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Mutational and pharmacological analysis of C-Kit-mediated, integrin-dependent cell spreading

Defense Thèse de doctorat : Univ. Genève, 2018 - Sc. 5187 - 2018/02/02
Abstract KitL and its receptor c-Kit form a paracrine system that permits cells to respond to their microenvironment. The c-Kit kinase activating mutations can cause mastocytosis as well as Gastrointestinal Stromal Tumors and Leukemias. Although successful clinical treatments with kinase inhibitors, notably imatinib, a tumor cell population persist within the tumoral microenvironment. Does KitL/c-Kit contribute to the niche-based interactions even in the presence of kinase inhibition? By using a “niche model” we showed that bound-KitL might bind to and stabilize c-Kit in an active conformation, which is insensitive to imatinib but not to dasatinib. In this “mechanically active” state, c-Kit might recruit the PI3K which in turns induces a kinase-independent spreading response. Moreover, we showed that the constitutively active kinases W556A and D814V caused a non-spread phenotype which seems to be reverted with imatinib. A better understanding of tumor cell interactions is essential to design drugs that specifically target oncogenic proteins and the tumor microenvironment.
Keywords C-KitKit ligandTyrosine Kinase ReceptorTyrosine Kinase InhibitorImatinibDasatinibIntegrinsFibronectinSpreadingSignalingNicheCancer
URN: urn:nbn:ch:unige-1032040
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Research group Migration cellulaire (645)
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CALDERIN SOLLET, Zuleika. Mutational and pharmacological analysis of C-Kit-mediated, integrin-dependent cell spreading. Université de Genève. Thèse, 2018. doi: 10.13097/archive-ouverte/unige:103204 https://archive-ouverte.unige.ch/unige:103204

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Deposited on : 2018-03-26

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