G protein-coupled receptor-mediated activation of p110b by Gβγ is required for cellular transformation and invasiveness

Hashem A. Dbouk, Oscar Vadas, Aliaksei Shymanets, John E. Burke, Rachel S. Salamon, Bassem D. Khalil, Mathew O. Barrett, Gary L. Waldo, Chinmay Surve, Christine Hsueh, Olga Perisic, Christian Harteneck, Peter R. Shepherd, T. Kendall Harden, Alan V. Smrcka, Ronald Taussig, Anne R. Bresnick, Bernd Nürnberg, Roger L. Williams, Jonathan M. Backer

Research output: Contribution to journalArticlepeer-review

113 Scopus citations

Abstract

Synergistic activation by heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) and receptor tyrosine kinases distinguishes p110β from other class IA phosphoinositide 3-kinases (PI3Ks). Activation of p110β 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 p110β-dependent functions, we identified the site in p110b that binds to the Gβγ subunit of G proteins. Mutation of this site eliminated Gβγ-dependent activation of PI3Kβ (a dimer of p110b and the p85 regulatory subunit) in vitro and in cells, without affecting basal activity or phosphotyrosine peptide-mediated activation. Disrupting the p110β-Gβγ interaction by mutation or with a cell-permeable peptide inhibitor blocked the transforming capacity of PI3Kb 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 PI3Kβ could provide a therapeutic approach for tumors that depend on p110β for growth and metastasis.

Original languageEnglish (US)
Article numberra89
JournalScience signaling
Volume5
Issue number253
DOIs
StatePublished - Dec 4 2012

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Fingerprint

Dive into the research topics of 'G protein-coupled receptor-mediated activation of p110b by Gβγ is required for cellular transformation and invasiveness'. Together they form a unique fingerprint.

Cite this