New Role for Shc in Activation of the Phosphatidylinositol 3-Kinase/Akt Pathway

摘要: Most, if not all, cytokines activate phosphatidylinositol 3-kinase (PI-3K). Although many cytokine receptors have direct binding sites for the p85 subunit of PI-3K, others, such as interleukin-3 (IL-3) receptor beta common chain (βc) and IL-2 (IL-2Rβ), lack sites, leaving mechanism by which they PI-3K unclear. Here, we show that protooncoprotein Shc, promotes Ras activation recruiting Grb2-Sos complex in response to stimulation stimulation, also signals PI-3K/Akt pathway. Analysis Y→F “add-back” mutants βc shows Y577, Shc site, is major site required Gab2 phosphorylation stimulation. When fused directly a mutant form IL-2Rβ lacks other cytoplasmic tyrosines, can promote tyrosyl phosphorylation. Mutation three bind Grb2, blocks ability chimera evoke Overexpression Grb2 with inactive SH2 or SH3 domains cytokine-stimulated The majority activity associates Gab2, inducible expression unable markedly impairs IL-3-induced Akt cell growth. Experiments chimeric indicate pathway IL-2. Our results suggest lacking via Shc/Grb2/Gab2/PI-3K pathway, thereby regulating survival and/or proliferation.