I. Timokhina et al., KIT SIGNALING THROUGH PI-3-KINASE AND SRC KINASE PATHWAYS - AN ESSENTIAL ROLE FOR RAC1 AND JNK ACTIVATION IN MAST-CELL PROLIFERATION, EMBO journal (Print), 17(21), 1998, pp. 6250-6262
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.