Bifurcation of Lipid and Protein Kinase Signals of PI3K[small gamma, Greek] to the Protein Kinases PKB and MAPK

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Abstract

Phosphoinositide 3-kinases (PI3Ks) activate protein kinase PKB (also termed Akt), and PI3K[small gamma, Greek] activated by heterotrimeric guanosine triphosphate-binding protein can stimulate mitogen-activated protein kinase (MAPK). Exchange of a putative lipid substrate-binding site generated PI3K[small gamma, Greek] proteins with altered or aborted lipid but retained protein kinase activity. Transiently expressed, PI3K[small gamma, Greek] hybrids exhibited wortmannin-sensitive activation of MAPK, whereas a catalytically inactive PI3K[small gamma, Greek] did not. Membrane-targeted PI3K[small gamma, Greek] 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 PI3K[small gamma, Greek] but not by hybrid PI3K[small gamma, Greek]s. Thus, two major signals emerge from PI3K[small gamma, Greek]: phosphoinositides that target PKB and protein phosphorylation that activates MAPK.

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