Synergistic activation of a family of phosphoinositide 3-kinase via G-protein coupled and tyrosine kinase-related receptors

Phosphoinositide 3-kinase (PI 3-kinase) is a key signaling enzyme implicate d in a variety of receptor-stimulated cell responses. Stimulation of recept ors possessing (or coupling to) protein-tyrosine kinase activates heterodim eric PI 3-kinases, which consist of an 85-kDa regulatory subunit (p85) cont aining Src-homology 2 (SH2) domains and a 110-kDa catalytic subunit (p110 a lpha or p110 beta). Thus, this form of PI 3-kinases could be activated in v itro by a phosphotyrosyl peptide containing a YMXM motif that binds to the SH2 domains of p85. Receptors coupling to alpha beta gamma-trimeric G prote ins also stimulate the lipid kinase activity of a novel p110 gamma isoform, which is not associated with p85, and thereby is not activated by tyrosine kinase receptors. The activation of p110 gamma PI 3-kinase appears to be m ediated through the beta gamma subunits of the G protein (G beta gamma) In addition, rat liver heterodimeric PI 3-kinases containing the p110 beta cat alytic subunit are synergistically activated by the phosphotyrosyl peptide plus G beta gamma. Such enzymatic properties were also observed with a reco mbinant p110 beta/p85 alpha expressed in COS-7 cells. 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 not activated by G beta gamma, though their activities were stimulated by the phosphotyro syl peptide. Synergistic activation of PI 3-kinase by the stimulation of th e two major receptor types was indeed observed in intact cells, such as che motactic peptide (N-formyl-Met-Leu-Phe) plus insulin (or Fc gamma II) recep tors in differentiated THP-1 and CHO cells and adenosine (Al) plus insulin receptors in rat adipocytes. Thus, PI 3-kinase isoforms consisting of p110 beta catalytic and SH2-containing (p85 or its related) regulatory subunits appeared to function as a 'cross-talk' enzyme between the two signal transd uction pathways mediated through tyrosine kinase and G protein-coupled rece ptors.