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

Hashem A Dbouk1, Oscar Vadas, Aliaksei Shymanets

  • 1Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.

Science Signaling
|December 6, 2012
PubMed

Insights

Targeting G protein-coupled receptor (GPCR) signaling to phosphoinositide 3-kinase beta (PI3Kβ) can inhibit tumor growth. Disrupting the p110β-Gβγ interaction blocks cancer cell proliferation and metastasis.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Class IA phosphoinositide 3-kinases (PI3Ks) are distinguished by synergistic activation from G protein-coupled receptors (GPCRs) and receptor tyrosine kinases.
  • p110β activation is crucial in physiological and pathophysiological processes, including the growth of tumors lacking phosphatase and tensin homolog deleted from chromosome 10 (PTEN).

Purpose of the Study:

  • To elucidate the specific role of GPCR signaling in p110β-dependent functions.
  • To identify the binding site of the Gβγ subunit on p110β.

Main Methods:

  • Site-directed mutagenesis of the p110β-Gβγ binding site.
  • In vitro and cellular assays to assess PI3Kβ activation.
  • Evaluation of cell proliferation, chemotaxis, and invasiveness in PTEN-null tumor cells.
  • Assessment of PI3Kβ transforming capacity in fibroblasts.

Main Results:

  • Mutation of the identified p110β-Gβγ binding site abolished Gβγ-dependent PI3Kβ activation without affecting basal or phosphotyrosine-mediated activation.
  • Disruption of the p110β-Gβγ interaction inhibited PI3Kβ transforming capacity in fibroblasts.
  • Targeting the p110β-Gβγ interaction reduced proliferation, chemotaxis, and invasiveness of PTEN-null tumor cells.

Conclusions:

  • GPCR signaling specifically activates p110β through the Gβγ subunit.
  • Targeting the GPCR-PI3Kβ pathway offers a potential therapeutic strategy for PTEN-null tumors.
  • Inhibition of the p110β-Gβγ interaction may impede tumor growth and metastasis.

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