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1
Rupniewska, Ewa. "Targeting SRC family kinases in lung cancer." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/9234.
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Lung cancer is the commonest cancer killer worldwide. This is mainly due to the rapid development of drug resistance and early metastatic dissemination of the disease. SRC family kinases (SFKs) are frequently over-expressed in various cancers and have been implicated in tumorigenesis through their ability to promote cancer cell proliferation, survival and invasiveness. Therefore, we sought to evaluate the involvement of SFKs in lung cancer biology and assess the possible therapeutic benefits of their inhibition, either alone or in combination with additional treatments. We demonstrate that SRC family kinases are over-expressed and activated in-vitro in a panel of lung cancer cell lines as compared to immortalised normal lung epithelial cells. SRC, FYN and LYN are expressed in a high proportion of lung cancer but not normal lung tissue sections. Furthermore, enhanced expression of LYN correlates with poor patients’ survival. Dasatinib is a novel SRC/ABL inhibitor which effectively blocks SFKs activity at nanomolar concentrations. Dasatinib reduces cell numbers in 10 out of 11 NSCLC cell lines tested, which correlates with a strong inhibition of DNA synthesis and cell proliferation, while apoptosis is moderately enhanced only in a few cell lines. Interestingly, dasatinib potently induces autophagy in all NSCLC cell lines tested. This appears to be a pro-survival mechanism as autophagy inhibition using chemical compounds or siRNA-mediated depletion of ATG5 sensitises NSCLC cells to dasatinib through enhanced apoptosis. Lastly, our results indicate that SFKs have both overlapping and isoform-specific functions in NSCLC cell biology, as demonstrated by the effects of siRNA-mediated knockdown of SRC, YES, FYN or LYN. Our results suggest that inhibition of SRC family kinases alone or in combination with autophagy inhibitors may be a beneficial therapeutic strategy in the management of lung cancer patients.
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Keenan, Sarah. "Structure-function studies of the neuronal Src kinases." Thesis, University of York, 2012. http://etheses.whiterose.ac.uk/3294/.
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N1- and N2-Src are neuronal specific splice variants of the ubiquitously expressed tyrosine kinase C-Src. They differ only by short amino acid inserts within their SH3 domains, a region known to confer substrate specificity. Due to their highly identical sequence it has been difficult to attribute specific neuronal functions to each Src enzyme, however, many C-Src SH3 domain substrates do not bind to the N-Src SH3 domains. The limited functional N1-Src data indicate that it is involved in neuronal differentiation. Furthermore, high expression levels of the N-Srcs in childhood neuroblastoma correlate with cases in which the tumour spontaneously differentiates to a harmless neuronal phenotype. In this study, I sought to explain how the amino acid inserts in the N-Src SH3 domains affect substrate specificity and kinase activity and how they might act to drive neuronal differentiation. I employed a multi-disciplinary approach to investigate the functions of the N Srcs. Studies in heterologous cells revealed a specific role for the N-Srcs in cytoskeletal rearrangement. A sensitive in vitro kinase assay was developed and this showed that the N-Src SH3 domain ligand preferences differ from those of C-Src. A subsequent phage display screen was able to identify a novel consensus sequence for the N1-Src SH3 domain and peptides containing this consensus motif were shown to be highly specific N1-Src inhibitors both in vitro and in cells. Bioinformatic analyses revealed the consensus sequence to be present in many neuronal proteins and identified a number of putative N1-Src substrates. In cultured neurons I identified a specific role for N1-Src acting in the L1-CAM pathway to modulate neurite outgrowth. The data presented here provide evidence that the inserts in the SH3 domains of the N-Srcs confer significant differences in their substrate preferences and that the functions mediated by the N-Srcs are different to those of C-Src. A role for N1-Src has been identified in the modulation of axon outgrowth in cultured neurons and the putative substrates identified now provide promising targets for the further study of N1-Src function. Future investigations will be able to utilise the data presented here to elucidate how N1-Src regulates the neuronal cytoskeleton, while tools I have developed; including a highly specific N1-Src inhibitor will greatly aid these investigations.
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Scales, Timothy M. E. "Tyrosine phosphorylation of tau protein by Src-family kinases." Thesis, King's College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406870.
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Lewis, Philip Alexander. "The role of N-Src kinases in neuronal differentiation." Thesis, University of York, 2014. http://etheses.whiterose.ac.uk/8000/.
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The ubiquitous proto-oncogene C-Src has two neuronal splice variants, N1- and N2-Src, which contain 6 and 17 amino acid inserts in their SH3 domains respectively. These inserts are thought to modify SH3 domain binding in a manner that decreases auto-inhibition and changes substrate specificity. Although high levels of neuronal Src expression are associated with neuronal differentiation, both during development and in the developmental cancer neuroblastoma, the functions, molecular mechanisms and specific substrate proteins of neuronal Srcs remain largely uncharacterised. Employing a highly multidisciplinary approach, this project aimed to characterise the role of N-Src expression in neuronal differentiation. Neuronal Srcs were demonstrated to be highly active in neuroblastoma cell lines, and overexpression can drive significant neuritogenesis in the retinoic acid-resistant cell lines KELLY and SK-N-AS. N2-Src expression was also shown to decrease the expression of Ki67 in SK-N-AS cells, indicating that N2-Src can drive neuroblastoma cells into quiescence. Using the Xenopus embryo as a model system for neuronal development, the expression pattern of xN1-Src during neurulation was characterised and a novel neuronal splice variant was identified in this species. It was demonstrated that xN1-Src is essential for healthy primary neurogenesis, and that xN1-Src knockdown caused a dramatic locomotive and patterning phenotype in X.tropicalis. Using stable, inducible HeLa cell lines, a phosphoproteomic screen demonstrated significant changes in the phosphotyrosine profile between C- and N2-Src over-expressing cells. Several candidate N2-Src substrates were identified, including paxillin, plakophilin and BCAR1. Bioinformatic analyses of the proteomic data revealed the enrichment of signalling pathways and protein complexes involved in membrane traffic and cell adhesion. Through these multidisciplinary approaches, the cellular effects of N1- and N2-Src signalling during both neuronal precursor and neuroblastoma differentiation have been characterised. Furthermore, a library of potential N-Src substrates has been generated that provides a framework for future studies.
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Gatesman, Ammer Amanda. "PKCalpha direct cSrc activation and podosome formation through the adaptor protein AFAP-110." Morgantown, W. Va. : [West Virginia University Libraries], 2004. https://etd.wvu.edu/etd/controller.jsp?moduleName=documentdata&jsp%5FetdId=3762.
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Thesis (Ph. D.)--West Virginia University, 2004Title from document title page. Document formatted into pages; contains vii, 350 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 322-346).
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Hooker, Erika. "Negative regulators of the Src family kinases in renal epithelial cells." Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=116932.
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The Src kinases are non-receptor tyrosine kinases involved in many epithelial processes in both normal and injured cells. Src was originally identified as a viral oncogene and has since been characterized as an important regulator of cellular proliferation, differentiation, and motility. Our lab has previously demonstrated that the Src kinases are important modifiers of gene expression in tubule cells of the kidney during ischemia-reperfusion injury. The signalling events that control and mediate the Src kinase transcriptional response in renal epithelial cells are not well understood. In this thesis, I have identified two novel negative regulators of the Src transcriptional response in renal epithelial cells. In Manuscript I and II, I demonstrate that the adapter protein Dok-4 can act as an inhibitor of Src-mediated transcription. Unlike most other adapter proteins, several members of the Dok family are primarily characterized by their inhibitory actions downstream of active tyrosine kinases. Despite being the most ubiquitously expressed Dok family member, Dok-4 function has remained elusive as few interacting proteins have been identified. In Manuscript I, we found that the previously defined boundaries of the Dok-4 PTB domain needed to be extended for proper function. We demonstrate that the PTB domain of Dok-4 contains an extended C-terminal alpha helix critical for canonical PTB-mediated interaction and identified the lipid phosphatase Ship1 as a novel partner of this redefined Dok-4 PTB domain. This interaction is greatly increased in the presence of active Src kinases and occurs through a canonical NPXpY motif present in the C-terminal region of Ship1. In contrast to the Dok-4-Ship1 interaction, in Manuscript II we present a non-canonical PTB-mediated interaction between Dok-4 and the nuclear transcription factor, Elk4. This interaction leads to relocalization of Elk4 from the nucleus to the cytoplasm and degradation of full-length Elk4. In renal cells, Dok-4 inhibits Src-mediated activation of Elk4 and represses expression of the immediate early genes, such as egr-1 and fos1, as well as some of their transcriptional targets. In agreement with this data, knock-down of Dok-4 was associated with increased proliferation of renal epithelial cells. During renal ischemia-reperfusion injury, where upregulation of immediate early genes is known to occur, we have for the first time detected a strong activation of the Src kinases and a delayed upregulation of Elk4, suggesting that Elk4 may be not only highly expressed, but also highly active. Dok-4, which is expressed in the kidney, may be essential for limiting damage to the kidney caused by Elk4-induced expression of the immediate early genes. In addition to activating transcription of the immediate early genes, we have previously shown that the Src kinases are responsible for transcriptionally upregulating the receptor tyrosine kinase, EphA2, during renal ischemia-reperfusion injury. In the preliminary manuscript presented here, we observed that while the Src kinases are highly active, the Stat proteins, downstream effectors of the Jak kinases, are dephosphorylated and inactive. As a corollary of this observation, overexpression of all three ubiquitous Jak family members, Jak1, Jak2 and Tyk2 could attenuate Src-mediated activation of the EphA2 promoter. Inhibition of endogenous Jak kinase by siRNA-mediated knock-down or incubation with the pharmacological inhibitor, Jak inhibitor I also activated EphA2 transcription. Surprisingly, Jak-mediated inhibition of EphA2 expression occurs independently of the Stat family and the cytokine receptors. Collectively, this thesis identifies two novel regulators of the Src kinase family in renal epithelial cells, the Dok-4 adapter protein and the family of Jak kinases.Les kinases Src sont des tyrosine-kinases cytosoliques qui sont impliquées dans multiples processus dans les cellules épithéliales et autres. Originalement identifiée comme un oncogène viral, la kinase Src est maintenant caractérisée comme une régulatrice de la prolifération, la différenciation et la motilité cellulaire. Nous avons précédemment montré que les kinases Src sont capables de modifier l'expression génique dans les tubules des reins durant le domage rénal par ischémie et réperfusion. Cependant, les mécanismes de signalisation qui contrôle la réponse transcriptionelle des kinases Src ne sont pas bien compris. La présente thèse décrit deux nouveaux inhibiteurs endogènes de la famille de kinases Src dans les cellules rénale épithéliales.Les deux premiers manuscrits établissent que la protéine adaptatrice Dok-4 fonctionne comme un inhibiteur des kinases Src. Contrairement à la plus part de protéines adaptatrices, la famille Dok est caractérisée par des actions inhibitrices durant la signalisation par les tyrosines kinases. Malgré que Dok-4 soit le membre de la famille Dok exprimé de manière la plus ubiquitaire, sa fonction est encore mal connue. Le premier manuscrit que je présente (Manuscrit I) décrit le domaine PTB de Dok-4. On y a démontré que le domaine PTB contient une extension C-terminal consistant probablement en une hélice alpha et que celle-ci est essentielle pour les interactions canoniques du domaine PTB de Dok-4. De plus, nous avons identifié la phosphatase lipidique Ship1 comme un nouveau partenaire de ce domaine PTB redéfini. Cette interaction est augmentée quand les kinases Src sont actives et elle implique un motif NPXpY dans la région C-terminale de Ship1. Contrairement à l'interaction entre Dok-4 et Ship1, l'interaction décrite dans le deuxième manuscrit (Manuscrit II) entre Dok-4 et le facteur de transcription, Elk4, implique le domaine PTB, mais se fait dans une manière atypique. L'interaction entre Dok-4 et Elk4 induit la relocalisation d'Elk4 du noyau au cytoplasme et cause la dégradation de la protéine Elk4. Dans les cellules rénales, Dok-4 inhibe l'activation d'Elk4 par les kinases Src et réprime l'expression des gènes de réponse précoce ("immediate early genes"), comme egr-1 et fos, et quelques cibles transcriptionelles de ces gènes. En accord avec ces données, suppression de Dok-4 est associée avec une augmentation de prolifération. En utilisant un modèle in vivo d'ischémie-reperfusion rénale, où la surexpression de gène de réponse précoce a déjà été démontrée, nous avons détecté une forte activation des kinases Src suivie d'une augmentation retardée de l'expression d'Elk4 dans les lysates de reins. Ces données suggèrent que dans ce modèle Dok-4 pourrait être critique pour limiter les dommages aux reins causé par l'induction des gènes de réponse précoce par Elk4. En plus d'activer l'expression des gènes de réponse précoce, nous avons précédemment montré que les kinases Src sont impliquées dans l'induction transcriptionnelle du récepteur tyrosine-kinase, EphA2, durant l'ischémie-reperfusion rénale. Dans le manuscrit préliminaire que je présente, nous avons noté que dans un modèle de déplétion et réplétion d'ATP, les kinases Src sont activées et les protéines Stat, des effecteurs des kinases Jak, sont déphsophorylés et inactives. Comme corollaire de cette observation, la surexpression de trois membres de de la famille Jak inhibent l'activation du promoteur d'EphA2 par les Src kinases. En plus, l'inhibition des kinases Jak endogènes par traitement aux siRNA ou par un inhibiteur pharmacologique, Jak Inhibitor I, active le promoteur d'EphA2. Étonnement, l'inhibition de l'expression d'EphA2 par les kinases Jak se fait indépendamment des protéines Stat et les récepteurs à cytokines. Mises ensemble, les données de cette thèse démontrent deux nouveaux inhibiteurs de la famille Src dans les cellules rénales épithéliales, la protéine adaptatrice, Dok-4 et les kinases, Jak1 et Jak2.
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Allard, Pierre. "Caractérisation des tyrosine kinases Src, Lyn et Fer dans la prostate." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0028/NQ52134.pdf.
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Brignatz, Constance. "Importance du repliement intramoléculaire dans la fonction biologique et l'évolution des Src-kinases." Aix-Marseille 2, 2008. http://www.theses.fr/2008AIX22081.
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Shor, Audrey Cathryn. "Src kinase inhibitors for the treatment of sarcomas : cellular and molecular mechanisms of action." [Tampa, Fla] : University of South Florida, 2007. http://purl.fcla.edu/usf/dc/et/SFE0001906.
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Tatton, Emma Louise. "The role of Src kinases in cytokine induced signalling in haemopoietic cells." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.406642.
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Bouchard, Véronique. "Rôles et régulation des tyrosine kinases Src dans la survie entérocytaire humaine." [S.l. : s.n.], 2005.
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Nash, Craig A. "Investigating the role of Src family kinases in αIIbβ3-mediated platelet signalling." Thesis, University of Birmingham, 2012. http://etheses.bham.ac.uk//id/eprint/3365/.
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αIIbβ3 is the major integrin expressed in platelets and plays a critical role in platelet aggregation and cessation of bleeding. Signalling via this integrin is critically dependent on the Src-family-kinases of which there are eight members, several of which are expressed in platelets. Platelets also express G protein-coupled receptors which signal through their G proteins, however some evidence for dependence on both Src family kinases and other platelet receptors exists. In this thesis, I have demonstrated that there are differential levels of expression of SFKs in mouse and human platelets. Further to this, utilising mouse models, I demonstrate that Src plays a critical positive role in αIIbβ3-mediated spreading on fibrinogen, with Lyn playing a negative role, potentially downstream of Src. In contrast, individual Src-family-kinases do not appear to play a role in clot retraction or tail bleeding assays, despite the Src-family-kinase inhibitor, Dasatinib having a significant effect. Finally, I demonstrate that both Gi-coupled receptors in human platelets are critically dependent on Src family kinases and αIIbβ3 for signalling, Interestingly, neither receptor stimulates tyrosine phosphorylation of Src family kinases in platelets. This suggests a role for the basal phosphorylation of Src-family-kinases which may be dependent on αIIbβ3-mediated signalling.
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Macfarlane, James Gray. "The role of src kinases in controlling neutrophil function in acute inflammation." Thesis, University of Newcastle upon Tyne, 2016. http://hdl.handle.net/10443/3180.
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The src family kinases are key cellular regulators of acute neutrophilic inflammation. When uncontrolled, this causes numerous inflammatory disorders, including the acute respiratory distress syndrome (ARDS). This is associated with an unacceptably high 90-day mortality and prolonged hospital admissions. ARDS currently has no effective pharmacological treatment. The work contained in this thesis aimed to characterise the anti-inflammatory, pro-resolutionary effects of src kinase inhibition on various neutrophil functions, using novel in vitro and in vivo models of acute inflammation and resolution. Results show that the src kinase inhibitors, PP1 and dasatinib, attenuate in vitro neutrophil extracellular degranulation in response to stimulation with formylated peptide, lipopolysaccharide and live bacteria. They also exert additional effects on integrin-dependent neutrophil functions, but have no effect on neutrophil fate or bacterial killing efficiency. Src kinase inhibition of neutrophils also attenuates in vitro epithelial cell damage and promotes a pro-resolutionary environment, with improved macrophage efferocytosis of apoptotic neutrophils, by inhibiting the release of an unidentified soluble factor believed to be a product of neutrophil degranulation. Extending these findings to in vivo murine models of bacteria- and acid-induced experimental lung inflammation, dasatinib exerts an inhibitory effect on markers of neutrophil degranulation in each model, at doses of 1mg/kg and 5mg/kg, respectively. At 10mg/kg, a detrimental effect is observed, as evidenced by reduced bacterial clearance, increased alveolar leak and extrapulmonary toxicity in the infection model and increased neutrophil influx, degranulation and alveolar haemorrhage in the acid model. These findings highlight a possible therapeutic role of src kinase inhibition in inflammatory conditions driven by neutrophil influx and degranulation that is worthy of further study in other models of lung inflammation. Future work should focus on developing more specific inhibitors to offer selective control over neutrophil granule processing, and careful dosing to avoid undesired effects on bacterial killing mechanisms.
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Bouchard, Véronique. "Rôles et régulation des tyrosine kinases Src dans la survie entérocytaire humaine." Mémoire, Université de Sherbrooke, 2005. http://savoirs.usherbrooke.ca/handle/11143/3799.
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Les mécanismes de régulation de la survie et/ou de l'apoptose/anoïkose sont connus pour être distincts selon l'état de différenciation des cellules épithéliales intestinales humaines. L'implication de la signalisation intégrines-Fak dans ces mécanismes diffère elle aussi le long de l'axe crypte-villosité. Les tyrosine kinases membres de la famille Src (TKs Src) sont reconnues pour leur participation dans la signalisation intégrines-Fak chez plusieurs types cellulaires. Jusqu'à ce jour, les différences entre chacune des TKs Src ont été très peu étudiées, notamment celles potentiellement retrouvées dans les mécanismes de régulation de la survie des cellules épithéliales intestinales selon l'état de différenciation de ces dernières. L'hypothèse de travail de mon sujet de recherche est que Src, Fyn et Yes sont exprimées, activées et régulées distinctement selon l'état de différenciation des cellules épithéliales intestinales, notamment dans les mécanismes de régulation de la survie et/ou de l'apoptose/anoïkose impliquant la signalisation intégrines-Fak."--résumé abrégé par UMI.
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Lorén, Christina. "Investigating the function of the Receptor Tyrosine Kinase ALK during Drosophila melanogaster development /." Umeå : Univ, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-411.
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Farard, Julien Duflos Muriel Logé Cédric. "Conception rationnelle, synthèse et évaluation de dérivés hétérocycliques oxygénés à potentialité antitumorale." [S.l.] : [s.n.], 2008. http://castore.univ-nantes.fr/castore/GetOAIRef?idDoc=52276.
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Summy, Justin Matthew. "Functional domain contributions to signaling specificity between the non-receptor tyrosine kinases c-src and c-yes." Morgantown, W. Va. : [West Virginia University Libraries], 2001. http://etd.wvu.edu/templates/showETD.cfm?recnum=2239.
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Thesis (Ph. D.)--West Virginia University, 2001.Title from document title page. Document formatted into pages; contains vi, 195 p. : ill. (some col.). Vita. Includes abstract. Includes bibliographical references (p. 182-190).
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Aponte, Emilie. "Régulation de la signalisation de Src par son domaine N-terminal intrinsèquement désordonné." Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTT095.
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La tyrosine kinase cytoplasmique Src est un régulateur essentiel de la croissance et de l’adhésion cellulaires induites par de nombreux stimuli extracellulaires, dont les facteurs de croissance et certains composants de la matrice extracellulaire. La dérégulation de son activité catalytique lui confère des propriétés oncogéniques importantes conduisant à la formation de tumeurs agressives chez l’Homme. La plupart des connaissances actuelles sur sa régulation catalytique repose sur des données structurales de cristallographie qui ont révélé l’importance des interactions intramoléculaires SH2 et SH3-dépendantes dans le contrôle des conformations ouvertes et actives de Src. Les domaines SH3, SH2 et kinase de Src sont associés au domaine SH4 N-terminal d'ancrage à la membrane plasmique via un domaine unique (DU) flexible. Le rôle du DU dans la régulation de Src reste obscur car il est intrinsèquement désordonné et par conséquent, cette région n'a pas été incluse dans les analyses structurales originelles. L'analyse par RMN de l'extrémité N-terminale de Src a révélé une conformation partiellement structurée du DU par le contact de séquences peptidiques spécifiques avec les lipides membranaires et le domaine SH3 (Perez et al, 2013; Maffei et al, 2015). De plus, cette interaction est régulée par phosphorylation des Ser69 et Ser75 localisées à proximité de ce domaine. L’objectif de ma thèse était d’adresser la relevance biologique de ces données structurales en me focalisant sur le rôle d’une partie du DU identifiée comme importante par RMN. J’ai montré que l’inactivation de cette région par des mutations perte de fonction, diminue fortement la signalisation de Src dans les cellules non transformées humaines ainsi que ses propriétés tumorales dans les cellules cancéreuses colorectales métastatiques révélant la pertinence biomédicale du système. Des analyses de protéomique m’ont permis de révéler un mécanisme original par lequel cette région contrôle la capacité de Src à phosphoryler ses substrats. En conclusion, ces données confirment un rôle important du DU sur l'activité et la signalisation de Src et révèlent un rôle critique des domaines désordonnés dans les tumeurs chez l’Homme. L’inhibition de cette région unique par de petites molécules devrait conduire à de nouvelles stratégies thérapeutiques dans le cancerThe membrane-anchored non-receptor tyrosine kinase Src is involved in numerous signal transduction pathways and hyperactive Src is a potent oncogene and driver of human metastasis. Most of our knowledge on Src kinase regulation relies on structural data, which revealed SH2 and SH3-dependent intramolecular interactions to control active conformations of the protein. The kinase, SH3 and SH2 domains of Src are attached to the membrane-anchored SH4 domain through the flexible unique domain (UD). The role of this UD remains obscure due to its intrinsically disordered properties for which reason it was not included in original structural analyses. Interestingly, membrane-associated intrinsic disordered domains are more prevalent among signaling and cancer-related proteins and they are thought to play critical roles in human disease. NMR analysis of Src N-terminus in the presence of lipids revealed a partially structured conformation of the UD through the contact of a small peptide sequence with membrane lipids and the SH3 domain of the protein (Perez et al, 2013; Maffei et al, 2015). This interaction was regulated by phosphorylation of Ser69 and Ser75 surrounded this central region. The aim of my thesis project was to assess the biological relevance of this structural data. Interestingly, I showed that expression of Src mutants with UD loss of function drastically affected Src activity and signaling in human non-transformed cells as well as Src oncogenic properties in metastatic colorectal cancer cells. This highlights the biomedical relevance of the system. Further proteomic analysis revealed an unsuspected mechanism by which this region controls the Src capacity to phosphorylate specific substrates involved in cancer cell activity. These data support a previously unrecognized important role of the UD on Src activity and signaling and reveals a critical role of intrinsic disordered domains in the regulation of kinase signaling in human disease. Targeting this unique region by small molecules may be of therapeutic value in human cancer
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Lin, Xiaofeng. "Probing the regulatory mechanisms of protein tyrosine kinases, using C-terminal SRC kinase (CSK) as a model system /." View online ; access limited to URI, 2005. http://0-wwwlib.umi.com.helin.uri.edu/dissertations/dlnow/3188064.
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Bouaouina, Mohamed. "Etude de la voie de signalisation activatrice des intégrines beta2 et beta3 dans les neutrophiles et les plaquettes." Paris 6, 2004. http://www.theses.fr/2004PA066013.
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Weir, Marion. "Novel Mechanisms Governing Autoregulation of the Src Family Kinase Fyn and its Crosstalk with Protein Kinase A." ScholarWorks @ UVM, 2016. http://scholarworks.uvm.edu/graddis/592.
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ABSTRACT
Phosphorylation is a post-translational modification important for regulating protein activity and protein binding capacity. It is used in many different signaling pathways within the cell. Src Family Kinases and Protein Kinase A (PKA) are two prototyptical non-receptor tyrosine and serine/ threonine kinases, respectively, which are found in canonical signaling pathways. These two kinases are critical for signaling in essentially every cell of a multicellular organism, and are particularly important in development, cell migration and proliferation. Although both proteins have been intensely studied for many decades, an understanding of the molecular mechanisms which govern their regulation and the regulation that they effect on other proteins are still being elucidated.
Fyn, like its related Src Family Kinase members, has previously been shown to be regulated by two tyrosine phosphorylation events at residues Y420 and Y531. Y420 is located in the kinase (Src Homology 1(SH1)) domain and it is a highly-characterized intermolecular autophosphorylation site that increases the activity of the kinase. Y531 is located near the C-terminus and is phosphorylated by C-terminal Src kinase (Csk). Phosphorylation of Y531 allows it to bind to R176 in the SH2 domain in an intramolecular fashion. In this conformation Fyn has only basal activity. Since these sites are essential for regulating the activity of the kinase, we hypothesized that four novel sites of tyrosine phosphorylation in Fyn could also importantly regulate the protein. Three of the novel sites lie in the SH2 domain, and one is located in the kinase domain. Mass spectrometry, in vitro kinase assays, as well as western blot analysis aided in uncovering that these novel Fyn phosphorylation sites fine tune the activity and substrate binding of the protein.
PKA has been implicated in a multitude of signaling pathways and is particularly important in cell growth, proliferation, and migration. Fyn and PKA have classically been considered to be in separate signaling pathways. However, research over the past several decades has provided evidence that there is crosstalk that exists between the two pathways. The SFK Fyn and PKA can phosphorylate each other, thereby regulating each other's activity. Based on these data, we hypothesized the existence of downstream effectors of this relatively uncharacterized pathway. It was hypothesized that the presence of Fyn could lead to PKA activation and to differences in PKA binding partners. Through the use of co-immunoprecipitations, Stable Isotope Labeling of Amino Acids in Cell Culture (SILAC) and quantitative mass spectrometry, many proteins were found to increase their binding to PKA in the presence of Fyn. Several proteins were selected and further biochemically validated. These data suggest that the presence of Fyn could allow for PKA to more importantly interact with discrete pools of proteins within the cell to effectuate its signal transduction. Together these studies provide understanding on critical and fundamental processes by which all cells function.
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Mitina, Olga. "Src kinases and Flt3 phosphorylation, interference with receptor maturation and mechanism of association /." Diss., [S.l.] : [s.n.], 2005. http://edoc.ub.uni-muenchen.de/archive/00004719.
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Ayrapetov, Marina K. "Structural and functional studies of the Csk and Src family protein tyrosine kinases /." View online ; access limited to URI, 2006. http://0-wwwlib.umi.com.helin.uri.edu/dissertations/dlnow/3225312.
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Xiao, Xiang, and 肖骧. "Regulation of spermatogenesis by intercellular adhesion molecules (ICAMS) and sarcoma (SRC) family kinases." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hub.hku.hk/bib/B4979940X.
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In rat testes, at stage VIII of the epithelial cycle of spermatogenesis, two cellular events, namely blood-testis barrier (BTB) restructuring and spermiation, take place simultaneously but at the opposite ends of the seminiferous epithelium. BTB is constituted by tight junctions (TJs), basal ectoplasmic specializations (ES), gap junctions and desmosomes, which must disassemble intermittently at stage VIII to facilitate preleptotene spermatocyte migration across the barrier. Synchronously, spermiation occurs at the luminal edge of the tubule lumen, involving the disruption of the apical ES, the only anchoring device there, and the release of sperm. The mechanism coordinating these events is not well understood. In this dissertation, I provide evidence that intercellular adhesion molecule (ICAM)-1 and -2, are working in concert with sarcoma (Src) family kinases to regulate these events.
ICAMs comprise an immunoglobulin subfamily of cell adhesion proteins expressed by hematopoietic, endothelial and epithelial cells. They are known to function in the transendothelial migration of leukocytes. In the rat testis, ICAM-1 was shown to localize to both BTB and apical ES stage-specifically, with its immunoreactivity highest at stage VIII at the BTB. Besides co-immunoprecipitation and co-localization with BTB proteins, such as occludin and N-cadherin, ICAM-1 was found to promote BTB integrity in that its over-expression (O-E) in Sertoli cells in vitro increased transepithelial electrical resistance (TER). However, O-E of a truncated form of ICAM-1 (sICAM-1) that only consisted of the extracellular domain resulted in decreased TER and down-regulation of several BTB constituent proteins, possibly via the Src/Pyk2 signaling pathway. O-E of sICAM-1 in vivo also compromised the BTB integrity. These findings illustrate that ICAM-1 is an important regulator of the BTB.
On the other hand, the localization of ICAM-2 was restricted to the Sertoli-germ cell interface and absent from the BTB, and associated with β1-integrin, nectin-3 and F-actin at the apical ES. Further, ICAM-2 was shown to interact with Src and Pyk2, as well as annexin II, a phospholipid-binding protein. Intriguingly, ICAM-2, Src and annexin II were specifically up-regulated during CdCl2-induced germ cell loss. These results reveal that ICAM-2 actively participates in the restructuring of apical ES based on studies using the cadmium model.
The function of c-Yes, a member of the Src family, was also investigated. It was found to be stage-specifically expressed at the BTB and the apical ES, and it structurally associated with BTB components (e.g., occludin and N-cadherin) and with the apical ES proteins (e.g., β1-integrin, laminin β3 and γ3). In the study, the knockdown of c-Yes by RNAi in vitro and in vivo affected BTB and apical ES function, causing changes in the distribution/localization of adhesion proteins at the BTB and the apical ES, inducing germ cell loss from the seminiferous epithelium, possibly via an interference with the F-actin network.
These findings implicate that ICAMs and c-Yes are regulatory molecules of cell adhesion at the BTB and the apical ES, and are biomarkers for male contraceptive development.published_or_final_version
Biological Sciences
Doctoral
Doctor of Philosophy
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Lang, Valérie. "Role des kinases src dans la phosphorylation de sam68 dans les lymphocytes t." Paris 6, 1999. http://www.theses.fr/1999PA066277.
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Sam68 (src-associated in mitosis) appartient a la famille des proteines gsg (pour grp33, sam68, gld-1) dont la fonction serait de lier l'export des arnm du noyau a des evenements de la signalisation par des mecanismes encore inconnus. Sam68 possede un domaine kh (hnrnpk homology) permettant son association a l'arn, un signal de localisation nucleaire, ainsi que plusieurs regions riches en proline et une partie c-terminale riche en tyrosine. Ceci lui permet d'interagir notamment avec les domaines sh (src homology)3 et sh2 des tyrosine kinases de la famille src, dont elle serait un substrat preferentiel. Deux ptk de la famille src, p56lck et p59fyn, avec lesquelles sam68 interagit, ont un role cle dans l'activation des lymphocytes t. Le but general de ce travail a ete de tenter de mieux comprendre comment s'effectuait dans ce modele cellulaire l'integration de sam68 en aval de ces deux molecules. Nous avons montre que la phosphorylation de sam68 augmente rapidement apres l'activation du rct. L'utilisation de cellules deficientes en p56lck nous a permis de decouvrir son importance dans le processus de phosphorylation de sam68 induit par la stimulation. Nos travaux suggerent une participation indirecte de p56lck dans ce processus a travers l'intervention de zap-70, une kinase cytosolique specifiquement exprimee par ces cellules et s'associant au rct active. Sam68 est egalement phosphorylee sur tyrosine de maniere constitutive, en dehors de toute stimulation du rct. Nous avons montre par l'utilisation de lymphocytes t surexprimant soit p56lck, soit p59fyn, que seule p59fyn est impliquee dans ce processus. Sam68 est tres fortement exprimee dans le noyau. Nous avons observe que, dans les cellules surexprimant p59fyn, cette forme nucleaire de sam68 est phosphorylee. Cependant, nous avons demontre, par l'utilisation de cellules surexprimant une forme de p59fyn mutee sur des residus essentiels pour son ancrage a la membrane, ainsi qu'en employant une forme de sam68 deletee de son domaine de localisation nucleaire ; que la phosphorylation de sam68 a lieu dans le compartiment membranaire. Une conclusion essentielle de ce travail est que la tyrosine phosphorylation de sam68 est un phenomene qui a lieu au contact des kinases src dans le compartiment membranaire. Il est seduisant d'imaginer un modele de circulation de sam68 a l'interieur de la cellule permettant la regulation de cette fonction de transport de l'arn par son etat de phosphorylation lie a la fois a sa repartition entre les deux compartiments ainsi qu'a l'etat d'activation et au niveau d'expression des ptk de la famille src auxquelles elle peut s'associer.
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Farard, Julien. "Conception rationnelle, synthèse et évaluation de dérivés hétérocycliques oxygénés à potentialité antitumorale." Nantes, 2008. https://archive.bu.univ-nantes.fr/pollux/show/show?id=f40d012d-692b-402b-99de-c93d12be5595.
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Malgré la découverte de nouvelles molécules antitumorales et l'application de nouveaux traitements, le cancer reste une des principales causes de décès dans les pays développés. Des travaux antérieurs réalisés au laboratoire ont montré que des composés à structure 1,4-benzoquinone possédaient des activités sur la protéine anti-apoptotique Bcl-XL et sur la protéine tyrosine kinase Src, toutes deux impliquées dans des pathologies cancéreuses. Dans le prolongement de ces travaux, des pharmacomodulations ont été réalisées autour du noyau benzoquinone, sans permettre l'amélioration des activités existantes. Notre intérêt s'est ensuite porté sur la conception et l'élaboration de nouveaux dérivés hétérocycliques oxygénés possibles inhibiteurs de Src kinase. Ainsi, la synthèse puis l'évaluation de composés possédant un noyau central 4H-pyran-4-one et 4H-pyrano[3,2-c]pyridin-4-one ont été effectuées via le développement de réactions d'amination palladocatalysée et d'hétérocyclisationDespite the discovery of novel antitumor agents and the application of new treatments, cancer remains one of the main cause of death in developed countries. Previous work in our laboratory demonstrated that 1,4-benzoquinone compounds exhibited a promising activity towards anti-apoptotic Bcl-XL protein and Src protein tyrosine kinase, both implied in cancerous pathologies. Expanding on this study, pharmacomodulations around benzoquinone moiety were realized, without allowing the improvement of existing activities. Then, our interest went on the design and the development of new oxygenated heterocyclic derivatives as potential Src kinase inhibitors. Thus, synthesis and evaluation of compounds containing a 4H-pyran-4-one and a 4H-pyrano[3,2-c]pyridin-4-one moiety was carried out via the development of a palladium-catalyzed amination reaction and a heterocyclisation reaction
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Carreno, Sébastien. "Etude moléculaire et cellulaire des fonctions associées à chacune des isoformes de la protéine tyrosine kinase Hck dans les phagocytes." Toulouse 3, 2001. http://www.theses.fr/2001TOU30196.
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Verachini, Laurence. "Rôle de la compartimentation subcellulaire des tyrosine kinases Src dans la signalisation induite par le PDGF." Montpellier 2, 2007. http://www.theses.fr/2007MON20160.
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Mon travail de thèse a consisté en l'étude de la régulation spatiale des tyrosine kinases Src dans la signalisation induite par le PDGF. J'ai montré que deux populations de Src étaient impliquées dans deux réponses cellulaires distinctes : la première localisée dans les caveolae est impliquée dans la synthèse d'ADN et la seconde située en dehors de ces structures induit la formation des ruffles dorsaux d'actine. Ce travail a également révelé une nouvelle fonction de la protéine adaptatrice transmembranaire CBP/PAG. En modulant le taux membranaire du ganglioside GM1, CBP/PAG affecte la localisation du récepteur du PDGF dans les caveolae inhibant ainsi son association avec Src. Cette nouvelle fonction est dépendante de l'enzyme sialidase Neu3 qui permet la synthèse du GM1 dans les caveolae. Ce travail met en évidence le rôle crucial de la compartimentation subcellulaire des kinases Src dans la régulation de leur fonction et un nouveau mécanisme de régulation de la voie Src mitogénique via CBP/PAGDuring the course of my work, I focused on the study of Src kinases regulation in PDGF-induced signaling. Firstly, we show that PDGF uses two distinct pools of Src kinases for mitogenesis and cystoskeleton rearrangement: the first one localized in caveolae is involved in DNA synthesis and the second one localized outside these structures induces dorsal ruffles formation. Secondly, our data identify a new mechanism for Src mitogenic regulation involving the transmembrane adaptor protein CBP/PAG. By modulating ganglioside GM1 membrane level, CBP/PAG displaces PDGF receptor from caveolae which prevents Src activation and mitogenic signaling. In addition, CBP/PAG-induced GM1 accumulation depends on the Neu3 sialidase, an enzyme of gangliosides metabolism. In conclusion, this work provides strong evidence that spatial regulation of Src kinases is an important feauture of signaling specificity and report a novel regulatory mechanism of Src mitogenic function by CBP/PAG
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Quek, Lynn S. "Regulation of platelet activation by the Src and Tec families of cytoplasmic tyrosine kinases." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343560.
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Tatarov, Oleg. "The role of SRC family kinases in the development and progression of prostate cancer." Thesis, University of Glasgow, 2010. http://theses.gla.ac.uk/1608/.
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Prostate cancer is the most common cancer in men and the second leading cause of cancer-related death in western world. Typically, the treatment of advanced and metastatic prostate cancer consists of castration therapy, which suppresses the development of the disease for 2 years in average. Virtually all patients, undergoing androgen deprivation therapy eventually develop castration-resistant prostate cancer. Currently, only taxane class of drugs has been proven to provide short survival advantage in patients with castration-resistant prostate cancer. This form of the disease is the cause of significant morbidity, resulting in long periods of gradual deterioration of patients’ condition, pain related to local extension of the tumour and distant metastases, renal failure due to the invasion into the ureters etc. Castration resistance allows prostate tumours to progress despite androgen deprivation. Several mechanisms have been described, outlining the nature of molecular pathways, employed by prostate cancer cells in order to proliferate and migrate in low androgen environment. Hormone-sensitive prostate cancer cells rely on androgens for their growth needs with androgens acting through the androgen receptor (AR). In castration-resistant prostate cancer AR can be activated by reduced concentrations of androgens, AR antagonists, protein kinases or bypassed altogether. Detailed knowledge of these processes should allow better understanding of molecular patterns, driving the progression of prostate cancer and, ultimately, could lead to the development of novel molecular targeted therapies. Molecular pathways, implicated in the development of castration-resistant prostate cancer frequently show cross-talk, resulting in the ability of cancer cells to adapt to changing microenvironment. Inhibiting the proteins, facilitating these cross-talks provides an attractive targeting mechanism. Src family of non-receptor tyrosine kinases (SFK) represent proteins involved in the development of various solid malignancies, including prostate cancer. These proteins are often found on the cross-roads of intracellular pathways, integrating molecular systems into complex signalling networks. SFK interact with receptor tyrosine kinases, G-protein coupled receptors, motility and adhesion factors and, thus, influence multiple cell functions. In prostate cancer, SFK have been demonstrated to form complexes with AR, activating AR by means of tyrosine phosphorylation. SFK inhibitory compounds have been developed and are now in Phase II clinical trial in patients with castration-resistant prostate cancer. However, there is considerable lack of data regarding the role of SFK expression and activation in prostate cancer in clinical settings. In this thesis, we studied the role of SFK in prostate cancer using matched paired prostate cancer samples, taken from patients prior to castration therapy being administered and following the development of castration resistance. Using paired tissue specimens allows following molecular changes through the natural history of the disease and correlating these changes with various clinical parameters. We also conducted in vitro experiments, employing hormone-sensitive LNCaP cell line and its counterpart, castration-resistant LNCaP-SDM cell line, developed by gradual withdrawal of androgens from the culture medium. Our main finding is that in a subgroup of prostate cancer patients, the increase in SFK activity in the transition of prostate cancer from hormone-sensitive to castration-resistant state is associated with significant decrease in survival (p<0.0001). Furthermore, the presence of bone metastases in patients with castration-resistant prostate cancer was associated with higher SFK activity in prostate tissue specimens. Our in vitro experiments have demonstrated that in prostate cancer the relationship between SFK and AR are important as androgen deprivation resulted in significant reduction in SFK activity. Using SFK inhibitor dasatinib, we have shown that in prostate cancer cell lines, SFK activity was inhibited at low nanomolar concentrations. Inhibition of SFK activity was accompanied by the inhibition of downstream protein FAK at Src-specific phsophorylation site. Although the treatment with SFK inhibitor suppressed migration of both LNCaP and LNCaP-SDM cell lines, only proliferation of LNCaP-SDM cell was affected by dasatinib. Taken together, our date suggests that SFK inhibitors may have a role in the treatment of castration-resistant prostate cancer. However, important considerations should be given to the molecular heterogeneity of prostate cancer in order to improve the outcomes of clinical trials and the response to treatment. There is considerable evidence that SFK inhibitors suppress prostate cancer cells migration and future studies will hopefully further clarify their role in cancer cells proliferation.
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Schäfer, Luisa [Verfasser], and Silke [Akademischer Betreuer] Laßmann. "Protein expression and interaction of the kinases Src and Aurora A in esophageal carcinoma." Freiburg : Universität, 2021. http://d-nb.info/1230321934/34.
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Kypta, Robert Martin. "The identification and characterisation of members of the src family of protein tyrosine kinases." Thesis, University College London (University of London), 1991. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.278797.
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Dietrich, Joanna Louise. "Phosphorylation of human platelet cytosolic phospholipase A₂ by the Src-family protein tyrosine kinases." Thesis, University of Cambridge, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621659.
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BOULET, ISABELLE. "Etude fonctionnelle de proteines tyrosines kinases de la famille src dans des cellules hematopoietiques." Paris 7, 1991. http://www.theses.fr/1991PA077140.
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Les tyrosines kinases de la famille src semblent participer a la transduction des signaux de proliferation et de differenciation. L'activite kinase de ces proteines et leur activite fonctionnelle sont indissociables. Quatre des neuf genes de la famille src sont exprimes de facon predominante dans les cellules hematopoietiques, il s'agit de src, lck, hck, fgr; ces proteines seraient impliquees dans l'activation des cellules dans lesquelles elles sont exprimees. Nous nous sommes interesses a l'activite fonctionnelle de trois tyrosines kinases de la famille src exprimees dans les cellules hematopoietiques, lck, lyn et hck. Nous avons etudie les facteurs regulant l'activite kinase, en prenant pour modele la p561ck. Nous montrons que l'autophosphorylation pourrait constituer un mecanisme activateur de l'activite kinase. Nous nous sommes ensuite interesses a l'activation des macrophages et avons examine la participation de lyn et hck, specifiques des cellules myeloides. Le niveau de stimulation des macrophages, mesure par quantification de la capacite cellulaire a generer une explosion respiratoire, et le niveau d'expression de lyn et hck subissent une evolution similaire au cours du temps, suggerant que lyn et hck pourraient participer a la stimulation de l'explosion respiratoire. Pour evaluer le role de la phosphorylation sur tyrosine dans la stimulation de cette reaction, nous avons utilise un inhibiteur des tyrosines phosphatases, le vanadate. Celui-ci est capable d'initier l'explosion respiratoire, suggerant que la phosphorylation sur tyrosine, potentiellement par a lyn et hck pourrait en effet etre un mecanisme activateur
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BOUGERET, CECILE. "Mecanismes de regulation de la proteine tyrosine kinase p50csk responsable de l'inhibition des proteines tyrosine kinases de la famille src." Paris 7, 1994. http://www.theses.fr/1994PA077207.
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L'activite kinase des proteines tyrosine kinases (ptks) de la famille src est regulee par phosphorylation de deux residus tyrosine tres conserves, l'un localise dans le domaine catalytique et implique dans une regulation positive par autophosphorylation, l'autre localise dans le domaine regulateur carboxy-terminal et implique dans une regulation negative. La kinase responsable de la phosphorylation du site de regulation negative est la ptk ubiquitaire p50csk qui contient les domaines src homology 3 et 2 (sh3 et sh2) impliques dans les interactions proteine-proteine permettant la transduction des signaux. La proteine csk est unique parmi les membres des ptks car elle a ete decrite comme ne possedant pas les sites tyrosine conserves de regulation de l'activite kinase, de ce fait les mecanismes de regulation de la fonction de csk ne sont pas connus. Le role majeur de la proteine csk dans l'inhibition des ptks de la famille src nous a conduit a etudier les mecanismes impliques dans la regulation de son activite kinase. D'une part, nous avons observe que dans un systeme surexpression procaryote, la proteine csk est capable de s'autophosphoryler sur residu tyrosine. Cette autophosphorylation a lieu suivant un mecanisme intermoleculaire et semble impliquee dans une regulation negative de l'activite kinase. D'autre part, nous avons detecte une interaction fonctionnelle entre csk et l'un de ses substrats, la ptk de la famille src p561ck. Cette interaction implique le domaine sh2 de csk et requiert l'autophosphorylation de lck sur son site de regulation positive, ce qui suggere que cette interaction est regulee par l'etat d'activation de lck. Nous proposons donc deux mecanismes de regulation de la fonction de csk, (1) une regulation directe par autophosphorylation de csk, et (2) une regulation indirecte via le domaine sh2 de csk par interaction de ce domaine avec les substrats de csk, ces deux mecanismes n'etant pas exclusifs l'un de l'autre
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Jetté, Alexandra. "Le rétromère : une nouvelle cible des kinases Src dans le transport polarisé et l'invasion tumorale." Master's thesis, Université Laval, 2015. http://hdl.handle.net/20.500.11794/26417.
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Tableau d'honneur de la Faculté des études supérieures et postdorales, 2015-2016Src régule le remodelage du cytosquelette d’actine et les propriétés invasives des cellules. Une régulation spatio-temporelle du transport endosomal polarisé est nécessaire pour ces fonctions et le rétromère, un substrat de Src, est un élément crucial de ce trafic. Nous avons postulé que le rétromère pourrait moduler le transport requis pour le remodelage cellulaire et la migration induits par Src. Nous montrons qu’une perte de fonction du rétromère dans des cellules épithéliales exprimant v-Src mène à la formation d’invadosomes désorganisés et anormalement stables, mais toujours aptes à dégrader la matrice extracellulaire. Dans un modèle de cellules cancéreuses, une perte de fonction du rétromère diminue la migration en affectant la polarisation et la directionalité des cellules, mais augmente la migration trans-endothéliale. Nos résultats suggèrent un rôle pour le rétromère en aval de Src dans le remodelage de l’actine, la polarité, la migration cellulaire et l’invasion, possiblement par la phosphorylation du rétromère.
Src-family kinases (Src) modulate actin cytoskeleton remodeling and tumor cell invasive properties. Directional endosomal trafficking needs to be regulated in time and space to support these processes, but little is known on the mechanisms involved. The retromer, a Src kinase target, is emerging as a key player of endosomal recycling. We postulated that the retromer could modulate the polarized trafficking of endosomes required to support Src-induced cell remodeling and migration. We show that retromer loss of function caused the assembly of disorganized, more stable invadosomes in epithelial cells expressing v-Src, which were nevertheless able to degrade extracellular matrix. In a cancer cell model, inhibition of retromer function reduced cell migration by affecting polarization and directionality of cells, but promoted transendothelial cancer cell migration. The results thus suggest the existence of a phosphorylation-regulated function for the retromer downstream of Src in actin remodeling, cell polarity, cell migration and invasion.
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Wolven, Amy K. "The role of the acylated amino terminus of FYN in mediating membrane binding /." Access full-text from WCMC, 1998. http://proquest.umi.com/pqdweb?did=733098911&sid=7&Fmt=2&clientId=8424&RQT=309&VName=PQD.
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Page, Stephanie T. "Signaling and lineage relationships during intraepithelial lymphocyte development /." Thesis, Connect to this title online; UW restricted, 1997. http://hdl.handle.net/1773/8362.
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Lennmyr, Fredrik. "Signal Transduction in Focal Cerebral Ischemia : Experimental Studies on VEGF, MAPK and Src family kinases." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2002. http://publications.uu.se/theses/91-554-5267-1/.
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Shi, Xiaoli. "Etude de la spécificité des interactions protéine-protéine : application au complexe Alix-domaine SH3 des Src Kinases." Thesis, Aix-Marseille 1, 2011. http://www.theses.fr/2011AIX10024/document.
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Les domaines SH3 (Src Homology domain) représentent l'un des modules protéiques le plus largement répandu dans la nature. Ils participent à des interactions intra- et intermoléculaires avec d’autre partenaires au travers de la formation et de la dissociation de complexes multi-protéiques. Le gène nef du Virus d'Immunodéficience Humain (VIH-1) code pour la protéine nef, importante pour la réplication du virus et le développement optimal du SIDA (Syndrome d’Immunodéficience Acquise) chez les personnes infectées. De précédentes études ont mis en évidence que la protéine nef utilise un mode « tertiaire » d’interaction pour mettre en place une affinité et une sélectivité élevées envers les domaines SH3 des kinases de la famille Src (SFKs). Savoir si cette stratégie de reconnaissance tertiaire des domaines SH3 peut être retrouvée dans des protéines cellulaires humaines est donc une question importante pour évaluer le degré de spécificité de la protéine nef comme cible anti-HIV. Nous avons identifié Alix (ALG-2 [apoptosis-linked gene 2]-interacting protein X) comme protéine originale interagissant avec le domaine SH3 de la kinase de cellules Hématopoïétique (Hck). Alix possède une sélectivité comparable à nef envers les domaines SH3 de SFKs. Nous avons combiné une analyse biophysique et structurale, alliant des méthodes telles que la microcalorimetrie à titration isotherme(‘ITC’), la Résonance Plasmonique de Surface (‘SPR’), des méthodes in vitro dites de ‘GST pulldown’, l'interférométrie (‘NPOI’), la Résonance Magnétique Nucléaire (‘NMR’ - HSQC) et la diffusion des rayons X aux petits angles (SAXS) pour explorer les caractéristiques définissant le mode d’interaction entre Alix et le domaine SH3 de la kinase Hck. Cette étude démontre que la protéine cellulaire Alix est unique, structurellement différente mais fonctionnellement semblable à nefSrc homology (SH) 3 domains is one of the most wide-spreaded protein modules found in nature. They mediate both inter- and intra-molecular protein-protein interactions (PPIs) through the formation and dissociation of multi-protein complexes. These SH3-mediated interactions are responsible for signal transduction, cytoskeleton organization and other cellular processes. The nef gene of Human immunodeficiency virus (HIV-1) encodes the HIV-1 Nef protein, which is important for optimal virus replication and development of AIDS (acquired immunize deficiency syndrome) in HIV-1 infected persons. Previous studies show that the HIV-1 Nef protein uses a “tertiary” binding mode to achieve high affinity and selectivity toward SH3 domains of Src-family kinases (SFKs). Whether this strategy of ‘tertiary’ binding mode of SH3 domains can be found in human cellular proteins, besides HIV-1 Nef, is an important question in the specificity of the HIV-1 Nef protein as an anti-HIV target. We identified Alix (ALG-2 [apoptosis-linked gene 2]-interacting protein X) as a novel protein interacting with Hemopoietic cell kinase (Hck) SH3 domain. Alix has similar selectivity towards SH3 domains of SFKs as the HIV-1 Nef. We have combined biophysical and structural biology analysis, including ITC (isothermal titration calorimetry), SPR (surface Plasmon resonance), GST (glutathione S-transferase) pull-down, interferometry, HSQC (heteronuclear single quantum coherence) and SAXS (small-angle X-ray scattering) to explore the characteristics of Alix-SH3 recognition mode. This study shows that Alix as a unique cellular protein, which is structurally different but functionally similar in recognizing HIV-1 Nef. The structural information of the Alix-Hck association facilitates the understanding of how Hck and Alix assist viral budding and cell surface receptor regulation
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Manes, Gae͏̈l. "Slap (Src-like adaptor protein)régulateur négatif de la croissance cellulaire induite par les tyrosine kinases." Montpellier 1, 1999. http://www.theses.fr/1999MON1T019.
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Arold, Stefan. "Etude structurale et thermodynamique de l'interaction de la protéine Nef des virus d'immunodéficience avec les domaines SH3 de protéine-tyrosine kinases de la famille Src." Montpellier 1, 1998. http://www.theses.fr/1998MON13510.
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Koh, Wonshill. "Molecular control of endothelial lumen formation by Rho GTPases in three dimensional collagen matrices." Diss., Columbia, Mo. : University of Missouri-Columbia, 2008. http://hdl.handle.net/10355/6045.
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Thesis (Ph. D.)--University of Missouri-Columbia, 2008.The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Vita. "May 2008" Includes bibliographical references.
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Picard, Christophe. "Régulations intramoléculaires et intermoléculaires des membres de la famille Src : implication des interactions du domaine SH3 avec l'interdomaine." Aix-Marseille 2, 2003. http://www.theses.fr/2003AIX20658.
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Les protéines Tyrosine kinase de la famille Src sont impliquées dans de nombreux processus physiologiques. Leur activité est régulée par des mécanismes qui modifient les contraintes moléculaires. Notre travail a apporté de nouvelles connaissances sur le rôle du domaine d'interaction SH3 et de l'interdomaine dans la régulation inter-et intra-moléculaire des protéines Src. Nous avons déterminé le mécanisme explicitant la spécificité d'interaction des protéines virales Nef pour le domaine SH3 de certaines protéines Src. De plus, nous avons validé un modèle d'étude de la pathogénie du SIDA. Enfin, l'analyse des deux isoformes de Fyn qui diffèrent par leur interdomaine nous a permis de mieux comprendre l'émergence du système immunitaire adaptatif et la fonction des interdomaines dans la sélection des substrats et dans la régulation intramoléculaire des protéines Src. Les conséquences potentielles morbides et thérapeutiques des anomalies de la réglation des protéines Src sont discutées.
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Tian, Jiang. "Na/K-ATPase : a signaling receptor." Connect to Online Resource-OhioLINK, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=mco1175177603.
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Thesis (Ph.D.)--University of Toledo, 2006."In partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Sciences." Major advisor: Zi-Jian Xie. Includes abstract. Title from title page of PDF document. Bibliography: pages 64-70, 104-108, 121-158.
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Van, Ziffle Jessica Ann Grant. "Src-family and Syk tyrosine kinases are required for neutrophil effector responses to infection and inflammation." Diss., Search in ProQuest Dissertations & Theses. UC Only, 2009. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3390082.
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Smolinska-Bylanska, Maria Joanna. "Investigation of the role of SRC family kinases in LPS-induced activation of primary human macrophages." Thesis, Imperial College London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.428071.
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Banin, Sharon. "Identification and characterisation of the interaction between Wiskott-Aldrich Syndrome Protein (WASP) and c-src kinases." Thesis, University College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264343.
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Kemble, David J. "A biochemical study on the regulation of the SRC and FGFR family of protein tyrosine kinases /." View online ; access limited to URI, 2009. http://0-digitalcommons.uri.edu.helin.uri.edu/dissertations/AAI3367994.
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Powell, Arfon Gethyn Morgan Tregellis. "The role of cancer related inflammation, Src family kinases and matrix metalloproteinase 9 in colorectal cancer." Thesis, University of Glasgow, 2016. http://theses.gla.ac.uk/7652/.
Full textAbstract:
Colorectal cancer (CRC) is the third most common cancer in the UK with 41,000 new cases diagnosed in 2011. Despite undergoing potentially curative resection, a significant amount of patients develop recurrence. Biomarkers that aid prognostication or identify patients who are suitable for adjuvant treatments are needed. The TNM staging system does a reasonably good job at offering prognostic information to the treating clinician, but it could be better and identifying methods of improving its accuracy are needed. Tumour progression is based on a complex relationship between tumour behaviour and the hosts’ inflammatory responses. Sustained tumour cell proliferation, evading growth suppressors, resisting apoptosis, replicative immortality, sustained angiogenesis, invasion & metastasis, avoiding immune destruction, deregulated cellular energetics, tumour promoting inflammation and genomic instability & mutation have been identified as hallmarks. These hallmarks are malignant behaviors are what makes the cell cancerous and the more extreme the behaviour the more aggressive the cancer the more likely the risk of a poor outcome. There are two primary genomic instability pathways: Microsatellite Instability (MSI) and Chromosomal Instability (CI) also referred to as Microsatellite Stability (MSS). Tumours arising by these pathways have a predilection for specific anatomical, histological and molecular biological features. It is possible that aberrant molecular expression of genes/proteins that promote malignant behaviors may also act as prognostic and predictive biomarkers, which may offer superior prognostic information to classical prognostic features. Cancer related inflammation has been described as a 7th hallmark of cancer. Despite the systemic inflammatory response (SIR) being associated with more aggressive malignant disease, infiltration by immune cells, particularly CD8+ lymphocytes, at the advancing edge of the tumour have been associated with improved outcome and tumour MSI. It remains unknown if the SIR is associated with tumour MSI and this requires further study. The mechanisms by which colorectal cancer cells locally invade through the bowel remain uncertain, but connective tissue degradation by matrix metalloproteinases (MMPs) such as MMP-9 have been implicated. MMP-9 has been found in the cancer cells, stromal cells and patient circulation. Although tumoural MMP-9 has been associated with poor survival, reports are conflicting and contain relatively small sample sizes. Furthermore, the influence of high serum MMP-9 on survival remains unknown. Src family kinases (SFKs) have been implicated in many adverse cancer cell behaviors. SFKs comprise 9 family members BLK, C-SRC, FGR, FYN, HCK, LCK, LYN, YES, YRK. C-SRC has been the most investigated of all SFKs, but the role of other SFKs in cellular behaviors and their prognostic value remains largely unknown. The development of Src inhibitors, such as Dasatinib, has identified SFKs as a potential therapeutic target for patients at higher risk of poor survival. Unfortunately, clinical trials so far have not been promising but this may reflect inadequate patient selection and SFKs may act as useful prognostic and predictive biomarkers. In chapter 3, the association between cancer related inflammation, tumour MSI, clinicopathological factors and survival was tested in two independent cohorts. A training cohort consisting of n=182 patients and a validation cohort of n=677 patients. MSI tumours were associated with a raised CRP (p=0.003). Hypoalbuminaemia was independently associated with poor overall survival in TNM stage II cancer (HR 3.04 (95% CI 1.44 – 6.43);p=0.004), poor recurrence free survival in TNM stage III cancer (HR 1.86 (95% 1.03 – 3.36);p=0.040) and poor overall survival in CI colorectal cancer (HR 1.49 (95% CI 1.06 – 2.10);p=0.022). Interestingly, MSI tumours were associated with poor overall survival in TNM stage III cancer (HR 2.20 (95% CI 1.10 – 4.37);p=0.025). In chapter 4, the role of MMP-9 in colorectal cancer progression and survival was examined. MMP-9 in the tissue was assessed using IHC and serum expression quantified using ELISA. Serum MMP-9 was associated with cancer cell expression (Spearman’s Correlation Coefficient (SCC) 0.393, p<0.001)) and stromal expression (SCC 0.319, p=0.002). Serum MMP-9 was associated with poor recurrence-free (HR 3.37 (95% CI 1.20 – 9.48);p=0.021) and overall survival (HR 3.16 (95% CI 1.22 – 8.15);p=0.018), but tumour MMP-9 was not survival or MSI status. In chapter 5, the role of SFK expression and activation in colorectal cancer progression and survival was studied. On PCR analysis, although LYN, C-SRC and YES were the most highly expressed, FGR and HCK had higher expression profiles as tumours progressed. Using IHC, raised cytoplasmic FAK (tyr 861) was independently associated with poor recurrence free survival in all cancers (HR 1.48 (95% CI 1.02 – 2.16);p=0.040) and CI cancers (HR 1.50 (95% CI 1.02 – 2.21);p=0.040). However, raised cytoplasmic HCK (HR 2.04 (95% CI 1.11 – 3.76);p=0.022) was independently associated with poor recurrence-free survival in TNM stage II cancers. T84 and HT29 cell lines were used to examine the cellular effects of Dasatinib. Cell viability was assessed using WST-1 assay and apoptosis assessed using an ELISA cell death detection assay. Dasatinib increased T84 tumour cell apoptosis in a dose dependent manner and resulted in reduced expression of nuclear (p=0.008) and cytoplasmic (p=0.016) FAK (tyr 861) expression and increased nuclear FGR expression (p=0.004). The results of this thesis confirm that colorectal cancer is a complex disease that represents several subtypes of cancer based on molecular biological behaviors. This thesis concentrated on features of the disease related to inflammation in terms of genetic and molecular characterisation. MSI cancers are closely associated with systemic inflammation but despite this observation, they retain their relatively improved survival. MMP-9 is a feature of tissue remodeling during inflammation and is also associated with degradation of connective tissue, advanced T-stage and poor outcome when measured in the serum. The lack of stromal quantification due to TMA use rather than full sections makes the value of tumoural MMP-9 immunoreactivity in the prognostication and its association with MSI unknown and requires further study. Finally, SFK activation was also associated with SIR, however, only cytoplasmic HCK was independently associated with poor survival in patients with TNM stage II disease, the group of patients where identifying a novel biomarker is most needed. There is still some way to go before these biomarkers are translated into clinical practice and future work needs to focus on obtaining a reliable and robust scientific technique with validation in an adequately powered independent cohort.