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Activation of Gi3 triggers cell migration via regulation of GIV

¹ Department of Cellular and Molecular Medicine and ² Department of Medicine, University of California, San Diego, La Jolla, CA 92093

Correspondence to Marilyn G. Farquhar: mfarquhar{at}ucsd.edu.

During migration, cells must couple direction sensing to signal transduction and actin remodeling. We previously identified GIV/Girdin as a Gi3 binding partner. We demonstrate that in mammalian cells Gi3 controls the functions of GIV during cell migration. We find that Gi3 preferentially localizes to the leading edge and that cells lacking Gi3 fail to polarize or migrate. A conformational change induced by association of GIV with Gi3 promotes Akt-mediated phosphorylation of GIV, resulting in its redistribution to the plasma membrane. Activation of Gi3 serves as a molecular switch that triggers dissociation of Gβ and GIV from the Gi3–GIV complex, thereby promoting cell migration by enhancing Akt signaling and actin remodeling. Gi3–GIV coupling is essential for cell migration during wound healing, macrophage chemotaxis, and tumor cell migration, indicating that the Gi3–GIV switch serves to link direction sensing from different families of chemotactic receptors to formation of the leading edge during cell migration.

Abbreviations used in this paper: β-GALT, β1-4 galactosyltransferase; DiD, 1,1'-Dioctadecyl-3,3,3',3'-tetramethyllindodicarbocyanine perchlorate; GPCR, G protein–coupled receptor; IF, immunofluorescence; mp-YFP, myristoyl-palmitoyl–modified YFP; MTOC, microtubule-organizing center; PI3K, phosphoinositide 3-kinase; PM, plasma membrane; RTK, receptor tyrosine kinase; scr siRNA, scrambled siRNA; TPA, tetradecanoyl-phorbol acetate.

© 2008 Ghosh et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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DRIVEN TO THE BRINK BY A G PROTEIN

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J. Cell Biol. 2008 182: 216. [Full Text] [PDF]

This article has been cited by other articles:

• Garcia-Marcos, M., Ghosh, P., Farquhar, M. G. (2009). GIV is a nonreceptor GEF for G{alpha}i with a unique motif that regulates Akt signaling. Proc. Natl. Acad. Sci. USA 106: 3178-3183 [Abstract] [Full Text]  
• Leslie, M. (2008). DRIVEN TO THE BRINK BY A G PROTEIN. JCB 182: 216-216 [Full Text]  

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