CELL BIOLOGY 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 p110 beta from other class IA phosphoinositide 3-kinases (PI3Ks). Activation of p110 beta 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 p110 beta-dependent functions, we identified the site in p110 beta that binds to the G beta gamma subunit of G proteins. Mutation of this site eliminated G beta gamma-dependent activation of PI3K beta (a dimer of p110 beta and the p85 regulatory subunit) in vitro and in cells, without affecting basal activity or phosphotyrosine peptide-mediated activation. Disrupting the p110 beta-G beta gamma interaction by mutation or with a cell-permeable peptide inhibitor blocked the transforming capacity of PI3K beta 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 PI3K beta could provide a therapeutic approach for tumors that depend on p110 beta for growth and metastasis.