THE PROTEIN-KINASE ENCODED BY THE AKT PROTOONCOGENE IS A TARGET OF THE PDGF-ACTIVATED PHOSPHATIDYLINOSITOL 3-KINASE

The serine/threonine protein kinase encoded by the Akt proto-oncogene is catalytically inactive in serum-starved primary and immortalized fi broblasts. Here we show that Akt and the Akt-related kinase AKT2 are a ctivated by PDGF. The activation was rapid and specific, and it was ab rogated by mutations in the Akt Pleckstrin homology (PH) domain. The A kt activation was also shown to depend on PDGFR beta tyrosines Y740 an d Y751, which bind phosphatidylinositol 3-kinase (Pl 3-kinase) upon ph osphorylation. Moreover, Akt activation was blocked by the Pl 3-kinase -specific inhibitor wortmannin and the dominant inhibitory N17Ras. Con versely, Akt activity was induced following the addition of phosphatid ylinositol-3-phosphate to Akt immunoprecipitates from serum-starved ce lls in vitro, These results identify Akt as a novel target of Pl 3-kin ase and suggest that the Akt PH domain may be a mediator of Pl 3-kinas e signaling.