierten HT1080 mittels Kinetworks Phosphosite Screen KPSS 1.3 Profiling (Multi-Immunoblot™) 37 verschiedene Proteinphosphorylierungen untersucht und regulierte Signalwege identifiziert. An 25 Phosphorylierungsstellen erfolgt eine Regulation durch CD97. Anschließend wurden die Ergebnisse der interessantesten Proteine hinsichtlich ihrer Expression und Phosphorylierung im Western Blot verifiziert und um Proteine erweitert, die klassisch an der Regulation der Zellmigration beteiligt sind. Es zeigt sich eine Aktivierung des PI3-Kinase/Akt-Signalweges und eine Inhibierung von Src durch CD97. 2D-Migrationsversuche von HT1080 CD97/TM7, CD97/TM2 und mock mit spezifischen Inhibitoren gegen den PI3-Kinase/Akt-Signalweg und gegen Src bestätigen, dass diese Kinasen an der CD97-induzierten Steigerung der 2D-Migration beteiligt sind. Weiterhin finden sich Hinweise, dass in HT1080 CD97 die Apoptose hemmt und die Proliferation reguliert.
Insgesamt wird in dieser Arbeit ein Überblick über die durch CD97 regulierten Signalwege gegeben. Die CD97-gesteigerte 2D-Migration von HT1080 wird durch eine Aktivierung des PI3-Kinase/ Akt-Signalweges und Inhibierung von Src vermittelt.
5
Thomas, Mélissa. "Etude de la voie non-apoptotique de CD95 et de l’implication du facteur d’initiation de la traduction eIF4A1." Thesis, Rennes 1, 2018. http://www.theses.fr/2018REN1B048.
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Depuis sa découverte en 1991, l’implication du récepteur CD95 dans l’induction de l’apoptose a été plus que largement décrite. Mais bien qu'ayant été identifié comme étant un récepteur de mort, CD95 est aussi capable d'induire un signal pro-oncogénique lorsqu'il est fixé au CD95L clivé. L’activation de cette voie de signalisation non-apoptotique par le s-CD95L contribue au processus inflammatoire dans le lupus et à la dissémination métastatique dans les cancers du sein triples négatifs. Cependant aucun traitement thérapeutique satisfaisant n’est à ce jour disponible. De par son implication dans des pathologies cancéreuses et inflammatoires, mieux comprendre les mécanismes à l’origine de la double signalisation de CD95 n’est plus un enjeu mais une nécessité. Afin de développer des molécules pour bloquer la signalisation non apoptotique de CD95, il est essentiel d’en identifier tous les protagonistes et de définir leur fonction biologique. C’est avec cet objectif que notre équipe a mené deux études protéomiques dont les résultats ont permis d’identifier eIF4A1 comme un nouveau partenaire direct de CD95. Nous montrons que eIF4A1 est indispensable à la mise en place de la signalisation pro-motile de CD95 dépendante de la voie PI3K. De plus eIF4A1 est recruté à la membrane ainsi que les autres protéines du complexe eIF4F. Nos données de séquençage ont montré que de par cette interaction, CD95 recrute à la membrane un ensemble d’ARNm impliqués dans la réponse immunitaire et l’adhésion cellulaire. En outre, une perte de CD95 dans certaines cellules cancéreuses conduit à la perte d’expression de ces ARNm. Ainsi CD95 pourrait protéger certains ARNm de la dégradation et favoriser la traduction des ARNm pro-inflammatoires de manière indépendante du ligand. Cibler spécifiquement cette interaction pourrait être une piste thérapeutique prometteuse dans la lutte contre les cancers du sein triples négatifs mais aussi contre le lupusSince its discovery in 1991, the involvement of the CD95 receptor in the induction of apoptosis has been more than widely described. But although identified as a death receptor, CD95 is also capable of inducing a pro-oncogenic signal when attached to the cleaved CD95L. Activation of this non-apoptotic signaling pathway by s-CD95L contributes to the inflammatory process in lupus and metastatic spread in triple negative breast cancers. However, no satisfactory therapeutic treatment is currently available. By its implication in cancerous and inflammatory pathologies, better understanding the mechanisms at the origin of the double signaling of CD95 is no longer an issue but a necessity. In order to develop molecules to block the non-apoptotic CD95 signaling, it is essential to identify all the protagonists and define their biological function. Our team conducted two proteomic studies, the results of which identified eIF4A1 as a new direct partner of CD95. We show that eIF4A1 is essential for the implementation of PI3K pathway-dependent CD95 signaling. In addition eIF4A1 is recruited to the membrane as well as the other eIF4F complex proteins. Our sequencing data showed that by this interaction, CD95 recruits a set of mRNAs involved in the immune response and cell adhesion. In addition, a loss of CD95 in some cancer cells leads to the loss of expression of these mRNAs. Thus CD95 could protect certain mRNA from degradation and promote the translation of pro-inflammatory mRNAs independently of the ligand. Specific targeting of this interaction could be a promising therapeutic avenue in the fight against triple negative breast cancers but also against lupus
6
Georgieva, Petya [Verfasser]. "Microglial purinergic signaling in mouse models of CD39 deficiency and schizophrenia / Petya Georgieva." Berlin : Freie Universität Berlin, 2015. http://d-nb.info/1069290173/34.
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Yamaoka, Ryoya. "CD90 expression in human intrahepatic cholangiocarcinoma is associated with lymph node metastasis and poor prognosis." Kyoto University, 2019. http://hdl.handle.net/2433/242375.
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Doma, Eszter. "Identification of noval critical steps in the early and late Fas signaling pathway : the role of Fas tyrosine phosphorylation and the formation of Fas complexes." Nice, 2009. http://www.theses.fr/2009NICE4078.
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Fas est un récepteur de mort de la superfamille des récepteurs au TNF (TNFR). Il est exprimé constitutivement dans de nombreux tissus et joue un rôle important dans l’homéostasie lymphocytaire. Suite à la liaison de son ligand (FasL), il est rapidement internalisé puis recrute les protéines FADD et procaspase-8 pour former le DISC (death-inducing signaling complex), conduisant ainsi à l��activation des caspases et la mort de la cellule. De nombreux travaux suggèrent que Fas, en plus d’être un récepteur de mort, peut transmettre des fonctions alternatives ou de survie. Or, le mécanisme moléculaire contrôlant l’orientation de la signalisation vers ces fonctions n’est pas élucidé. Cette thèse est focalisée sur deux aspects différents de la signalisation par Fas afin de préciser ses mécanismes de régulation. Deux tyrosines intracellulaires de Fas sont localisées dans des motifs importants pour la phosphorylation et l’internalisation. Nous avons démontré que ces deux résidus ont un rôle critique dans la mort induite par Fas. Cependant, ils ont profil de phosphorylation différent et recrutent différents adaptateurs ? Ainsi, comme d’autres importants régulateurs de la signalisation de Fas, son profil de phosphorylation pourrait représenter un des événements précoces responsable de la bifurcation du signal vers des voies de mort ou de survie. Pendant la phase d’exécution de la mort par Fas, nous avons observé la formation de différents complexes de Fas stables en présence de SDS. Ceci a lieu en aval du DISC et nécessite l’activité des caspases. Ces complexes diffèrent entre eux quant à la nécessité d’un cytosquelette d’actine et microtubulaire intègre pour leur formation. Ainsi, nous avons identifié un nouveau rôle des microtubules dans l’organisation des molécules de Fas pendant l’apoptose. L’ensemble de ces résultats a é=révélé certaines nouvelles étapes dans les phases très précoces et tardives de la signalisation par Fas et qui contribuent à la compréhension de la versatilité fonctionnelle de FasFas is a prototypic death receptor of the tumor necrosis factor receptor (TNFR) superfamily. It is constitutively expressed in a wide range of tissues and plays a particularly important role in the lymphocyte homeostasis. Upon engagement by its ligand (FastL), it undergoes rapid internalization, whereupon the adapter FADD and the caspase-8 proenzyme are recruited to form the death-inducing signalling complex (DISC), leading to caspase activation and cell death. Accumulating evidence suggests that Fas, besides being a death-inducing receptor, can also mediate a variety of non-death activities. However the precise molecular mechanism of the divergence of these two pathways is not fully understood. This thesis is focused on two different aspects of the Fas signalling in order to gain deeper in sight in its precise regulation. We found that the intracellular tyrosines of Fas are located in important phosphorylation and internalization sorting motives, and therefore focused on the role of the receptor tyrosine phosphorylation. We show that the two tyrosine residues are critical for Fas mediated cell death. However they have different phosphorylation pattern and adaptor recruitments. As important regulators of internalization and downstream signalling, Fas tyrosine phosphorylation pattern might be one of the early events which are responsible for the bifurcation of the cell death and survival pathways. At the execution phase of FasL-induced apoptosis we noticed the formation of distinct SDS-stable Fas complexes. This complex formation occurs downstream of the DISC assembly and requires distinct caspase activities. Subgroup of Fas complexes differ in the requirement for the integrity of actin and microtubular cytoskeleton. Consequently, we identified a novel role of microtubule in the organization of Fas molecules during apoptosis. Altogether, the findings reveal some new steps in the very early and late stages of Fas signalling which contribute to the understanding of its functional versatility
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Pawar, Pritish Subhash. "Calmodulin binding to cellular FLICE like inhibitory protein modulates Fas-induced signaling and tumorigenesis in cholangiocarcinoma." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2008. https://www.mhsl.uab.edu/dt/2008p/pawar.pdf.
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Chen, Si [Verfasser], and Ana [Akademischer Betreuer] Martin-Villalba. "The CD95/CD95L signaling system in developmental and tumor angiogenesis of the central nervous system / Si Chen ; Betreuer: Ana Martin-Villalba." Heidelberg : Universitätsbibliothek Heidelberg, 2018. http://d-nb.info/1177688484/34.
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Hidalgo, Sastre Ana. "Crosstalk between Notch and Wnt signalling pathways in vertebrates." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/crosstalk-between-notch-and-wnt-signalling-pathways-in-vertebrates(9b4411a3-cd03-4af3-b3b5-8c432c7a2c68).html.
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The development of complex metazoans depends on the integration of a handful of signalling pathways that eventually modulate precise patterns of gene expression. The fact that just a few pathways are involved in the generation of such complexity in different organisms, suggests that these are highly regulated and conserved processes. The accurate spatio-temporal coordination of the signalling pathways controls the assignation of different cell fates and their patterning into tissues and organs. The source of diversity relies on the different possible interactions between signalling pathways, such as, the combination of signals and the order in which they are received by the cell or crosstalk. Due to their importance in development, abnormal signalling through these pathways has been strongly associated with developmental disorders, cancers and other diseases. The Notch and Wnt signalling pathways are key components of the intricate network that controls gene expression during development, and genetic analysis in Drosophila has highlighted that interactions between these two signalling pathways are important during this process.This thesis investigates the cross-regulatory interactions between Notch and Wnt signalling pathways in mammals. Using transcriptional reporter assays and biochemical analysis, I have found two molecular mechanisms underlying the inhibitory crosstalk between Notch and β-catenin, the effector of Wnt signalling pathway, in mammalian cells. At the membrane Notch inhibits β-catenin transcriptional activity through Deltex mediated endocytosis of Notch and a component required for β-catenin activation. This is similar to results observed in Drosophila. In the nucleus, I have identified a novel mechanism by which NICD-dependent transcription of Hes/Hey family of transcription factors prevents the activation of Wnt signalling pathway. This mechanism involves the formation of a physical complex between Hey1 and β-catenin/TCF, which allows Hey to block Wnt transcriptional activation. Additionally, I have found that these two mechanisms are conserved across vertebrates.Together the findings of this thesis improve our understanding of the molecular mechanism underlying the Notch/Wnt crosstalk. In turn, this will give an insight into unravelling how a handful of signalling pathways can generate sufficient diversity in signalling output to specify the hundreds of different cell fates generated to make a mammal. Elucidating these signalling networks will also contribute to our understanding of diseases, both their aetiology, by knowing how changes in one signal can influence another, and their treatment as mimicking points of crosstalk is likely to generate very specific therapeutic agents.
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Kral, Rosana Maria. "The versatility of Fas in death and survival signalling : role of a basic motif in the membrane-proximal intracellular region of the receptor." Nice, 2009. http://www.theses.fr/2009NICE4061.
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The receptor Fas/CD95 can trigger cell death if activated by its ligand, FasL. In addition, Fas can mediate proliferation and differentiation. An imbalance between these life-and-death decisions can cause diseases (e. G. Cancer), thus understanding how these different pathways are controlled is important for the development of therapeutic strategies. Our objective is to dissect the initial events of Fas-mediated signalling at the plasma membrane, focussing on the role of specialized nanodomains enriched in sphingolipids and cholesterol (SCNs or lipid rafts). Chakrabandhu et al. (2007) showed that palmitoylation of an intracellular cysteine constitutively targets a fraction of Fas to SCNs. FasL rapidly induces raft recruitment of partners to form the death-inducing signalling complex (DISC). Efficient DISC formation then occurs upon raft-dependent receptor internalization. Here we provide evidence for a second determinant of Fas SCN localization, a membrane-proximal intracellular group of basic residues. Despite being palmitoylated, a receptor mutated at these residues showed reduced SCN association and consequently, diminished ability to relay the death signal. This mutant also showed exacerbated promotion of non-death signals, as well as increased interaction with the actin cytoskeleton, that had previously been held to depend on SCN localization of Fas. This basic region is similar to motifs that target proteins to phosphoinositides (PIs), suggesting a potential link between Fas and PIs. These versatile regulatory lipids are rapidly convertible and can tightly control the presence of membrane-anchoring sites for proteins. We also studied this potential linkLe récepteur Fas/CD95 peut induire la mort cellulaire s’il est activé par son ligand, FasL. Fas peut aussi induire la prolifération et la différenciation. Une imbalance entre ces décisions de mort et survie peut entraîner des maladies (p. E. Cancer). Comprendre comment ces voies différentes sont contrôlées est important pour dévélopper des stratégies thérapeutiques. Notre objectif est de disséquer les evenements précoces de la signalisation de Fas à la membrane plasmique, en focalisant sur le rôle de domaines spécialisés, riches en sphingolipides et choléstérol (rafts). Chakrabandhu et al. (2007) ont identifié la palmitoylation d’un cystéine intracellulaire comme signal d’adressage constitutif de Fas aux rafts. FasL induit le recrutement rapide de partenaires aux rafts pour la formation du DISC (death-inducing signalling complex). Le DISC est formé plus efficacement après l’internalisation raft-dépendante de Fas. Ici, nous avons identifié un deuxième signal d’adressage aux rafts, un groupe intracellulaire de résidus basiques. Quoiqu’étant palmitoylé, un récepteur muté était moins associé aux rafts et, par conséquence, montrait une induction réduite du signal de mort. Ce mutant induisait des signaux de survie excessifs et montrait une association accrue avec le cytosquélette d’actine, qui a été considérée auparavant être dépendante de l’association aux rafts. Cette région basique est similaire aux motifs qui permettent l’interaction avec des phosphoinositides (PI), suggérant un lien potentiel entre Fas et les PI. Ces lipides versatiles sont rapidement convertibles et peuvent réguler la présence de sites d’ancrage pour des protéines à la membrane. Nous avons étudié ce lien
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Leve, Simone de [Verfasser], and Verena [Akademischer Betreuer] Jendrossek. "Role of radiation-induced immune changes for normal tissue toxicity with a focus on CD73/adenosine signaling and macrophages / Simone de Leve ; Betreuer: Verena Jendrossek." Duisburg, 2017. http://d-nb.info/1129598284/34.
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Papargyris, Loukas. "Mécanismes de génération des macrophages immunorégulateurs humains : rôle de l’axe IL-27 / Adénosine / PGE2 The ecto-ATPDase CD39 is involved in the acquisition of the immunoregulatory phenotype by M-CSF-macrophages and ovarian cancer tumor-associated macrophages: Regulatory role of IL-27 Faecalibacterium prausnitzii Skews Human DC to Prime IL10-Producing T Cells Through TLR2/6/JNK Signaling and IL-10, IL-27, CD39, and IDO-1 Induction." Thesis, Angers, 2019. http://www.theses.fr/2019ANGE0038.
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Ce projet de thèse s’inscrit dans l’étude des mécanismes moléculaires associés à la polarisation des macrophages humains vers un phénotype immunorégulateur similaire à celui des macrophages tumoraux (TAM). Des données du laboratoire avaient montré le rôle de l'IL-27 dans ce processus, notamment au travers de sa capacité à moduler l'expression de CD39 qui contrôle, au moins en partie, l’acquisition d’un phénotype immunorégulateur par les macrophages humains. L’objectif de ce travail a été de préciser les mécanismes moléculaires impliqués dans l’acquisition du phénotype régulateur, en aval de l’IL-27. Les résultats confirment le rôle central de l’adénosine, et donc de l’ectonucléotidase CD39, et identifient la molécule PGE2 dans la polarisation fonctionnelle des macrophages immunorégulateurs. Ces données confirment l'importance de l'IL-27 dans la génération des macrophages immunorégulateurs humains et précisent les mécanismes moléculaires impliqués. A plus long terme, ces résultats permettront d’évaluer de nouvelles stratégies dans le traitement de tumeurs solides dont l’immunosuppression locale est associée à un fort infiltrat de macrophages exprimant CD39The purpose of the present thesis is to study the molecular mechanisms associated with the polarization of human macrophages towards an immunoregulatory phenotype, similar to that of tumor associated macrophages (TAM). Laboratory data have shown the role of IL-27 in this process, mostly by its capacity to modulate CD39 expression, which controls, at least in part, the acquisition of an immunoregulatory phenotype by human macrophages.The purpose of this work was to specify the molecular mechanisms involved in the acquisition of the regulatory phenotype, downstream IL-27. The results confirm the central role of adenosine, and therefore of the ectonucleotidase CD39, and identify the molecule PGE2 in the functional polarization of immunoregulatory macrophages. These data confirm the importance of IL-27 in the generation of human immunoregulatory macrophages and specify the involved molecular mechanisms. Over the long term, these results will allow to evaluate new strategies in the treatment of solid tumors, whose local immunosuppression is associated with a strong infiltrate of CD39-expressing macrophages
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Lehmann, Anne-Christin [Verfasser], and Daniela C. [Akademischer Betreuer] Dieterich. "Immune proteins in neurons : towards an understanding of the neuronal role of the immune protein CD3[Zeta] in NMDA receptor signaling and cytoskeleton remodeling / Anne-Christin Lehmann ; Betreuer: Daniela C. Dieterich." Magdeburg : Universitätsbibliothek, 2016. http://d-nb.info/1113687118/34.
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Shatnyeva, Olga M. [Verfasser]. "The role of CD95 glycosylation in CD95 signaling / presented by Olga M. Shatnyeva." 2010. http://d-nb.info/1003101844/34.
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Brosig, Susann. "Signaltransduktion von CD97 in humanen Fibrosarkomzellen." Doctoral thesis, 2014. https://ul.qucosa.de/id/qucosa%3A13244.
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CD97 gehört zur Familie der Adhäsions-G-Protein gekoppelten Rezeptoren (aGPCR), die aus einem langen extrazellulären N-terminalen Fragment (NTF) und einem nicht-kovalent gekoppelten C-terminalen Fragment (CTF) mit der sieben-transmembranären (TM7) Region und dem intrazellulären Teil bestehen. CD97 wird in malignen Tumoren exprimiert. In der humanen Fibrosarkomzelllinie HT1080 steigert die stabile Überexpression von CD97 die ungerichtete zweidimensionale (2D) Migration einzelner Zellen. Eine Verkürzung von CD97 im CTF auf zwei transmembranäre (TM2) Domänen führt zu einer Suppression der 2D-Migration im Vergleich zu stabil mock-transfektierten HT1080 Kontrollzellen. Wahrscheinlich supprimiert CD97/TM2 die endogene CD97-Wirkung. Unbekannt ist, welche Signalwege durch CD97-Überexpression in HT1080 reguliert werden und welche Signalwege für die Migrationssteigerung von HT1080 verantwortlich sind. Die Klärung dieser Signalwege ist Gegenstand der vorliegenden Arbeit.
Die Phosphorylierung von Proteinkinasen ist eine posttranslationale Modifikation zur Regulation der Kinaseaktivität mit nachfolgender Aktivierung oder Inaktivierung eines Signalweges. Daher sind Expression und Phosphorylierung der Proteinkinasen zur Identifikation regulierter Signalwege interessant. Dazu wurden in Lysaten von CD97/TM7, CD97/TM2 und mock-transfektierten HT1080 mittels Kinetworks Phosphosite Screen KPSS 1.3 Profiling (Multi-Immunoblot™) 37 verschiedene Proteinphosphorylierungen untersucht und regulierte Signalwege identifiziert. An 25 Phosphorylierungsstellen erfolgt eine Regulation durch CD97. Anschließend wurden die Ergebnisse der interessantesten Proteine hinsichtlich ihrer Expression und Phosphorylierung im Western Blot verifiziert und um Proteine erweitert, die klassisch an der Regulation der Zellmigration beteiligt sind. Es zeigt sich eine Aktivierung des PI3-Kinase/Akt-Signalweges und eine Inhibierung von Src durch CD97. 2D-Migrationsversuche von HT1080 CD97/TM7, CD97/TM2 und mock mit spezifischen Inhibitoren gegen den PI3-Kinase/Akt-Signalweg und gegen Src bestätigen, dass diese Kinasen an der CD97-induzierten Steigerung der 2D-Migration beteiligt sind. Weiterhin finden sich Hinweise, dass in HT1080 CD97 die Apoptose hemmt und die Proliferation reguliert.
Insgesamt wird in dieser Arbeit ein Überblick über die durch CD97 regulierten Signalwege gegeben. Die CD97-gesteigerte 2D-Migration von HT1080 wird durch eine Aktivierung des PI3-Kinase/ Akt-Signalweges und Inhibierung von Src vermittelt.
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Watts, Laura. "Characterization of a Novel Signaling Motif in the CD3epsilon Subunit of the T Cell Receptor." 2008. http://www4.utsouthwestern.edu/library/ETD/etdDetails.cfm?etdID=385.
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Nash, Rodney James. "Tetraspanin CD9 regulates apoptosis in mouse embryonic stem cells through the suppression of epidermal growth factor receptor signaling." 2006. http://purl.galileo.usg.edu/uga%5Fetd/nash%5Frodney%5Fj%5F200608%5Fphd.
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Tomic, Jelena. "Aberrations in Cytokine Signaling in Leukemia: Variations in Phosphorylation and O-GlcNAcylation." Thesis, 2012. http://hdl.handle.net/1807/32829.
Full textAbstract:
Tumor-induced immunosuppression can occur by multiple mechanisms, each posing a significant obstacle to immunotherapy. Evidence presented in this dissertation suggests that aberrant cytokine signaling, as a result of altered metabolism of Chronic Lymphocytic Leukemia (CLL) cells, confers a selective advantage for tumor survival and growth. Cells from CLL patients with aggressive disease (as indicated by high-risk cytogenetics) were found to exhibit prolongation in Interferon (IFN)-induced STAT3 phosphorylation, and increased levels of reactive oxygen species (ROS) in these cells reflected these signaling processes. Changes in the relative balance of phospho-STAT3 and phospho-STAT1 levels, in response to combinations of IL-2 + Toll-like receptor (TLR)-7 agonist + phorbol esters, as well as IFN, were associated with the immunosuppressive and immunogenic states of CLL cells. In addition, immunosuppressive leukemic cells were found to express high levels of proteins with O-linked N-acetylglucosamine (O-GlcNAc) modifications, due to increased metabolic activity through the Hexosamine Biosynthetic Pathway (HBP), which caused impaired intracellular signaling responses and affected disease progression. A conclusion of the studies presented here is that the intrinsic immunosuppressive properties of leukemic cells may be overcome by agents such as Resveratrol that target metabolic pathways of these cells.