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Anderson, Ian Paul. "Met receptor signalling." Thesis, University of Liverpool, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.526784.
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Carter, Stephanie. "Met receptor dynamics and signalling." Thesis, University of Liverpool, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404701.
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Kamikura, Darren M. "Structurefunction analysis of the met receptor oncoprotein, Tpr-met." Thesis, McGill University, 1999. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=37575.
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The Met protooncogene encodes a receptor tyrosine kinase that is deregulated by point mutation, and overexpression/amplification in a number of human tumours. The Met receptor is also oncogenically activated following genomic rearrangement which generates a cytoplasmic, constitutively activated fusion protein, Tpr-Met. In addition to autophosphorylation sites within the catalytic domain, the carboxy terminus of Tpr-Met/Met contains a single major site of autophosphorylation, tyrosine 489. This tyrosine residue represents a unique multisubstrate binding site, capable of binding numerous intracellular proteins, and is critical for the biological activities of both the Met receptor and Tpr-Met oncoprotein. Addition of the c-src myristoylation sequence to the amino terminus of the normally cytoplasmic Tpr-Met, localizes Tpr-Met to plasma membranes and enhances cellular transformation, in vitro invasion, and tumourigenicity. Furthermore, a membrane targetted Tpr-Met is localized to a similar subcellular compartment as the Met receptor, and alters the complement of signalling proteins required for efficient transformation. In this respect, a membrane localized Tpr-Met resembles oncogenic forms of the transmembrane Met receptor, and provides a model with which to study transformation by Met receptor oncoproteins. Significantly, membrane localization of Tpr-Met induces a phosphoinositide 3' kinase (PI3' K) dependent autocrine loop, involving the production of hyaluronic acid (HA), and post-translational modification of the cell surface receptor for HA, CD44. PI3'K activity and the HA/CD44 autocrine loop, are dependent on the multisubstrate binding site, tyrosine 489, and tyrosine residue 498, a residue with no previously described biochemical function. Although the exact mechanisms by which PI3'K regulates HA production are unclear, the induction of a HA/CD44 autocrine loop may represent a novel mechanism by which deregulated receptor tyrosine kinases increase their onco
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Kamikura, Darren M. "Structure/function analysis of the Met receptor oncoprotein, Tpr-Met." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape7/PQDD_0019/NQ55343.pdf.
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Sirulnik, Leonardo Andres. "Studies on the human c-Met receptor." Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362813.
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Cheung, Man-ting, and 張敏婷. "Expression of met receptor tyrosine kinase in hepatocellularcarcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B4669965X.
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Paliouras, Grigorios. "Regulation of met receptor tyrosine kinase signalling and biology." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=86661.
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Growth factor receptor tyrosine kinases (RTKs) are critical initiators of signal transduction pathways necessary for cell growth, differentiation, migration and survival. Many of these signals are coordinated through scaffold proteins that are phosphorylated upon their recruitment to the activated receptor complex. This provides binding sites for multiple proteins to activate and generate distinct biological responses. The amplitude and duration of a signal is regulated via dephosphorylation and degradation of target proteins. Signal regulation in this manner acts to promote the formation and disassembly of multi-protein complexes and diversify and localize signals downstream from RTKs.The Met RTK and its ligand, hepatocyte growth factor (HGF), are positive regulators of epithelial morphogenesis, scatter, and survival. However little was known regarding the proteins responsible for attenuating Met receptor activation. In Chapter II, I demonstrated that the Met receptor was hyperphopshorylated in PTP1B-null mice in response to Fas-induced liver damage. Inhibition of Met signaling with PHA665752, removed protection from liver failure in PTP1B-null hepatocytes, demonstrating that PTP1B was a negative regulator of the Met RTK and its removal promoted cell survival against Fas-induced hepatic failure.
In response to Met receptor stimulation, the Gab1 scaffold protein is the prominent protein recruited and phosphorylated downstream from Met and is critical in mediating Met-dependent biological responses. In chapters III and IV, I identified the serine/threonine kinase Pak4 and the microtubule-bound guanine nucleotide exchange factor GEF-H1 as novel proteins recruited to Gab1 following Met receptor activation. I demonstrate that Gab1 and Pak4 synergize to enhance migration and invasion following HGF stimulation. Furthermore, the recruitment of Pak4 to Gab1 is important for its subcellular localization to lamellipodia and critical for epithelial cell dispersal and morphogenesis downstream from Met. In addition, GEF-H1 is important in focal adhesion formation and turnover and this correlates with the ability of GEF-H1 to promote epithelial migration and invasion downstream from Met.
Overall, these studies investigate molecular mechanisms regulating Met-dependent signals and demonstrate for the first time that the Met receptor is a substrate for PTP1B and identify Pak4 and GEF-H1 as key integrators of Met dependent cellular migration and invasion.
Les récepteurs tyrosine kinase aux facteurs de croissance sont des initiateurs critiques des voies de signalisation nécessaires à la croissance, la différentiation, la migration et la survie cellulaire. Beaucoup de ces signaux sont coordonnés par des protéines d'échafaudage qui sont phosphorylées au cours de leur recrutement au complexe de récepteurs activés. Ceci fournit des sites de liaison à de multiples protéines permettant l'activation et la génération de différentes réponses biologiques. L'amplitude et la durée d'un signal est régulée via la déphosphorylation et la dégradation des protéines cibles. De cette façon, la régulation du signal agit pour promouvoir la formation et le désassemblage de complexes protéiques et pour diversifier et localiser les signaux en aval des récepteurs tyrosine kinase.
Le récepteur Met et son ligand HGF (Hepatocyte Growth Factor) sont des régulateurs de la morphogenèse, la dispersion et la survie des cellules épithéliales. Toutefois, peu d'informations sont disponibles sur les protéines responsables de l'extinction des signaux issus du récepteur Met. Dans le chapitre II, je démontre que le récepteur Met est hyperphosphorylé dans les souris knock-out pour PTP1B en réponse aux dommages induits par Fas. L'inhibition par le composé PHA665752 de la signalisation par Met, relève la protection contre les crises hépatiques dans les souris KO pour PTP1B. Ceci démontre que PTP1B est un régulateur négatif de Met et son retrait permet la survie cellulaire contre les crises hépatiques induites par Fas.
En réponse à la stimulation du récepteur Met, la protéine d'échafaudage Gab1 est la plus importante des protéines recrutées et phosphorylées en aval de Met et cette protéine est critique dans la médiation des réponses biologiques dépendantes de Met. Dans les chapitres III et IV, j'ai identifié la kinase Ser/Thr Pak4 et le facteur d'échange de guanine lié aux microtubules (GEF-H1) en tant que nouvelles protéines recrutées à Gab1 suite à l'activation de Met. Je démontre que Gab1 et Pak4 agissent de façon synergique pour promouvoir la migration et l'invasion suite à la stimulation par HGF. De plus, le recrutement de Pak4 à Gab1 est important pour sa localisation cellulaire dans les lamellipodes et est critique pour la dispersion et la morphogenèse des cellules épithéliales en aval de Met. En outre, GEF-H1 est important pour la formation et le roulement des points d'adhésion focaux ce qui est en corrélation avec la capacité de GEF-H1 de promouvoir la migration et l'invasion épithéliale en aval de Met.
Ces études ont pour but d'investiguer les mécanismes moléculaires régulant les signaux dépendants de Met et démontrent pour la première fois que le récepteur Met est un substrat pour PTP1B. Finalement, Pak4 et GEF-H1 sont identifiés comme des intégrateurs clés de la migration et l'invasion cellulaire dépendante de Met.
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Yamamoto, Brent Joseph. "Norleual, an angiotensin IV receptor ligand and C-Met antagonist." Online access for everyone, 2006. http://www.dissertations.wsu.edu/Dissertations/Summer2006/B%5FYamamoto%5F071206.pdf.
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Petkiewicz, Stephanie L. "The Met receptor tyrosine kinase in mammary gland tumorigenesis and development /." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=103278.
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The Met receptor tyrosine kinase (RTK) is expressed in the mammary gland under both normal and neoplastic conditions. Overexpression of the Met receptor is found in 15--20% of human breast cancers and is correlated with shortened disease-free interval and overall survival. In order to explore the role of dysregulated Met receptor signaling on the development of mammary tumors I have characterized a transgenic mouse model that expresses either wild type or a dysregulated Met receptor in the mammary epithelium under the control of the mouse mammary tumor virus promoter/enhancer (MMTV-Met). The Met receptor variants contained a mutation that results in decreased receptor ubiquitination and prolonged receptor signaling (Y1003F) or an activating mutation that was originally observed in patients with papillary renal carcinoma (M1250T) or both mutations (YF/MT). In vitro and in vivo transformation assays demonstrated that each mutation singly is weakly transforming, however, there was an additive effect on transformation when both mutations were present. This additive effect was observed in the transgenic mice where multiparous MMTV-Met-YF/MT mice developed tumors earlier and with much greater penetrance than did mice expressing either of the single mutants. This provides the first in vivo model that demonstrates a role for ubiquitination in suppression of transforming activity of an RTK. MMTV-Met-YF/MT tumors displayed a range of histological phenotypes but were mainly comprised of luminal lineage cells. Notably, MMTV-Met-M1250T tumors contained cells from both the basal and luminal populations, suggesting transformation of a progenitor cell. Progenitor cell transformation in RTK transgenic mouse models is uncommon and highlights distinct signaling differences and potentially lineage specificity of the two Met mutants.Through assays of overexpression in vivo and inhibition in vitro, Met receptor signaling has been correlated with the development of the mammary gland. To examine the effects of loss of Met receptor signaling on mammary gland development I have utilized the Cre/LoxP1 recombination system to knock-out the Met receptor from the mammary epithelium. Mammary-specific Cre recombinase efficiently excised floxed DNA as visualized by activation of a beta-galactosidase reporter In Met+/+ glands, however, few beta-galactosidase positive cells are retained In the Mefl/fl glands and an intermediate number are retained in the Met fl/+ glands. This indicates that Met-null cells are selected against and supports a role for Met in the development of the mammary gland.
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Luzac, Michal Leonie. "Small Molecules as Potential Inhibitors of the Met Tyrosine Kinase Receptor." Thesis, University College London (University of London), 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.498510.
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Gui, Yirui. "Régulation de la signalisation du récepteur MET par la protéine SOCS1 dans le carcinome hépatocellulaire." Thèse, Université de Sherbrooke, 2014. http://hdl.handle.net/11143/5390.
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Résumé : La répression fréquente du gène encodant pour le « suppressor of cytokine signaling 1 » (SOCS1) dans le carcinome hépatocellulaire (CHC) et la forte susceptibilité des souris déficientes pour SOCS1 à développer des tumeurs hépatiques expérimentales suggèrent que SOCS joue un rôle de suppresseur de tumeur. Cette notion est supportée par les études impliquant la répression de l’expression de SOCS1 via des évènements épigénétiques ou par les microARN dans plusieurs autres types de cancers. Les mécanismes moléculaires sous-jacents au rôle potentiel de suppresseur de tumeur de SOCS1 dans le foie demeurent à ce jour inconnus. Bien que les récepteurs à activité tyrosine kinase (RTK) sont reconnus pour induire l’expression de l’ARNm de SOCS1, le rôle et les mécanismes par lesquels SOCS1 peut réguler la signalisation des RTK sont incertains. Le RTK MET, qui a pour ligand le facteur de croissance des hépatocytes (HGF), régule plusieurs fonctions cellulaires normales. La dérégulation de la signalisation du récepteur MET joue des rôles importants dans la pathogenèse du CHC. Des études ont démontré que l’activation de MET promeut la prolifération, l’invasion et la migration des cellules cancéreuses du foie ainsi que leur dissémination métastatique. La signalisation aberrante de MET est un trait commun de plusieurs autres cancers et serait à l’origine de l’émergence de la résistance à la chimiothérapie. Dans ce projet, j’ai investigué les mécanismes moléculaires par lesquels SOCS1 régule l’activité du récepteur MET.
Mes résultats indiquent que le foie des souris Socs1[indice supérieur -/-]Ifng[indice supérieur -/-] se régénère plus rapidement que celui des souris contrôles. Suivant une stimulation au HGF, les hépatocytes issus des souris Socs1[indice supérieur -/-] Ifng[indice supérieur -/-] présentent une augmentation de la signalisation de MET, de la migration et de la prolifération cellulaires. L’expression exogène de SOCS1 dans différentes lignées cellulaires d’hépatocarcinomes humains et murins inhibe la signalisation induite par HGF. De plus, SOCS1 diminue la prolifération, la croissance indépendante de l’anchrage et la migration dans ces lignées de CHC in cellulo et réduit de façon significative leur croissance dans les essais de xénogreffes chez les souris immunodéficientes. Mes résultats suggèrent que l’activation de la signalisation HGF-MET induit la transcription du gène SOCS1, suivi par une interaction physique entre SOCS1 et MET. L’analyse de divers mutants de SOCS1 révèle que cette interaction implique principalement les domaines SH2 et « kinase inhibitory region » (KIR) de SOCS1. L’activité kinasique de MET est requise pour cette interaction puisque l’interaction entre SOCS1 et un mutant kinase-inactif de MET est fortement réduite. SOCS1 est aussi phosphorylé en aval de MET sur quatre résidus tyrosine (Tyr). Quoique ces résidus Tyr représentent théoriquement des sites d’interaction pour des protéines adaptatrices possédant des domaines de liaison aux phospho-Tyr, elles ne semblent pas impliquées dans l’interaction de SOCS1 avec MET. Je démontre également que SOCS1 induit l’ubiquitination de MET via l’élongation de chaînes de polyubiquitine de type K48, conduisant à sa dégradation par le protéasome. Cette modulation négative de MET par SOCS1 dans les cellules CHC survient indépendamment de la voie de dégradation lysosomale de Cbl qui est partagée par plusieurs autres RTK. // Abstract : Frequent repression of the gene coding for the suppressor of cytokine signaling 1 (SOCS1) in hepatocellular carcinoma (HCC) and increased susceptibility of SOCS1 deficient mice to experimental hepatocarcinogenesis suggest a tumor suppressor role for SOCS1. This notion is supported by epigenetic and micro-RNA-mediated blockade of SOCS1 expression in several other cancers. Molecular mechanisms underlying the putative tumor suppressor function of SOCS1 in the liver have not been elucidated yet. Although receptor tyrosine kinases (RTK) can induce SOCS1 mRNA expression, the role and mechanisms of SOCS1 in regulating RTK signaling are not yet clear. c-Met is the RTK for hepatocyte growth factor (HGF) and mediates several normal cellular functions. HGF signaling and MET activation also play important roles in the pathogenesis of HCC. Experimental studies have shown that the activated MET promotes proliferation, invasion and migration of liver cancer cells and enhances metastasis. Aberrant MET signaling is a hallmark of many other cancers and underlies the emergence of chemoresistant clones. In this project, I investigated the molecular mechanisms by which SOCS1 regulates MET RTK activity. My results illustrate that the Socs1[superscript -/-]Ifng[superscript -/-] liver regenerates at a faster rate than the control one. Following HGF stimulation, hepatocytes from Socs1[superscrip -/-]Ifng[superscript -/-] mice display increased MET signaling, cell migration and proliferation. Forced expression of SOCS1 inhibits HGF-induced signaling pathways in different human or murine hepatoma cell lines. Furthermore, SOCS1 also decreases cell proliferation, anchorage-independent growth, and migration of HCC cell lines in cellulo, and results in significant inhibition of their growth as xenografts in immunodeficient mice. My findings show that activation of HGF-MET signaling results in transcriptional activation of SOCS1 gene, followed a physical interaction between SOCS1 and MET. Analysis of various SOCS1 mutants reveals that this interaction is mediated primarily via the SH2 and the kinase inhibitory region (KIR) domain of SOCS1. MET kinase activity is required for this interaction since SOCS1 binding to a kinase-dead MET mutant is dramatically reduced. MET promotes phosphorylation of SOCS1 on four tyrosine (Tyr) residues. Although these Tyr might represent potential binding sites for adaptors containing phospho-Tyr-binding domains, they do not appear to be involved in the interaction of SOCS1 with MET. I also show that SOCS1 induces polyubiquitination of MET via K48-ubiquitin chain elongation leading to its degradation by proteasomes. The SOCS1-mediated downmodulation of MET expression in HCC cells occurs independently of the Cbl-mediated lysosomal degradation pathway shared by many other RTKs. Taken together, my findings show that SOCS1 attenuates HGF-induced cellular functions by targeting the activated MET receptor for proteasomal degradation.
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Chmielowiec, Jolanta. "The role of the Met tyrosine kinase receptor in skin maintenance and regeneration." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2007. http://dx.doi.org/10.18452/15690.
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Met und der korrespondierende Ligand HGF/SF sind im hyperproliferativen Epithelium von Hautwunden exprimiert. Aus diesem Grund ist es wahrscheinlich, dass der Rezeptor und sein Ligand in autokriner Weise wechselwirken und wichtige Funktionen für den Heilungsprozess der Haut besitzen. Unter Verwendung der Keratin 14 Cre-Rekombinase konnte ein „Knockout“ des Met-Rezeptors spezifisch in der Epidermis erzielt werden. In der Tat zeigten die Ergebnisse, dass Met für die Re-epithelisierung in Wundschlussprozessen essentiell ist, da in den an der Wundheilung beteiligten Keratinozyten keine Rekombination des Met-Gens stattgefunden hat. In Met-Mausmutanten war der Wundschlussprozess verlangsamt, denn er erfolgte ausschließlich durch wenige Keratinozyten, in denen die Cre-Rekombinase keine Rekombination bewirkte. Met konnte als erstes Gen identifiziert werden, das absolut erforderlich für Re epithelisierungsprozesse von Wunden ist. Diese Arbeit trägt daher wesentlich zum Verständnis der Regulation von Wundheilungsprozessen bei.Met and its ligand, HGF/SF are expressed in the hyperproliferative epithelium of the wound. This suggests that receptor and ligand may act in an autocrine manner to promote wound healing in the skin. Using Keratin 14 cre recombinase, Met receptor was specifically knockout in the epidermis. In this way, it was demonstrated that Met receptor is essential for wound healing process and that keratinocytes, which contributed to the wound closure were Met-postitive. In the Met mutant mice, wound closure was slightly attenuated, but occurred exclusively by a few keratinocytes that had escaped recombination. Met is therefore the fist gene, which is absolutely required for re-epithelialization of the wound. This finding is fundamental for understanding the regulation of wound healing process.
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Ponzo, Marisa Grace 1980. "Gene expression profiling of Met receptor tyrosine kinase-induced mouse mammary tumors." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=115881.
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Breast cancer is a heterogeneous disease comprised of distinct biological entities that correlate with diverse clinical outcomes. Gene expression profiling has divided this heterogeneity into luminal, ERBB2+ and basal molecular subtypes. Basal breast cancers are difficult to treat as they lack expression of candidates suitable for targeted therapies and are associated with poor outcome.Elevated protein level of the hepatocyte growth factor receptor, MET, is observed in 20% of human breast cancers and correlates with poor prognosis. However, the role of MET in mammary tumorigenesis is poorly understood. To address this, we generated a murine model that expresses weakly oncogenic mutants of Met (Metmt) in the mammary epithelium under the transcriptional control of the mouse mammary tumor virus promoter. We demonstrate that Metmt induces mammary carcinomas with diverse phenotypes and used gene expression microarrays to elucidate gene expression changes induced by Met. Since mammary tumors contained variable contents of epithelium and stroma, we used laser capture microdissection to procure epithelial cells for microarray analysis. Based on immunohistochemistry and expression profiling, we show that Metmt produces tumors with luminal or basal characteristics. From hierarchical clustering, Metmt-induced basal tumors clustered with murine models that share features of epithelial to mesenchymal transition and human basal breast cancers. Moreover, Metmt basal tumors clustered with human basal breast cancer. The status of MET among the human breast cancer subtypes has not previously been addressed. We demonstrate that MET levels are variable across molecular subtypes but show elevation in the basal subtype and correlates with poor outcome. We used a candidate gene approach derived from microarray data to gain an understanding of signals required for Met-dependent tumorigenesis. We investigated Nck adaptor proteins and demonstrate a role for Nck in cell motility and actin dynamics of Met-dependent breast carcinoma cells and show elevated expression in human basal breast cancers. By generating a unique mouse model in which Met is expressed in mammary epithelia, with the examination of MET levels in human breast cancer, we have established a novel link between MET and basal breast cancer. This work identifies poor outcome basal breast cancers that may benefit from anti-MET therapies.
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Hervieu, Vilches Alexia. "Understanding and targeting PI3K downstream of oncogenic Met mutant." Thesis, Queen Mary, University of London, 2015. http://qmro.qmul.ac.uk/xmlui/handle/123456789/33935.
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The Receptor Tyrosine Kinase (RTK) Met, overexpressed or mutated in cancer, plays a major role in cancer progression and represents an attractive target for cancer therapy. This study aimed to investigate whether PI3K plays a role in Met oncogenicity. Three cell models were used: (i) NIH3T3 cells expressing WT Met or the constitutively active mutant M1268T Met; (ii) U87MG glioblastoma cells, with endogenous WT Met constitutively activated due to an autocrine loop; (iii) A549 lung cancer cells expressing endogenous WT Met, activated upon binding exogenous HGF. Met dependent Rac1 translocation to the plasma membrane, actin cytoskeleton organisation, cell migration, anchorage independent growth in soft agar and tumour growth were studied in the presence of inhibitors of pan-PI3K / mTOR, various PI3K Class I isoforms, mTOR or Akt, or following siRNA knock-down of PI3K isoforms. We report that PI3K class I (but not class III) regulates Met dependent cell migration. The PI3K class I isoforms required varies among the cell models. Interestingly, the combined inhibition of all p110 Class I isoforms lead to the strongest reduction of Met dependent cell migration. Met dependent phosphorylation of Akt, an effector of PI3K class I, is reduced upon endocytosis inhibition, suggesting that Met signals to PI3K Class I on endosomes. Our results indicate that mTOR is responsible for Met dependent anchorage independent growth and tumour growth in vivo. Surprisingly, PI3K class I (and class III) are not required. Moreover, Rac1 is required for Met dependent mTOR activation, (phosphorylation of mTORC1's effector, p70 S6K) subcellular translocation of mTOR and anchorage independent growth. Finally, our results suggest that this Met-Rac1- mTOR pathway occurs on endosomes. Thus while PI3K class I regulates Met dependent cell migration, mTOR regulates Met driven anchorage independent growth and in vivo tumorigenesis. Thus PI3K Class I / mTOR may be targeted in Met driven cancers.
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Fournier, Tanya M. "The role of signalling pathways downstream from the Grb2 adaptor protein in Met receptor and Tpr-Met oncoprotein biological activities /." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=36925.
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Activation of the Met receptor tyrosine kinase by its ligand, Hepatocyte Growth Factor (HGF), leads to mitogenesis, cell motility, morphogenesis, and angiogenesis. Mutational analysis has demonstrated the requirement of a single tyrosine within the carboxy-terminus (Y1356) of the Met receptor for the recruitment and activation of all Met-dependent signalling pathways and for the transformation of fibroblasts by the Tpr-Met oncogene. The selective abolishment of Grb2 from the Tpr-Met oncoprotein, by generating an asparagine to histidine mutation two amino acids downstream from Y1356 (N1358H), led to a reduction in Tpr-Met-mediated transformation of fibroblasts. Moreover, Met receptor studies demonstrate that while a Grb2 binding site is not required for epithelial cell motility, it is critical for the formation of branching tubules when cells are suspended in a collagen matrix. This suggests that Grb2-dependent pathways are involved in the organization and polarization of epithelial cells following Met receptor stimulation.Grb2 associated molecules, Gab1 and Cbl, are highly phosphorylated following stimulation of the Met receptor. Moreover, signaling pathways associated with Gab1 are critical for branching tubulogenesis in epithelial cells. Expression of a constitutively active version of Cbl, 70z-Cbl, results in an epithelial-mesenchymal transition, leading to the breakdown of cellular junctions and reorganization of the actin cytoskeleton. The amino-terminal SH2 domain is the minimal region required to induce morphological changes, which may be mediated through its interaction with the Met receptor, and/or an unidentified protein of 150 kDa.
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Eigeldinger-Berthou, Sylvie. "The receptor tyrosine kinase met in cancer : novel diagnostic and experimental therapeutic approaches /." [S.l.] : [s.n.], 2004. http://www.zb.unibe.ch/download/eldiss/04eigeldinger_s.pdf.
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Olaku, Vivienne. "Intercellular adhesion molecule 1 (ICAM-1) a novel co-receptor for c-Met." Karlsruhe Forschungszentrum Karlsruhe, 2008. http://d-nb.info/99093215X/34.
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Lin, Jenny Catherine 1970. "Involvement of the Met receptor tyrosine kinase in the development of human breast cancer." Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=37764.
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Met is a transmembrane receptor tyrosine kinase whose ligand is hepatocyte growth factor/scatter factor (HGF/SF). HGF/SF stimulates epithelial cell mitogenesis, motility and branching tubulogenesis. Met and HGF/SF are essential for embryonic development, and are implicated in oncogenesis. In this thesis, the possible role of Met in the development of human breast cancer is examined. The MET gene is located at chromosome 7q31, a region frequently deleted in breast cancer. In this thesis, I demonstrate that MET is included in the smallest common region of deletion of chromosome 7q31 in breast cancer, and is therefore a candidate for a breast cancer tumor suppressor gene. To investigate this further, I elucidated the intron-exon structure of the MET gene. The MET gene is composed of 21 exons, spanning approximately 130 kilobases(kb) of chromosomal DNA. Interestingly, the first coding exon of MET, exon 2, is unusually large, at 1214 nucleotides (nt). Exon 2 is subject to alternative splicing in all epithelial cells studied, and is skipped to produce a 7kb mRNA species which does not encode a protein product. Furthermore, in seven of 13 human breast cancer cell lines studied, exon-skipping of MET exon 2 occurs more frequently when compared to two immortalized breast epithelial cell lines. These seven breast cancer cell lines have an altered ratio of Met mRNA isoforms, with increased levels of the non-protein-encoding 7kb exon 2-skipped mRNA, and a corresponding decrease in the expression of Met receptor in these cells. Significantly, in all other carcinoma types studied to date, the Met receptor is expressed at high levels, as in normal epithelial cells, indicating that loss of Met protein is specific to breast carcinoma cells. The alteration in the normal splicing pattern of MET is correlated with alterations in the normal pattern of expression of SR splicing proteins, which are responsible for regulating alternative splicing. I propose that loss of Met is an event s
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Wan, Kai-fung. "Hepatocyte growth factor and met receptor signaling in nasopharyngeal carcinoma cell migration and invasion." Click to view the E-thesis via HKUTO, 2007. http://sunzi.lib.hku.hk/HKUTO/record/B39557029.
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溫啟峰 and Kai-fung Wan. "Hepatocyte growth factor and met receptor signaling in nasopharyngeal carcinoma cell migration and invasion." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39557029.
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Nagy, Janos. "Hepatocyte growth factor/scatter factor and C-met ligand-receptor in human breast cancer." Thesis, University of Glasgow, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366258.
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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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McCleese, Jennifer Kay. "Investigating the Biological and Biochemical Consequences of Met Function and Dysfunction in Canine Osteosarcoma." The Ohio State University, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=osu1308079186.
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Olaku, Vivienne [Verfasser]. "Intercellular adhesion molecule 1 (ICAM-1) a novel co-receptor for c-Met / Vivienne Olaku." Karlsruhe : Forschungszentrum Karlsruhe, 2008. http://d-nb.info/99093215X/34.
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Peschard, Pascal. "The role of Cbl-mediated ubiquitination in the regulation of the Met receptor tyrosine kinase /." Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=102150.
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The Met receptor tyrosine kinase (RTK) and its ligand, the hepatocyte growth factor/scatter factor (HGF/SF), which regulate epithelial cell remodelling, dispersal and invasion, are deregulated in many human cancers. In the last twenty years, mechanisms of RTK activation and signalling have been studied extensively. In contrast, very little is known about the mechanisms of down-regulation of RTKs. At the time I began my thesis work, the family of Cbl ubiquitin-protein ligases emerged as negative regulators for RTKs. In this thesis, I demonstrate that c-Cbl is an important negative regulator of the Met receptor. Upon HGF stimulation, c-Cbl promotes ubiquitination of the Met RTK. This requires the association of the c-Cbl tyrosine kinase binding (TKB) domain with a DpYR binding motif, including Y1003, present in the juxtamembrane of the Met receptor. A Met Y1003F receptor, which lacks the c-Cbl TKB binding site, is not ubiquitinated, transforms fibroblast and epithelial cells in vitro and is tumorigenic in vivo. I demonstrate that ubiquitination of the Met receptor is not required for its internalization from the plasma membrane, but is essential for its lysosomal degradation. In the presence of HGF, the Met Y1003F receptor is poorly degraded and remains phosphorylated, leading to sustained activation of the Ras-MAPK pathway. Moreover, fusion of a ubiquitin moiety to the carboxy-terminus of Met Y1003F is sufficient to decrease Met receptor stability, prevent sustained MEK1/2 activation and reduce cell transformation.To examine the tumorigenicity of the Met Y1003F receptor in animals, I generated a murine model expressing Met Y1003F under the MMTV promoter, and observed that Y1003F substitution increases Met receptor tumorigenicity in mammary glands. This demonstrates for the first time that ubiquitination of a RTK is required for its biological functions in vivo. Furthermore, this highlights synergy between an activating mutation (M1250T) and a loss of down-regulation mutation (Y1003F) in the tumorigenicity of the Met receptor. Based on these results and on the observation that several RTKs escape the lysosomal degradative pathway in human tumours, I propose that loss of RTK down-regulation is a common mechanism for oncogenic activation of RTKs in human tumours.
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Lock, Lisa S. "Recruitment specificity of Gab family docking proteins and implications for MET receptor-mediated epithelial morphogenesis." Thesis, McGill University, 2002. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=82919.
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Activation of cell-surface receptors by extracellular signals can generate distinct biological responses. Many of these signals are coordinated through docking proteins, including those in the Gab family (Gab1, Gab2 and Gab3). Following activation of receptor tyrosine kinases (RTKs), cytokine or antigen receptors, docking proteins are recruited to the receptor complex and become phosphorylated on tyrosine residues, providing binding sites for multiple proteins involved in signal transduction. In this manner, they act to diversify and localize signals downstream from receptors by virtue of their ability to assemble multiprotein complexes.The recruitment of docking proteins to RTKs depends on the ability of the protein to interact directly or indirectly with the receptor. In chapter II, I established that Gab1 and Gab2 can be recruited to RTKs indirectly, through constitutive association of Gab1 or Gab2 with the C-terminal SH3 domain of the adapter protein Grb2. This requires two highly conserved Grb2 binding sites in Gab proteins. One site corresponds to a canonical SH3 domain binding motif, whereas the second contains an atypical PXXXRXXKP motif that I also identified in the unrelated Grb2-binding protein, Slp-76.
In contrast to the other Gab proteins, Gab1 can also interact in a Grb2-independent manner with the Met/Hepatocyte growth factor receptor. In chapter IV, I established that this interaction requires the structural integrity of the Met receptor, phosphorylation of tyrosine 1349 in the Met C-terminus, and a 13 amino acid Met binding motif (MBM) in Gab1. Instead of the expected interaction of a phosphotyrosine-binding domain in Gab1 with a phosphotyrosine-containing motif in the Met receptor, I propose that the activated kinase domain of Met and the negative charge of phosphotyrosine 1349 engage the Gab1 MBM as an extended peptide ligand.
In response to Met receptor stimulation, Gab1 overexpression promotes an invasive morphogenic program in epithelial cells. In contrast, I have shown in chapter III that Gab2 overexpression fails to induce this response. Mutation of the MBM in Gab1 abolishes the ability of Gab1 to promote morphogenesis, whereas its insertion into Gab2 increases Gab2 association with Met, but does not confer on Gab2 the ability to promote morphogenesis. This indicates that the Grb2-independent recruitment of Gab proteins to Met is necessary but not sufficient to promote epithelial morphogenesis. Overall, these studies have identified both common and unique mechanisms through which receptor tyrosine kinases can recruit Gab docking proteins, and have established that Gab1 and Gab2 do not share redundant biological functions in epithelial cells.
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Thayaparan, Thivyan. "Development of c-Met targeted chimeric antigen receptor T-cell immunotherapy for malignant pleural mesothelioma." Thesis, King's College London (University of London), 2016. https://kclpure.kcl.ac.uk/portal/en/theses/development-of-cmet-targeted-chimeric-antigen-receptor-tcell-immunotherapy-for-malignant-pleural-mesothelioma(0b08a5d1-8a96-4393-baa2-30219dbd8d87).html.
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Malignant pleural mesothelioma (MPM) is an incurable cancer that commonly presents at an advanced stage. Although surgery, chemotherapy and radiotherapy treatment may be used, median survival from diagnosis is less than 12 months. Consequently, new therapeutic approaches are essential. Chimeric antigen receptors (CARs) are fusion molecules that couple the HLA-independent binding of a cell surface target to the delivery of a tailored T-cell activating signal. The receptor tyrosine kinase c-Met is overexpressed in >80% of MPM making it an attractive candidate for CAR T-cell immunotherapy. To target c-Met, three candidate CARs were developed named N28z, M28z and cM28z. All contained a CD28/CD3ζ endodomain fused to one of three stabilised peptides based on the N and K1 domains of hepatocyte growth factor, which is the only natural ligand for c-Met. Specificity and functionality of c-Met re-targeted CAR+ T-cells was confirmed by co-cultivation with c-Met-expressing NIH 3T3 and MPM cell lines. This was indicated by target-dependent cytotoxicity and enhanced cytokine release (IL-2 and IFN-γ), when compared to appropriate controls. Anti-tumour activity of all three candidate CARs could be further enhanced by pre-treatment of tumour cells with poorly cytotoxic doses of chemotherapy (cisplatin and pemetrexed) or by co-incubation with the PD-1 blocker, pembrolizumab. No differences between function of the three candidate CARs were evident in these studies. To evaluate in vivo anti-tumour activity, an intraperitoneal MPM xenograft model was established that was amenable to monitoring using bioluminescence imaging. Candidate c-Met re-targeted CARs were coexpressed with the chimeric cytokine receptor, 4αβ, enabling IL-4 mediated, selective enrichment of CAR+ T-cells. In mice with an established tumour burden, I found that cM28z/4αβ+ T-cells were superior to other c-Met re-targeted or control T-cells in eliciting sustained disease control. Together, these findings demonstrate proof of concept for the utility of c-Met re-targeted CAR+ T-cells to recognise and destroy mesothelioma tumour cells.
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Abella, Jasmine. "The role of endocytosis and subcellular localisation on Met receptor tyrosine kinase signal transduction and stability." Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=86540.
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The hepatocyte growth factor (HGF)/Met receptor tyrosine kinase (RTK), regulates a wide variety of biological responses including cell migration, proliferation and invasion and deregulation of these processes can lead to cancer development. At the start of this PhD thesis, the concept that deregulation of RTKs can occur through loss of negative regulatory mechanisms, had emerged. RTKs are down-regulated through the endocytic pathway, which involves receptor ubiquitination. Work from this thesis demonstrates that uncoupling the Met RTK from Cbl-mediated ubiquitination (Met Y1003F) results in oncogenic activation of Met both in vitro and in vivo. Met ubiquitination is not required for internalization but is essential for lysosomal degradation. Loss of Met ubiquitination abrogates association with endocytic sorting machinery for degradation and leads to enhanced stability and retention of Met Y1003F within an intracellular compartment. Here, MetY1003F induces sustained activation of the Ras-MAPK pathway, required for cell transformation. Fusion of a mono-ubiquitin moiety to the C-tail of MetY1003F, is sufficient to restore engagement with endocytic machinery and down-regulation of Met and consequently inhibit sustained activation of MAPK as well as cell transformation.Numerous modes of RTK internalisation have been identified, including clathrin mediated endocytosis, yet little is known about the signals determining which route is taken and the contribution of each to RTK signalling and stability. Work from this thesis demonstrates that Met induces and is localised to a form of membrane protrusion, called dorsal ruffles. Internalisation of Met from these protrusions delivers Met to the endocytic pathway in manner which promotes efficient degradation. I have established a requirement for the Gab1 scaffold protein for dorsal ruffle induction. Moreover, a novel Gab1-Nck complex is a common and essential requirement for dorsal ruffle formation downstream from the Met, EGF and PDGF RTKs. My data supports a role for dorsal ruffles in cell migration and epithelial morphogenesis. Met is active within dorsal ruffles and we propose that these membrane structures function as signalling microdomains in a manner similar to endosomes. Importantly, disruption of dorsal ruffles alters Met RTK signalling and biological response. These studies illustrate the critical relationship between RTK localisation and signalling and underscore the importance of understanding how receptors traffic.
Le récepteur à activité tyrosine kinase (RTK) Met (ou récepteur au HGF), régule une large variété de réponses biologiques, dont la migration, la prolifération et l'invasion cellulaires; la dérégulation de ces processus pouvant conduire au développement de cancers. Lorsque j'ai débuté cette thèse, une notion venait d'émerger selon laquelle la suractivation des RTK dans les cellules cancéreuses pouvait être la conséquence d'une perte de régulation négative. Les RTK sont négativement régulés par endocytose, un processus impliquant l'ubiquitination du récepteur. Le travail réalisé dans cette thèse démontre que le découplage entre le récepteur Met et son ubiquitination par la protéine Cbl (Met Y1003F) conduit à l'activation oncogénique de Met à la fois in vivo et in vitro. L'ubiquitination de Met n'est pas nécessaire à son internalisation, mais est essentielle à sa dégradation par le lysosome. La perte de l'ubiquitination de Met empêche son association avec la machinerie de l'endosome de triage, conduisant à une plus grande stabilité et au maintien de Met 1003F dans un compartiment intracellulaire. Met 1003F provoque alors une activation prolongée de la voie de signalisation Ras-MAPK, impliquée dans la transformation cellulaire. La fusion d'une molécule de mono-ubiquitine à l'extrémité C-terminale de Met 1003F est suffisante pour restaurer l'engagement vers la voie endocytique et la régulation négative de Met, et par conséquent inhibe l'activation prolongée de MAPK ainsi que la transformation cellulaire. fr
Plusieurs modes d'internalisation des RTKs ont été identifiés, dont l'endocytose rapide par l'entremise des clathrines. Par contre, les signaux déterminant leur choix et la contribution de chacun dans la signalisation et la stabilité des RTKs restent peu connus. J'ai identifié que Met stimule la formation de protrusions membranaires appelées "protrusions dorsales" et s'y localise. L'internalisation de Met à partir de ces protrusions permet de l'intégrer à la voie d'endocytose et de promouvoir sa dégradation de manière efficace. J'ai pu établir que la protéine d'échaffaudage Gab1 était nécessaire à l'induction de ces protrusions dorsales. De plus, j'ai identifié que la formation d'un nouveau complexe entre les protéines Gab1 et Nck est un pré-requis essentiel pour la formation de ces protrusions membranaires en aval des récepteurs Met, EGFR et PDGFR. Mes résultats montrent aussi que ces protrusions dorsales jouent un rôle dans la migration cellulaire et la morphogénèse épithéliale. Met étant actif dans ces protrusions dorsales, nous proposons ici l'idée selon laquelle ces structures membranaires fonctionnent comme des microdomaines de signalisation d'une manière similaire aux endosomes. D'ailleurs, la signalisation et la réponse biologique du récepteur Met sont altérées sans ces protrusions dorsales. Cette étude illustre le lien étroit entre la localisation des RTK et leur signalisation, et souligne l'importance d'une meilleure compréhension de la circulation intracellulaire des récepteurs. fr
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To, Christine Ting Ting. "Overexpression of hepatocyte growth factor receptor/Met suppresses tumorigenecity of NCI-H1264 lung squamous carcimona cells." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape11/PQDD_0002/MQ45533.pdf.
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Buchstein, Nils [Verfasser]. "The role of hepatocyte growth factor and its receptor c-MET in wound repair / Nils Buchstein." Köln : Deutsche Zentralbibliothek für Medizin, 2010. http://d-nb.info/100610500X/34.
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Hedou, Élodie. "Modulation de la signalisation glutamatergique par l'activateur tissulaire du plasminogène et le récepteur MET dans le système nerveux central Tissue type plasminogen activator dependant crosstalk between MET and NMDA receptors containing gluN2B: possible involvement in autism spectrum disorders." Thesis, Normandie, 2020. http://www.theses.fr/2020NORMC410.
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L’activateur tissulaire du plasminogène (tPA) est une sérine protéase initialement découverte dans le compartiment vasculaire, qui constitue la molécule active de l’Actilyse®, médicament utilisé en clinique dans la phase aigüe de l’AVC ischémique pour ses propriétés fibrinolytiques. Le tPA est également exprimé dans le parenchyme cérébral où il peut moduler la neurotransmission glutamatergique de type NMDA (N-Methyl-D-Aspartate). Cette protéase existe sous deux formes actives : une forme simple chaîne (sc-tPA) et une forme double chaîne (tc-tPA). Malgré une activité fibrinolytique similaire, ces deux formes de tPA ont des rôles distincts. En effet, seul le sc-tPA peut potentialiser la mort neuronale de type excitotoxique induite par du NMDA. Ainsi, afin de mieux comprendre ces différences de signalisation entre les deux formes de tPA, nous avons utilisé des cultures primaires de neurones corticaux traitées avec du sc-tPA et du tc-tPA. Nos résultats ont mis en évidence l’implication d’un nouveau récepteur partenaire, le récepteur MET au sein de la signalisation glutamatergique de type NMDA. Nous avons montré que seul le tc-tPA active les récepteurs MET, conduisant à une augmentation de la proximité des récepteurs NMDA et MET à la surface neuronale. De plus, le tc-tPA diminue la phosphorylation de GluN2B et dégrade cette même sous-unité. En imagerie calcique, l’utilisation d’inhibiteurs sélectifs de MET réverse l’effet du tc-tPA sur la signalisation des récepteurs NMDA. En parallèle, l’étude transcriptomique menée sur des souris déficientes en tPA (tPA Null) a révélé une diminution du nombre de transcrits MET dans l’amygdale et le cortex entorhinal ainsi que des déficits comportementaux caractéristiques des troubles du spectre autistiqueTissue-type plasminogen activator (tPA) is a serine protease originally discovered in the vascular compartment. It is the active compound of Actilyse®, the only-approved drug for the clinical treatment of the acute phase of ischemic stroke thanks to its fibrinolytic properties. tPA is also expressed in the cerebral parenchyma where it modulates the NMDA (N-Methyl-D-aspartate) glutamatergic neurotransmission. This protease exists in two active forms: a single chain tPA form (sc-tPA) and a two chain tPA form (tc-tPA). Despite a similar fibrinolytic activity, these two forms have different roles within the parenchyma. Indeed, only sc-tPA potentiates excitotoxic neuronal death induced by NMDA. In order to better understand the signalling pathways involved by each forms of tPA, we used primary cultures of cortical neurons treated with sc-tPA or tc-tPA. Our results have highlighted the implication of a new partner receptor, MET, within NMDA glutamatergic signalling. We have shown that only tc-tPA activates MET receptors, leading to an increase of the proximity between MET and NMDA receptors at the neuronal surface. Moreover, tc-tPA decreases the GluN2B phosphorylation and allows the degradation of this subunit. By using calcium imaging, MET inhibitors reverses the effect of tc-tPA on NMDA receptors signalling. In parallel, a transcriptomic study realized on tPA-deficient mice (tPA Null) revealed a decrease of MET gene in two cerebral structures: amygdala and entorhinal cortex in addition to behavioural deficits which are features of autism spectrum disorder
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Parachoniak, Christine. "Characterization of met receptor tyrosine kinase-mediated endocytosis and its role in signal transduction and cellular migration." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=106403.
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The Met receptor tyrosine kinase (RTK) and its ligand, hepatocyte growth factor (HGF) are potent regulators of epithelial remodeling, dispersal, and invasion and their deregulation is frequently observed in human cancers. These processes are coordinated through signal transduction pathways activated downstream of Met. In turn, it is now understood that an important aspect of signalling outcome is modulated through RTK downregulation via receptor internalization, degradation and also RTK recycling to spatially restricted subcellular domains. Although a strong relationship between RTK endocytosis and signalling had been established prior to this thesis, the precise mechanism(s) of how this is achieved is still poorly understood and little was known for the Met RTK.To address this specifically for the Met RTK, I have characterized the function of two endocytic proteins in Met RTK trafficking and the consequence for biological response. Work in this thesis shows that following HGF-mediated Met activation, the endocytic adaptor protein, Eps15, is recruited to the Met receptor, and becomes both tyrosine-phosphorylated and ubiquitinated. Recruitment of Eps15 requires Met receptor kinase activity and involves two distinct Eps15 domains. Unlike previous reports for other receptors, recruitment of Eps15 to Met involves a distinct mode of recruitment involving the coiled-coil domain of Eps15 and the signaling adaptor molecule, Grb2. This identified a new mechanism of recruitment for Eps15 downstream of the Met receptor.In the third part of my thesis, I establish that the endocytic adaptor molecule, Golgi-localized gamma-ear containing Arf-binding protein 3 (GGA3), interacts selectively with Met when stimulated by HGF, to sort Met for recycling through a Rab4 positive compartment rather than degradation. I provide evidence supporting a molecular mechanism through which GGA3 regulates Met recycling and demonstrate that this is essential for both prolonged signaling and HGF-mediated biological response. This data defines an active recycling pathway involving GGA3, and supports a broader role for GGA3-mediated cargo selection in targeting receptors destined for recycling.Finally, in the fourth chapter of this thesis, evidence for microtubule interactions in Met-mediated Rab4 vesicle recycling is presented. We characterize a mechanism reliant on the microtubule +TIP, CLIP-170, linking Met/Rab4-positive recycling vesicles to microtubules for transport to the lamellipodia. We propose that the specific targeting of the Met receptor to the leading edge functions as a specialized signalling microenvironment, required for maintaining normal migration dynamics. These studies identify Met RTK endocytosis as a crucial regulatory process for RTK signalling and biology and stress the need for further studies examining the interplay of RTK endocytosis and signalling in the context of normal development and cancer settings.Le récepteur tyrosine kinase (RTK) Met, ainsi que son ligand, le facteur de croissance des hepathocytes (HGF), sont de puissants régulateurs du remodelage, de la dispersion et de l'invasion des cellules épithéliales, et leur dérèglement est fréquemment observé dans divers types de cancers chez l'humain. Ces processus sont coordonnés par l'activation de voies de signalisation induites par Met. Il est maintenant connu que l'internalisation, la dégradation ainsi que le recyclage des RTKs vers des domaines spécifiques de la cellule constituent des facteurs importants influençant les conséquences de l'activation de ces voies de signalisation. Bien que le lien entre l'endocytose et la signalisation des RTKs ait été démontré avant ce mémoire, les mécanismes spécifiques de cette association restent encore mal compris. Pour aborder ce problème spécifiquement concernant le récepteur Met, j'ai caractérisé les rôles de deux protéines endocytiques impliquées dans le trafic de Met, et leur implication dans les réponses biologiques induites par Met. Les travaux présentés dans ce mémoire montrent qu'en réponse à l'activation de Met par HGF, l'adaptateur endocytique Eps15 est recruté par le récepteur et devient tyrosine phosphorylé et ubiquiné. Le recrutement d'Eps15 requiert l'activation du récepteur tyrosine kinase Met, et implique deux domaines distincts d'Eps15. Contrairement à ce qui a été rapporté pour d'autres récepteurs, le recrutement d'Eps15 par Met met en jeu un mode de recrutement distinct impliquant le faisceau d'hélices (coiled-coil domain) d'Eps15 et l'adapteur signalétique Grb2. Ceci a permis d'identifié un nouveau mécanisme de recrutement d'Eps15 par le récepteur Met.Dans la troisième partie de ce mémoire, j'ai établi que l'adaptateur endocytique Golgi-localized gamma-ear containing Arf-binding protein 3 (GGA3) interagit spécifiquement avec Met lorsque celui-ci est stimulé par HGF. En conséquence, GGA3 trie Met pour le recyclage via un compartiment contenant Rab4, plutôt que de le trier pour être dégradé. J'y démontre un nouveau mécanisme moléculaire par lequel GGA3 contrôle le recyclage de Met, ce qui est essentiel pour la signalisation prolongée de Met et des réponses biologiques induites par HGF. Ces données définissent un nouveau mécanisme de recyclage actif impliquant GGA3 et supportent un rôle plus large joué par GGA3 dans la sélection des récepteurs destinés au recyclage.Finalement, le rôle des microtubules dans le recyclage des vésicules contenant Rab4 induit par Met est présenté dans le quatrième chapitre de ce mémoire. Nous avons caractérisé un mécanisme dépendant d'une protéine de l'extrémité (+TIP), CLIP-170, qui lie les vésicules de recyclage contenant Met et Rab4 aux microtubules, contrôlant ainsi leur transport vers les lamellipodes. Nous proposons que le ciblage spécifique du récepteur Met vers le front de migration fonctionne comme un microenvironnement signalétique spécifique requis pour le maintient de la dynamique migratoire. Ces travaux ont permis d'identifié l'endocytose du récepteur tyrosine kinase Met comme étant un processus de régulation cruciale pour la signalisation des RTK et pour les réponses biologiques associées à cette signalisation. Ces travaux démontrent qu'il y a un besoin important d'examiner la relation entre l'endocytose des RTKs et leur signalisation aussi bien dans le contexte du développement normal que dans le cadre du développement cancéreux.
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Durrant, Michael 1982. "Differential regulation of c-Cbl and Cbl-b ubiquitin ligases downstream of the Met receptor tyrosine kinase." Thesis, McGill University, 2007. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=112619.
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The Cbl family of E3 ubiquitin ligases are important negative regulators of multiple receptor and cytoplasmic tyrosine kinases, and participate in a wide variety of cellular processes. Uncoupling of Cbl-mediated negative regulation allows activated receptor tyrosine kinases such as the Met receptor to escape degradation, enhancing their oncogenic potential in vitro and in vivo. Despite the consequences of loss of Cbl-mediated negative regulation for human disease, little is known about the mechanisms regulating Cbl protein levels themselves.In this thesis work, I demonstrate a differential regulation of c-Cbl and Cbl-b downstream of the Met receptor tyrosine kinase. Cbl-b protein levels decrease in response to Met kinase activity, whereas c-Cbl levels remain stable. Cbl-b is partially degraded in a proteasome-dependant manner. This requires Cbl-b ubiquitin ligase activity and a carboxy terminal domain region located between the RING and UBA domains. I conclude that the regulation of c-Cbl and Cbl-b differs downstream of Met, and propose that negative regulation of Cbl-b by a dysregulated Met receptor may contribute to tumourigenesis.
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Baek, Jea-Hyun [Verfasser]. "The role of scatter factor receptor/met in mobilizing antigen-presenting dendritic cells in vivo / Jea-Hyun Baek." Aachen : Hochschulbibliothek der Rheinisch-Westfälischen Technischen Hochschule Aachen, 2011. http://d-nb.info/1014457920/34.
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Cañadas, Castillo Israel 1984. "MET and epithelial to mesenchymal transition as novel targets in small cell lung cancer." Doctoral thesis, Universitat Pompeu Fabra, 2013. http://hdl.handle.net/10803/128576.
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Small cell lung carcinoma (SCLC) is a highly lethal disease due to its chemorefractory nature
after first line treatment. The mechanisms to overcome this resistance have remained elusive to
tackle up to date. MET is a transmembrane tyrosine kinase receptor and its activation is
associated with increased motility, migration and invasion in cancer cells. MET is activated in
several tumour types and has been linked to patient prognosis. MET activation by its natural
ligand Hepatocyte Growth Factor (HGF) has been involved in Epithelial to Mesenchymal
Transition (EMT), a process by which cells decrease adhesion, lose polarity, acquire the ability
to migrate and invade surrounding tissue. EMT is also associated with resistance to anticancer
agents. We hypothesized that HGF-induced EMT would explain resistance to chemotherapy in
SCLC and that MET inhibitors could revert this phenomenon.
In our work we demonstrated that HGF-induced MET activation in SCLC cells resulted in a
more aggressive phenotype. In human SCLC we demonstrated in two independent series that
MET phosphorylation was associated with poor prognosis. In preclinical models we observed
that MET activation by HGF induced EMT that resulted in chemoresistance in vitro and in vivo.
MET inhibition was able to block or reverse this process and resensitized cells to
chemotherapy. Mesenchymal markers in human SCLC specimens were associated with MET
activation, predicted a worse survival and were upregulated in chemorefractory disease. Finally,
increased HGF serum levels in SCLC patients correlated with higher risk of death. These
results suggest that the use of MET inhibitors in combination with chemotherapy as a
therapeutic approach in the MET-activated subpopulation of SCLC merits further
investigation.El Cáncer de Pulmón de Célula Pequeña (CPCP) es una enfermedad altamente letal debido a su naturaleza quimiorefractaria después del tratamiento de primera línea. Los mecanismos para derrotar estar quimioresistencia han fracasado hasta la fecha. MET es un receptor de membrana tirosina cinasa y su activación está asociada a una incrementada motilidad, migración e invasión en células tumorales. MET está activado en diversos tipos tumorales y está asociado al pronóstico de los pacientes. La activación de MET mediante su ligando natural “Factor de Crecimiento Hepatocitario” (HGF) ha estado involucrado en la Transición Epitelio- Mesenquimal (EMT), un proceso mediante el cual las células disminuyen su adhesión, pierden la polaridad, adquieren la habilidad de migrar e invaden los tejidos adyacentes. La EMT está también asociada a la resistencia a agentes antitumorales. Nuestra hipótesis es que la EMT inducida por HGF explicaría la resistencia a la quimioterapia en el CPCP y que los inhibidores de MET podrían revertir este fenómeno. En nuestro trabajo demostramos que la activación de MET inducida por HGF en líneas celulares de CPCP dio lugar a un fenotipo más agresivo. En dos series independientes de CPCP humano demostramos que la fosforilación de MET estaba asociada a un peor pronóstico. En modelos preclínicos observamos que la activación de MET mediante HGF indujo la EMT, dando lugar a quimioresistencia in vitro e in vivo. La inhibición de MET fue capaz de bloquear o revertir este proceso, sensibilizando las células tumorales a la quimioterapia. Los marcadores mesenquimales en muestras humanas de CPCP se asociaron a activación de MET, prediciendo una peor supervivencia. Además, la expresión de estos marcadores estaba incrementada en la enfermedad quimiorefractaria. Estos resultados sugieren que el uso de inhibidores de MET en combinación con quimioterapia como una aproximación terapéutica en la subpoblación de pacientes de CPCP con activación de MET merece una investigación más extensa.
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Peng, Yun, Zhongming Lu, Guohui Li, Mariel Piechowicz, Miranda Anderson, Yasin Uddin, Jie Wu, and Shengfeng Qiu. "The autism associated MET receptor tyrosine kinase engages early neuronal growth mechanism and controls glutamatergic circuits development in the forebrain." NATURE PUBLISHING GROUP, 2016. http://hdl.handle.net/10150/617181.
Full textAbstract:
The human MET gene imparts a replicated risk for autism spectrum disorder (ASD), and is implicated in
the structural and functional integrity of brain. MET encodes a receptor tyrosine kinase, MET, which
plays a pleiotropic role in embryogenesis and modifies a large number of neurodevelopmental events.
Very little is known, however, on how MET signaling engages distinct cellular events to collectively affect
brain development in ASD-relevant disease domains. Here, we show that MET protein expression is
dynamically regulated and compartmentalized in developing neurons. MET is heavily expressed in
neuronal growth cones at early developmental stages and its activation engages small GTPase Cdc42 to
promote neuronal growth, dendritic arborization, and spine formation. Genetic ablation of MET
signaling in mouse dorsal pallium leads to altered neuronal morphology indicative of early functional
maturation. In contrast, prolonged activation of MET represses the formation and functional
maturation of glutamatergic synapses. Moreover, manipulating MET signaling levels in vivo in the
developing prefrontal projection neurons disrupts the local circuit connectivity made onto these
neurons. Therefore, normal time-delimited MET signaling is critical in regulating the timing of neuronal
growth, glutamatergic synapse maturation and cortical circuit function. Dysregulated MET signaling may
lead to pathological changes in forebrain maturation and connectivity, and thus contribute to the
emergence of neurological symptoms associated with ASD.
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Chmielowiec, Jolanta [Verfasser], W. [Gutachter] Birchmeier, H. [Gutachter] Saumweber, and B. [Gutachter] Munz. "The role of the Met tyrosine kinase receptor in skin maintenance and regeneration / Jolanta Chmielowiec ; Gutachter: W. Birchmeier, H. Saumweber, B. Munz." Berlin : Humboldt-Universität zu Berlin, 2007. http://d-nb.info/120807931X/34.
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Fisher, Ann Doreen. "An investigation of the role of the tyrosine kinase receptor met and its ligand Hepatocyte growth Factor in growth regulation in ovarian cancer." Thesis, University of Newcastle Upon Tyne, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.515099.
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Mekki, Meriem Sarah. "Conséquences de l'hypoxie sur la régulation de la signalisation HGF/SF-MET." Thesis, Lille 2, 2015. http://www.theses.fr/2015LIL2S047/document.
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Le récepteur à activité tyrosine kinase MET et son ligand le facteur de croissance des hepatocytes (Hepatocyte Growth Factor/Scattor Factor (HGF/SF)) sont essentiels pour la migration, la morphogenèse et la survie des cellules épithéliales. En plus de son implication et son importance physiologiques, la dérégulation de la signalisation de MET favorise la progression et l’invasion tumorales dans plusieurs types de cancers. Au sein des tumeurs, l’hypoxie est également un phénomène crucial qui induit une réponse adaptative menant à l’invasion, la métastase cancéreuses et la résistance aux traitements.Nous avons démontré que dans des conditions hypoxiques, la phosphorylation de MET induite par sa liaison au ligand, des mutations activatrices ou sa surexpression, est diminuée de manière importante in vitro et in vivo dans des modèles de tumeurs expérimentales chez la souris. Cette baisse de phosphorylation est très rapide et est réversible quand les cellules sont replacées en normoxie. Alors que la phosphorylation de GAB1, principal partenaire de MET, est également diminuée en hypoxie, l’activation des voies de signalisation en aval AKT et ERK n’est pas affectée et reste bien dépendante de l’activité du récepteur et du recrutement de GAB1. De la même façon, l’HGF/SF induit des réponses de motilité, de dispersion, de morphogenèse et de survie similaires en normoxie et en hypoxie. De manière intéressante, le traitement par deux inhibiteurs de tyrosine kinase (ITK) ciblant MET (PHA-665752 et SU11274) est moins efficace en hypoxie pour inhiber les voies de signalisation AKT et ERK ainsi les réponses cellulaires induites par MET. Comme pour la phosphorylation de MET, la résistance à ces ITK est un phénomène réversible. Ainsi, alors que l’hypoxie n’affecte pas les voies de signalisation en aval ni les effets biologiques, elle diminue la sensibilité de MET aux ITK induisant donc une résistance immédiate. L’ensemble de ces données pourrait fournir de nouvelles perspectives dans l’utilisation des thérapies ciblant MET dans les tumeurs solidesThe receptor tyrosine kinase MET and its ligand the Hepatocyte Growth Factor/Scattor Factor (HGF/SF) are essential for migration, morphogenesis and survival of epithelial cells. Beside its physiological involvement, deregulation of MET signaling has been shown to promote tumor progression and invasion in many cancers. Inside the tumors, hypoxia is also a crucial phenomenon promoting an adaptive response able to induce invasion, metastasis and resistance to treatment.We show that under hypoxia, MET phosphorylation induced by ligand-stimulation, activating mutation or overexpression, is drastically decreased both in cell culture and in experimental tumors. This decrease in MET phosphorylation occurs within minutes and is reversible when cells are returned to normoxia. While phosphorylation of the proximal signaling adaptor GAB1 is also decreased in hypoxia, activation of the downstream kinases ERK and AKT is not affected, but is still dependent on MET receptor activity. Consistently, several cellular responses induced by HGF/SF, including motility, morphogenesis or survival, are still efficiently induced. Interestingly, treatment with two tyrosine kinase inhibitors targeting MET (PHA-665752 and SU11274) are less efficient to inhibit the downstream kinases ERK and AKT and cellular responses induced by MET in hypoxia compared to normoxia. Similarly to MET phosphorylation, this resistance to TKI is a reversible phenomenon. Therefore, while hypoxia does not affect downstream signaling and cellular responses, it decreases MET sensitivity to TKIs targeting the receptor thus providing an immediate resistance. This may provide new insights in the use of MET targeted therapies in solid tumors
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Simonneau, Claire. "Mécanismes d'activation du récepteur tyrosine kinase MET par son ligand l'HGF/SF : rôles des domaines N et K1." Thesis, Lille 2, 2015. http://www.theses.fr/2015LIL2S071.
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L’HGF/SF (Hepatocyte Growth Factor/Scatter Factor) est le ligand du Récepteur Tyrosine Kinase (RTK) MET. Ce couple ligand-récepteur joue un rôle essentiel dans de nombreux processus biologiques tels que l’embryogenèse, la régénération tissulaire et l’angiogenèse. Comme pour de nombreux RTK, la dérégulation de l’activité de MET est associée à la progression et l’invasion tumorales. Bien que le récepteur MET ait été intensivement étudié au cours de ces dernières décennies, les processus moléculaires conduisant à son activation par l’HGF/SF restent encore mal connus et controversés.NK1, un variant naturel de l’HGF/SF, comprenant la partie N-terminale (N) et le premier domaine kringle (K1) de l’HGF/SF, possède une activité agoniste. En effet, NK1 dimérise spontanément en position « tête-bêche » et est considéré aujourd’hui comme la structure minimale permettant la dimérisation de MET et son activation. Afin de déterminer leur contribution respective, les domaines N et K1 isolés ont été produits par voie recombinante et ne montrent aucune ou qu’une très faible activité agoniste respectivement. Une présentation monovalente de ces domaines au récepteur MET ne semble donc pas pertinente pour déterminer leur fonction.Par conséquent, nous avons souhaité générer des complexes multivalents mimant le positionnement des domaines N et K1 au sein du dimère naturel. En tirant partie de la « One-Pot SEA ligation » développée au laboratoire, ces domaines ont été synthétisés par voie chimique et fonctionnalisés avec une extrémité C-terminale biotinylée (NB et K1B). En utilisant la streptavidine (S) comme plateforme de multimérisation, nous avons généré des complexes semi-synthétiques NB/S et K1B/S et déterminé les propriétés biologiques de ces nouvelles constructions multivalentes.L’ensemble des analyses de signalisations cellulaires et phénotypiques démontre sans équivoque que le complexe K1B/S est capable de mimer les réponses biologiques induites par l’HGF/SF et son variant NK1. De plus, le complexe K1B/S, injecté dans la circulation systémique, déclenche la signalisation de MET dans le foie. L’utilisation de ce complexe K1B/S nous a permis de démontrer que deux domaines K1, correctement assemblés et orientés, constituent l'interface minimale et suffisante requise pour déclencher une pleine activation de MET. A l’inverse, les premières données fonctionnelles ont démontré que le complexe NB/S ne lie pas directement MET mais utilise les héparanes sulfates comme pont moléculaire.Ces études utilisant de nouvelles configurations structurales pourraient donc servir de modèle de base au développement de nouveaux agonistes de MET dans le cadre de thérapies régénératives ou préservatrices, mais aussi d’antagonistes dans le cadre de thérapies anticancéreuses cibléesHepatocyte Growth Factor/Scatter Factor (HGF/SF) and its receptor tyrosine kinase (RTK) MET play an essential role in embryogenesis, tissue regeneration and angiogenesis. As observed for many others RTK, MET is also strongly involved in tumor progression and invasion mechanisms. Although numerous biological and structural approaches have been focused on the molecular processes leading to MET activation by HGF/SF, the HGF/SF-MET interaction framework remains only partially understood due to the complexity of the multivalent ligand-receptor binding events.NK1, a naturally occurring splice variant of HGF/SF, comprising the N-terminal part and the first kringle domain (K1) of HGF/SF, exhibits a partial agonistic activity toward MET. Indeed, in presence of heparan sulfates, NK1 self-associates into a “head-to-tail” dimer and is considered as the minimal structural module able to trigger MET dimerization and activation. Nevertheless, the individual role of N and K1 domains in the dimerization/activation of MET remain elusive.Stimulated by the conviction that monomeric N and K1 domains are not suitable for studying the functioning of HGF/SF-MET, we produced, by total chemical synthesis, biotinylated analogs of the N and K1 domains (NB and K1B). By combining with streptavidin (S), we engineered the semisynthetic constructs NB/S and K1B/S in order to determine the biological properties of these new multivalent architectures of N and K1 domains.In vitro, as observed with HGF/SF or NK1, we show that the K1B/S complex is able to fully activate MET signaling cascades to promote scattering, morphogenesis and survival phenotypes in various cell types. Even more, the K1B/S complex stimulates angiogenesis in vivo and, when injected systemically, triggers MET signaling in the liver. The use of this K1B/S complex allows us to demonstrate that two K1 domains, correctly assembled and oriented, constitute the minimal unit for sufficient MET activation. In contrast, first in vitro data have demonstrated that NB/S complex does not bind directly MET as previously thought, but rather, uses heparan sulfates as a molecular bridge.We envision these new structural configurations serving as a template for both the rational design of potent MET agonists (e.g. using K1B/S for regenerative therapies) and antagonists (e.g. using NB/S for targeted cancer therapies)
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Economou, Mario A. "Uveal melanoma and macular degeneration : molecular biology and potential therapeutic applications /." Stockholm : Karolinska institutet, 2007. http://diss.kib.ki.se/2007/978-91-7357-254-5/.
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Villalobos, Hernandez Alberto. "Role of suppressor of cytokine signalling 1 (SOCS1) in the pathogenesis of prostate cancer." Mémoire, Université de Sherbrooke, 2016. http://hdl.handle.net/11143/11618.
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Le cancer de la prostate (PCa) est le deuxième cancer le plus courant chez les hommes au niveau mondial. Le suppresseur de la signalisation des cytokines 1 (SOCS1) est considéré comme un suppresseur de tumeur en raison de la fréquente répression épigénétique de ce gène dans de nombreux cancers. Il a été reporté que SOCS1 inhibait l’activation de STAT3 induite par l’IL-6, ainsi que les cyclines et les kinases dépendantes des cyclines dans les cellules malignes de la prostate. D’autre part, il a été montré que SOCS1 n’était pas essentiel lors du contrôle de la signalisation de l’IL-6 dans les hépatocytes dépourvus de cette protéine, cependant elle est essentielle pour atténuer la signalisation du facteur de croissance des hépatocytes (HGF) via son récepteur MET. MET est un récepteur de tyrosine kinases qui est surexprimé dans le PCa agressif et métastatique. Notre hypothèse de recherche propose que la répression de SOCS1 par méthylation du promoteur et la dérégulation de l’expression de MET et de sa signalisation, sont des mécanismes pathogéniques liés au développement et à la progression du PCa. Nous avons généré des lignées de cellules PC3 et DU145 stables exprimant SOCS1. Les cellules ont été stimulées avec HGF et l’activation des voies de signalisation a été évaluée par immunobuvardage. Des essais in vitro de migration, de prolifération et d’invasion ont été effectués en présence de HGF. Des gènes de transition épithélio-mésenchymateuse ont été évalués par PCR quantitatif en présence ou non du facteur de croissance. Les cellules du PCa transfectées ou pas avec SOCS1 ont été inoculées dans des souris NOD SCID gamma de façon sous-cutanée ou orthoptique afin d’évaluer respectivement la croissance tumorale et la formation de métastases. Les tumeurs reséquées ont été analysées histologiquement et biochimiquement. Nos résultats montrent que SOCS1 atténue l'activation de MET induite par HGF et la phosphorylation d’ERK dans les cellules PC3, ainsi que la phosphorylation d’ERK et d’AKT dans les cellules DU145. SOCS1 inhibe également la prolifération cellulaire induite par HGF, ainsi que la migration et l’invasion in vitro. De plus, SOCS1 réduit l’expression des gènes de transition épithélio-mésenchymateuse impliqués dans la dégradation des composants de la matrice extracellulaire dans les cellules DU145 mais pas dans les cellules PC3. La surexpression de SOCS1 a stimulé l’augmentation de déposition de collagène, in vivo. Les tumeurs formées par les cellules exprimant SOCS1 étaient de taille significativement plus petites avec une réduction de la prolifération comparé aux tumeurs provenant des cellules contrôles. En outre, SOCS1 a inhibé la formation de métastases à distance dans un modèle orthotopique. En conclusion, nous suggérons que SOCS1 est un suppresseur de tumeur indispensable de la prostate, et qu’au moins une partie de sa fonction a lieu via la régulation négative de la signalisation du récepteur MET.Abstract : Prostate cancer (PCa) is the second most common cancer among men worldwide. Suppressor of cytokine signaling 1 (SOCS1) is considered a tumor suppressor due to frequent epigenetic repression of the SOCS1 gene in several human malignancies. Inactivation of SOCS1 also occurs in PCa by gene methylation and micro-RNA-mediated repression. SOCS1 has been reported to inhibit IL-6-induced STAT3 activation and down-regulates cyclins and cyclin-dependent kinases in PCa cells. It has been shown that SOCS1 is not required to control IL-6 signaling in SOCS1-deficient hepatocytes, but is essential to attenuate hepatocyte growth factor (HGF) signaling via its receptor MET. This protein is a receptor tyrosine kinase (RTK), overexpressed in aggressive and metastatic PCa. Thus we hypothesized that the repression of SOCS1 via promoter methylation and deregulated MET expression and signaling are inter-related pathogenic mechanisms in PCa development and progression. We generated stable SOCS1-expressing PCa cell lines (PC3 and DU145) using lentiviral transduction followed by clonal selection via limiting dilution. Cells were stimulated with HGF and downstream signaling events were assessed by Western blot. Proliferation, migration and invasion assays were also conducted in the presence of HGF in vitro. Epithelial mesenchymal transition genes were evaluated by qPCR in the presence or absence of the growth factor. The PCa cells transfected with SOCS1 and non-transfected controls were inoculated into NOD SCID gamma mice as xenografts or as orthotopic tumors to assess tumor growth and metastasis formation, respectively. Resected tumors were further analyzed histologically and biochemically. Our results showed that SOCS1 attenuates HGF-induced MET activation and ERK phosphorylation in PC3 and DU145 PCa cell lines. SOCS1 inhibited HGF induced cell proliferation, migration and invasion in vitro. Additionally, SOCS1 decreased epithelial mesenchymal transition genes involved in the degradation of extracellular matrix components in DU145 cells but not in PC3. In vivo, SOCS1 overexpression leads to an increase of collagen deposition. Tumors formed by SOCS1 expressing cells were significantly smaller in size with reduced cell proliferation compared to tumors arising from control cells. Furthermore, SOCS1 inhibited distant metastasis formation in the orthotopic model. Overall our results suggest that SOCS1 has a tumor suppressor role in PCa evolution and part of this function is mediated by the negative regulation of MET receptor signalling and down-regulation of genes supporting migration and invasion processes such as matrix metalloproteinases.
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Liu, Lei [Verfasser], Sunami [Akademischer Betreuer] Yoshiaki, Norbert [Akademischer Betreuer] Hüser, and Helmut [Akademischer Betreuer] Friess. "Peroxisome Proliferator-Activated Receptor gamma negatively regulates liver regeneration after partial hepatectomy via the HGF/c-met/ERK1/2 pathway : PPAR gamma in liver regeneration / Lei Liu. Gutachter: Helmut Friess ; Norbert Hüser. Betreuer: Sunami Yoshiaki ; Norbert Hüser." München : Universitätsbibliothek der TU München, 2015. http://d-nb.info/1076866328/34.
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Garcia, Ratés Sara. "Interacció dels derivats amfetamínics amb els receptors nicotínics: Aspectes moleculars i funcionals." Doctoral thesis, Universitat de Barcelona, 2011. http://hdl.handle.net/10803/32009.
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En treballs anteriors del nostre grup de recerca es va demostrar que l’antagonista específic del receptor nicotínic α7, metillicaconitina (MLA), inhibia in vitro la producció d’espècies reactives d’oxigen (EROS) i protegia de la neurotoxicitat in vivo induïda per metamfetamina (METH) i per la 3,4-metilendioxi-N-metamfetamina (MDMA). En aquesta tesi, es descriu un nou mecanisme d’acció dels derivats amfetamínics. Mitjançant assajos de fixació de radiolligands, es va comprovar que ambdós derivats amfetamínics competien amb els radiolligands específics dels receptors nicotínics α7 ([3H]Metillicaconitina), i dels heteromèrics ([3H]Epibatidina), el que indicava que en les cèl•lules PC12, el nostre model experimental, i també en una preparació de cervell total de ratolí, aquestes substàncies interaccionaven directament amb els receptors nicotínics. L’MDMA mostrava més afinitat per ambdós subtipus de receptors. Està descrit que el tractament crònic amb nicotina provoca un augment en la densitat de receptors nicotínics tan in vivo com in vitro en cèl•lules PC12. Ambdós derivats amfetamínics van provocar una regulació a l’alça dels dos subtipus de receptors ja a les 6 hores de pretractament. A la vegada, in vivo, l’MDMA i la Nicotina van provocar la regulació a l’alça que va ser potenciada per la seva associació en determinades zones cerebrals on s’expressen cada subtipus de nAChR. De l’estudi dels mecanismes implicats en aquesta regulació a l’alça, mitjançant inhibidors a diferents nivells, es va concluir que, igual com passa amb la nicotina, es produeixen a nivell postraduccional. A nivell funcional, vam determinar que aquests derivats amfetamínics eren capaços d’activar els receptors nicotínics i, d’acord amb les hipòtesis de treballs anteriors, induir una entrada de calci i de sodi que podria estar implicada en els esdeveniments que comportarien la seva neurotoxicitat. Per una banda, l’MDMA i la METH es van comportar com agonistes parcials dels nAChR α7 induïnt un increment de Ca2+ citosòlic. Per altra banda, l’MDMA es va comportar com antagonista dels nAChR heteromèrics i la METH com agonista parcial induint l’entrada de Na+ de la mateixa manera, el qual explicaria diferències a nivell de dependència, ja que els nAChR α4β2 estan implicats en la via mesolímbica o de recompensa. Paral•lelament a l’increment de fixació de radiolligands, es va determinar que la preincubació amb MDMA indueix un increment en la resposta per activació de receptors nicotínics, demostrant que l’ MDMA també indueix regulació a l’alça funcional. Alhora, es va observar que la preincubació de les cèl•lules durant 24 hores amb MDMA dona lloc a un increment perllongat dels nivells basals de Ca2+, el qual indica que l’MDMA inhibeix la desensibilització dels receptors i fa que entri calci durant un temps més llarg. Aquesta entrada persistent podria estar implicada en fenòmens de neurotoxicitat ja que va seguida de l’activació de vies dependents de calci com la calpaïna i la caspasa-3.During the last years, our emphasis has focused in the study of the neurotoxic effects of MDMA and methamphetamine (METH) on central nervous system and their pharmacological prevention. It has been demonstrated that these amphetamine derivatives produce oxygen species (ROS) in an in vitro model of synaptosomes. In previous works, we demonstrated that blockade of alpha7 nicotinic receptors with methyllycaconitine (MLA) prevented ROS production induced by MDMA and METH, consequently the alpha7 receptor would be involved in the neurotoxicity induced by these drugs. Studies at molecular level, using radioligand binding assays, showed the interaction of METH and MDMA with homomeric alpha7 nAChR and heteromeric subtypes of nicotinic receptors, such as aplha4 beta2. In addition, we investigated the effects of pretreatment with METH and MDMA on nAChR densities. We used PC 12 cells as an experimental model due to the fact other authors have similarly utilised them to evaluate the neurotoxicity of amphetamines. Moreover, they not only express nAChR, including the alpha7 subtype, but also provide an in vitro model for the up-regulation of nAChR, which occurs in vivo following chronic exposure to nicotine. In recent works, we demonstrated in vitro that Ca2+ chelation with EGTA prevented the production of reactive oxygen species (ROS) to a similar extent as nAChR blockade. This indicates that calcium influx, probably through alpha7 nAChR, is a key step in this process. Consequently, one of the objectives of this work was to use a fluorimetric method to investigate the effect of MDMA on Ca2+ and Na+ levels in cultured PC12 cells and the involvement of different nAChR subtypes and other cell pathways related to Ca2+ mobilization. In addition, we used electrophysiology in transfected Xenopus oocytes to corroborate the effects on alpha7 and alpha4 beta2 nAChR. Moreover, pretreatment with MDMA induced functional upregulation by potentiating the effects of specific nAChR agonists or whether it provoked a persistent Ca2+ increase, leading to calpain, caspase 3, NFκB, GSK-3 and Cyt C activation, which was involved in toxicity.
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Lampinen, Milla. "AMPA receptor ligand-binding domain : site-directed mutagenesis study of ligand-receptor interactions." Helsinki : University of Helsinki, 2003. http://ethesis.helsinki.fi/julkaisut/mat/bioti/vk/lampinen/.
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Albertyn, Zulfah. "The role of Toll-like receptor 4 (TLR-4) in wine-induced cardioprotection." Master's thesis, University of Cape Town, 2012. http://hdl.handle.net/11427/11789.
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Includes abstract.Includes bibliographical references.
Moderate and chronic consumption of red wine confers cardioprotection. Melatonin, present in wine, may contribute to this cardioprotective effect. Melatonin confers cardioprotection via the activation of tumor necrosis factoralpha (TNF-α) and the signal transducer and activator of transcription-3(STAT-3), via mechanisms that still remain to be delineated. We therefore hypothesise that South African red and white wines confer a cardioprotective effect in relation to their melatonin content. Furthermore, we propose that the cardioprotective effect of melatonin (at a concentration found in red wine) is dependent on the activation of Toll-like receptor 4 (TLR-4) to activate TNF-α/STAT-3.
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Kuusinen, Arja. "Structure-function relations in AMPA receptors." Helsinki : University of Helsinki, 2000. http://ethesis.helsinki.fi/julkaisut/mat/bioti/vk/kuusinen/.
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Caraffi, Stefano Giuseppe <1977>. "Analysis of TNFRSF5 gene mutations and splicing variants in CD40 receptor regulation." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2007. http://amsdottorato.unibo.it/605/.
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Lämsä, Karri. "GABAA receptor-mediated excitation in the hippocampus of adult and newborn rats." Helsinki : University of Helsinki, 2000. http://ethesis.helsinki.fi/julkaisut/mat/bioti/vk/lamsa/.
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Zhou, Hongyan, and 周紅艷. "Hepatocyte growth factor-met signaling in ovarian cancer progression." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B37937984.
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