The Kit receptor promotes cell survival via activation of PI 3-kinase and subsequent Akt-mediated phosphorylation of Bad on Ser136

The c-kit-encoded receptor protein tyrosine kinase for stem cell factor (Kit/SCF-R) is essential for the development of cells within the hematopoietic, melanogenic and gametogenic lineages [1]. SCF stimulation induces activation of phosphatidylinositol (PI) 3-kinase, which is required for SCF-induced mitogenesis and cell survival [2-4], and for activation of the serine/threonine protein kinase Akt [5-7]. Using Kit/SCF-R mutants, we found that, in response to SCF, Akt became activated and mediated phosphorylation of Bad, a pro-apoptotic molecule, in a PI-3-kinase-dependent manner. Phosphorylation of Bad was restricted to Ser112 and Ser136 in vivo, but only the Akt phosphorylation site Ser136 was essential for SCF-promoted cell survival. Furthermore, Bad and Akt interacted and colocalized in intact cells. A Kit/SCF-R gain of-function mutant that has increased mitogenic and PI 3-kinase activation potential, due to the absence of the two protein kinase C negative feedback phosphorylation sites [8,9], enhanced both Akt activation and Bad phosphorylation and also resulted in increased cell survival. Such a mechanism may account for how deregulated PI 8 kinase activity and naturally occurring gain-of-function point mutants of Kit/SCF-R lead to cellular transformation and fatal malignancies in man [10-12]. (C) Current Biology Ltd.