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Sci. Signal., 27 September 2011
Vol. 4, Issue 192, p. ra64
[DOI: 10.1126/scisignal.2002049]

RESEARCH ARTICLES

Tyrosine Phosphorylation of the Gα-Interacting Protein GIV Promotes Activation of Phosphoinositide 3-Kinase During Cell Migration

Changsheng Lin1, Jason Ear1, Yelena Pavlova1, Yash Mittal1, Irina Kufareva2, Majid Ghassemian3, Ruben Abagyan2, Mikel Garcia-Marcos4, and Pradipta Ghosh1*

1 Department of Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.
2 School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
3 Department of Chemistry and Biochemistry, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.
4 Department of Cellular and Molecular Medicine, University of California, San Diego, School of Medicine, La Jolla, CA 92093, USA.

Abstract: GIV (Gα-interacting vesicle-associated protein; also known as Girdin) enhances Akt activation downstream of multiple growth factor– and G protein (heterotrimeric guanosine 5'-triphosphate–binding protein)–coupled receptors to trigger cell migration and cancer invasion. We demonstrate that GIV is a tyrosine phosphoprotein that directly binds to and activates phosphoinositide 3-kinase (PI3K). Upon ligand stimulation of various receptors, GIV was phosphorylated at tyrosine-1764 and tyrosine-1798 by both receptor and non-receptor tyrosine kinases. These phosphorylation events enabled direct binding of GIV to the amino- and carboxyl-terminal Src homology 2 domains of p85α, a regulatory subunit of PI3K; stabilized receptor association with PI3K; and enhanced PI3K activity at the plasma membrane to trigger cell migration. Tyrosine phosphorylation of GIV and its association with p85α increased during metastatic progression of a breast carcinoma. These results suggest a mechanism by which multiple receptors activate PI3K through tyrosine phosphorylation of GIV, thereby making the GIV-PI3K interaction a potential therapeutic target within the PI3K-Akt pathway.

* To whom correspondence should be addressed. E-mail: prghosh{at}ucsd.edu

Citation: C. Lin, J. Ear, Y. Pavlova, Y. Mittal, I. Kufareva, M. Ghassemian, R. Abagyan, M. Garcia-Marcos, P. Ghosh, Tyrosine Phosphorylation of the Gα-Interacting Protein GIV Promotes Activation of Phosphoinositide 3-Kinase During Cell Migration. Sci. Signal. 4, ra64 (2011).

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