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 implicated in variety of receptor-stimulated cell responses, Receptors with intrinsic or associated tyrosine kinase activity recruit heterodimeric PI 3-kinases consisting of a 110-kDa catalytic subunit (p110) and an 85-kDa regulatory subunit (p85). We separated a PI 3-kinase that could 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 subunits), The stimulation by G beta gamma was inhibited by the GDP-bound alpha subunit of the inhibitory GTP-binding protein, Moreover, the stimulatory action of G beta gamma was markedly enhanced by the simultaneous 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 expressed in COS-7 cells with their cDNAs, In contrast, another heterodimeric PI 3-kinase consisting of p110 alpha and p85 in the same rat liver, together with a recombinant p110 alpha/p85 alpha, was mot activated by G beta gamma, although their activities were stimulated by the phosphotyrosyl 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 the other activating GTP-binding proteins.