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Published online July 28, 2008
doi:10.1083/jcb.200712066
The Journal of Cell Biology, Vol. 182, No. 2, 381-393
The Rockefeller University Press, 0021-9525 $30.00
© 2008 Ghosh et al.
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Article

Activation of G{alpha}i3 triggers cell migration via regulation of GIV



Pradipta Ghosh1,2, Mikel Garcia-Marcos1, Scott J. Bornheimer1, and Marilyn G. Farquhar1

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 G{alpha}i3 binding partner. We demonstrate that in mammalian cells G{alpha}i3 controls the functions of GIV during cell migration. We find that G{alpha}i3 preferentially localizes to the leading edge and that cells lacking G{alpha}i3 fail to polarize or migrate. A conformational change induced by association of GIV with G{alpha}i3 promotes Akt-mediated phosphorylation of GIV, resulting in its redistribution to the plasma membrane. Activation of G{alpha}i3 serves as a molecular switch that triggers dissociation of Gβ{gamma} and GIV from the Gi3–GIV complex, thereby promoting cell migration by enhancing Akt signaling and actin remodeling. G{alpha}i3–GIV coupling is essential for cell migration during wound healing, macrophage chemotaxis, and tumor cell migration, indicating that the G{alpha}i3–GIV switch serves to link direction sensing from different families of chemotactic receptors to formation of the leading edge during cell migration.

P. Ghosh and M. Garcia-Marcos contributed equally to this paper.

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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