Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.

Subscribe

Sci. Signal., 4 December 2012
Vol. 5, Issue 253, p. ra89
[DOI: 10.1126/scisignal.2003264]

RESEARCH ARTICLES

G Protein–Coupled Receptor–Mediated Activation of p110β by Gβ{gamma} Is Required for Cellular Transformation and Invasiveness

Hashem A. Dbouk1*, Oscar Vadas2*, Aliaksei Shymanets3, John E. Burke2, Rachel S. Salamon1, Bassem D. Khalil1, Mathew O. Barrett4, Gary L. Waldo4, Chinmay Surve5, Christine Hsueh6, Olga Perisic2, Christian Harteneck3, Peter R. Shepherd7, T. Kendall Harden4, Alan V. Smrcka5, Ronald Taussig8, Anne R. Bresnick6, Bernd Nürnberg3, Roger L. Williams2{dagger}, and Jonathan M. Backer1{dagger}

1 Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
2 MRC Laboratory of Molecular Biology, Cambridge CB2 0QH, UK.
3 Department of Pharmacology and Experimental Therapy, Institute for Pharmacology and Toxicology and Interfaculty Center of Pharmacogenomics and Pharma Research Eberhard-Karls-Universität Tübingen, Tübingen 72074, Germany.
4 Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC 27599, USA.
5 Department of Pharmacology and Physiology, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
6 Department of Biochemistry, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
7 Department of Molecular Medicine and Pathology, University of Auckland, Auckland 1142, New Zealand.
8 Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

* These authors contributed equally to this work.

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 p110β that binds to the Gβ{gamma} subunit of G proteins. Mutation of this site eliminated Gβ{gamma}-dependent activation of PI3Kβ (a dimer of p110β and the p85 regulatory subunit) in vitro and in cells, without affecting basal activity or phosphotyrosine peptide–mediated activation. Disrupting the p110β-Gβ{gamma} interaction by mutation or with a cell-permeable peptide inhibitor blocked the transforming capacity of PI3Kβ 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.

{dagger} To whom correspondence should be addressed. E-mail: rlw{at}mrc-lmb.cam.ac.uk (R.L.W.); jonathan.backer{at}einstein.yu.edu (J.M.B.)

Citation: H. A. Dbouk, O. Vadas, A. Shymanets, J. E. Burke, R. S. Salamon, B. D. Khalil, M. O. Barrett, G. L. Waldo, C. Surve, C. Hsueh, O. Perisic, C. Harteneck, P. R. Shepherd, T. K. Harden, A. V. Smrcka, R. Taussig, A. R. Bresnick, B. Nürnberg, R. L. Williams, J. M. Backer, G Protein–Coupled Receptor–Mediated Activation of p110β by Gβ{gamma} Is Required for Cellular Transformation and Invasiveness. Sci. Signal. 5, ra89 (2012).

Read the Full Text


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Classes of phosphoinositide 3-kinases at a glance.
S. Jean and A. A. Kiger (2014)
J. Cell Sci. 127, 923-928
   Abstract »    Full Text »    PDF »
Molecular determinants of PI3K{gamma}-mediated activation downstream of G-protein-coupled receptors (GPCRs).
O. Vadas, H. A. Dbouk, A. Shymanets, O. Perisic, J. E. Burke, W. F. Abi Saab, B. D. Khalil, C. Harteneck, A. R. Bresnick, B. Nurnberg, et al. (2013)
PNAS 110, 18862-18867
   Abstract »    Full Text »    PDF »
p87 and p101 Subunits Are Distinct Regulators Determining Class IB Phosphoinositide 3-Kinase (PI3K) Specificity.
A. Shymanets, Prajwal, K. Bucher, S. Beer-Hammer, C. Harteneck, and B. Nurnberg (2013)
J. Biol. Chem. 288, 31059-31068
   Abstract »    Full Text »    PDF »
Phosphoinositides: Tiny Lipids With Giant Impact on Cell Regulation.
T. Balla (2013)
Physiol Rev 93, 1019-1137
   Abstract »    Full Text »    PDF »

To Advertise     Find Products


Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882