New role for Shc in activation of the phosphatidylinositol 3-kinase/Akt pathway

Most, if not all, cytokines activate phosphatidylinositol 3-kinase (PI-3K). Although many cytokine receptors have direct binding sites for the p85 sub unit of PI-3K, others, such as the interleukin-3 (IL-3) receptor beta commo n chain (beta c) and the IL-2 receptor beta chain (IL-2R beta), lack such s ites, leaving the mechanism by which they activate PI-3K unclear. Here, we show that the protooncoprotein Shc, which promotes Ras activation by recrui ting the Grb2-Sos complex in response to stimulation of cytokine stimulatio n, also signals to the PI-3K/Akt pathway. Analysis of Y--> F and "add-back" mutants of beta c show's that Y577, the Shc binding site, is the major sit e required for Gab2 phosphorylation in response to cytokine stimulation. Wh en fused directly to a mutant form of IL-2R beta that lacks other cytoplasm ic tyrosines. Shc can promote Gab2 tyrosyl phosphorylation. Mutation of the three tyrosyl phosphorylation sites of Shc, which bind Grb2, blocks the ab ility of the Shc chimera to evoke Gab2 tyrosyl phosphorylation. Overexpress ion of mutants of Grb2 with inactive SH2 or SH3 domains also blocks cytokin e-stimulated Gab2 phosphorylation. The majority of cytokine-stimulated PI-3 K activity associates with Gab2, and inducible expression of a Gab2 mutant unable to bind PI-3K markedly impairs IL-3-induced Akt activation and cell growth. Experiments with the chimeric receptors indicate that Shc also sign als to the PI-3K/Akt pathway in response to IL-2, Our results suggest that cytokine receptors lacking direct PI-3K binding sites activate Akt via a Sh c/Grb2/Gab2/PI-3K pathway, thereby regulating cell survival and/or prolifer ation.