KIT SIGNALING THROUGH PI-3-KINASE AND SRC KINASE PATHWAYS - AN ESSENTIAL ROLE FOR RAC1 AND JNK ACTIVATION IN MAST-CELL PROLIFERATION

The receptor tyrosine kinase Kit plays critical roles in hematopoiesis , gametogenesis and melanogenesis. In mast cells, Kit receptor activat ion mediates several cellular responses including cell proliferation a nd suppression of apoptosis induced by growth factor deprivation apd g amma-irradiation. Kit receptor functions are mediated by kinase activa tion, receptor autophosphorylation and association with various signal ing molecules. We have investigated the role of phosphatidylinositol 3 '-kinase (PI 3-kinase) and Src kinases in Kit-mediated cell proliferat ion and suppression of apoptosis induced both by factor deprivation an d irradiation in bone marrow-derived mast cells (BMMC). Analysis of Ki t(-/-) BMMC expressing mutant Kit receptors and the use of pharmacolog ical inhibitors revealed that both signaling pathways contribute to th ese Kit-mediated responses and that elimination of both pathways aboli shes them. We demonstrate that the PI 3-kinase and Src kinase signalin g pathways converge to activate Rad and JNK. Analysis of BMMC expressi ng wild-type and dominant-negative mutant forms of Rad and JNK reveale d that the Rac1/JNK pathway is critical for Kit ligand (KL)-induced pr oliferation of mast cells but not for suppression of apoptosis. In add ition, KL was shown to inhibit sustained activation of JNK induced by gamma-irradiation and concomitant irradiation-induced apoptosis.