HETERODIMERIC PHOSPHOINOSITIDE 3-KINASE CONSISTING OF P85 AND P110-BETA IS SYNERGISTICALLY ACTIVATED BY THE BETA-GAMMA-SUBUNITS OF G-PROTEINS AND PHOSPHOTYROSYL PEPTIDE

Phosphoinositide 3-kinase (PI 3-kinase) is a key signaling enzyme impl icated in variety of receptor-stimulated cell responses, Receptors wit h intrinsic or associated tyrosine kinase activity recruit heterodimer ic PI 3-kinases consisting of a 110-kDa catalytic subunit (p110) and a n 85-kDa regulatory subunit (p85). We separated a PI 3-kinase that cou ld be stimulated by the beta gamma subunits of G protein (G beta gamma ) from rack liver, The G beta gamma-sensitive PI 3-kinase appeared to be a heterodimer consisting of p110 beta and p85 (or their related sub units), The stimulation by G beta gamma was inhibited by the GDP-bound alpha subunit of the inhibitory GTP-binding protein, Moreover, the st imulatory action of G beta gamma was markedly enhanced by the simultan eous addition of a phosphotyrosyl peptide synthesized according to the amino acid sequence of the insulin receptor substrate-1, Such enzymic properties could be observed with a recombinant p110 beta/p85 alpha e xpressed in COS-7 cells with their cDNAs, In contrast, another heterod imeric PI 3-kinase consisting of p110 alpha and p85 in the same rat li ver, together with a recombinant p110 alpha/p85 alpha, was mot activat ed by G beta gamma, although their activities were stimulated by the p hosphotyrosyl peptide. These results indicate khat p110 beta/p85 PI 3- kinase may be regulated in a cooperative manner by two different types of membrane receptors, one possessing tyrosine kinase activity and th e other activating GTP-binding proteins.