Studies on normal and oncogenic kit receptor signaling in primary murine mast cells and gastrointestinal stromal tumors
FacultiesFakultät für Naturwissenschaften
LicenseStandard (Fassung vom 03.05.2003)
Kit is a receptor tyrosine kinase that is activated by Kit ligand (KitL). It plays a role in hematopoiesis, gametogenesis, melanogenesis and intestinal tract motility. In this study the importance of Kit tyrosine 567 (Y567) and Kit tyrosine 719 (Y719) for cellular events and downstream Kit signaling as well as the mechanism of oncogenic Kit receptor signaling in gastrointestinal stromal tumors (GISTs) were investigated in knock-in mouse models. The Kit Y567 and Kit Y719 binding sites were abolished by mutation into phenylalanines. Comparing primary mast cells from wildtype and mutant mice with respect to their Kit/KitL mediated biological functions revealed that abolishing Y719 decreased survival, proliferation, degranulation, chemotaxis and adhesion, while abolishing Y567 led to increased survival, proliferation and adhesion, whereas chemotaxis was reduced. Molecular mechanisms for the differences detected were sought by characterizing protein activation upon KitL stimulation in wild type and mutant mast cell lysates. Based on a Kit activating mutation found in a case of human familial GIST syndrome, a knock-in mouse model for GISTs deleting Kit valine 558 had been created in the lab. Using this mouse model, mechanisms of oncogenic Kit signaling and consequences of therapeutic intervention were investigated. Treatment of the mice with the Kit kinase inhibitor imatinib led to the induction of apoptosis and the arrest of cell cycle progression in GIST. Biochemical analysis of tumor lysates after imatinib treatment showed diminished PI3K and mTOR signaling suggesting that Kit signaling critically contributes to the translational response in GIST. Accordingly, treatment with RAD001, an mTOR inhibitor, diminished the translational response and cell proliferation in the tumors. These studies aimed at identifying critical components implicated in the response to therapy, a necessary step towards the development of new strategies for treatment of imatinib resistant GISTs.
Subject HeadingsImatinib mesilat [GND]
Signal transduction [LCSH]
Mast cells [MeSH]