BIFURCATION OF LIPID AND PROTEIN-KINASE SIGNALS OF PI3K-GAMMA TO THE PROTEIN-KINASES PKB AND MAPK

Phosphoinositide 3-kinases (PI3Ks) activate protein kinase PKB (also t ermed Akt), and PI3K gamma activated by heterotrimeric guanosine triph osphate-binding protein can stimulate mitogen-activated protein kinase (MAPK). Exchange of a putative Lipid substrate-binding site generated PI3K gamma proteins with altered or aborted Lipid but retained protei n kinase activity. Transiently expressed, PI3K gamma hybrids exhibited wortmannin-sensitive activation of MAPK, whereas a catalytically inac tive PI3K gamma did not. Membrane-targeted PI3K gamma constitutively p roduced phosphatidylinositol 3,4,5-trisphosphate and activated PKB but not MAPK. Moreover, stimulation of MAPK in response to Lysophosphatid ic acid was blocked by catalytically inactive PI3K gamma but not by hy brid PI3K gamma s. Thus, two major signals emerge from PI3K gamma: pho sphoinositides that target PKB and protein phosphorylation that activa tes MAPK.