G protein-coupled receptor-mediated activation of p110β by Gβγ is required for cellular transformation and invasiveness

Synergistic activation by heterotrimeric guanine nucleotide binding protein (G protein) coupled receptors (GPCRs) and receptor tyrosine kinases distinguishes p110beta from other class IA phosphoinositide 3 kinases (PI3Ks). Activation of p110beta is specifically implicated in various physiological and pathophysiological processes such as the growth of tumors deficient in phosphatase and tensin homolog deleted from chromosome 10 (PTEN). To determine the specific contribution of GPCR signaling to p110beta dependent functions we identified the site in p110beta that binds to the Gbetagamma subunit of G proteins. Mutation of this site eliminated Gbetagamma dependent activation of PI3Kbeta (a dimer of p110beta and the p85 regulatory subunit) in vitro and in cells without affecting basal activity or phosphotyrosine peptide mediated activation. Disrupting the p110beta Gbetagamma interaction by mutation or with a cell permeable peptide inhibitor blocked the transforming capacity of PI3Kbeta in fibroblasts and reduced the proliferation chemotaxis and invasiveness of PTEN null tumor cells in culture. Our data suggest that specifically targeting GPCR signaling to PI3Kbeta could provide a therapeutic approach for tumors that depend on p110beta for growth and metastasis.