Phosphoinositide 3-kinases (PI3Ks) activate protein kinase PKB (also termed Akt), and PI3Kγ activated by heterotrimeric guanosine triphosphate–binding protein can stimulate mitogen-activated protein kinase (MAPK). Exchange of a putative lipid substrate-binding site generated PI3Kγ proteins with altered or aborted lipid but retained protein kinase activity. Transiently expressed, PI3Kγ hybrids exhibited wortmannin-sensitive activation of MAPK, whereas a catalytically inactive PI3Kγ did not. Membrane-targeted PI3Kγ constitutively produced phosphatidylinositol 3,4,5-trisphosphate and activated PKB but not MAPK. Moreover, stimulation of MAPK in response to lysophosphatidic acid was blocked by catalytically inactive PI3Kγ but not by hybrid PI3Kγs. Thus, two major signals emerge from PI3Kγ: phosphoinositides that target PKB and protein phosphorylation that activates MAPK.