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J. Biol. Chem., Vol. 283, Issue 30, 20978-20988, July 25, 2008

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 283/30/20978    most recent M802588200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jiang, W. Articles by Settleman, J. Search for Related Content PubMed PubMed Citation Articles by Jiang, W. Articles by Settleman, J. Social Bookmarking                      What's this?

p190A RhoGAP Is a Glycogen Synthase Kinase-3-β Substrate Required for Polarized Cell Migration^*

Wei Jiang, Martha Betson, Roseann Mulloy, Rosemary Foster, Magdolna Lévay, Erzsébet Ligeti¹, and Jeffrey Settleman²

From the Massachusetts General Hospital Cancer Center and Harvard Medical School, Charlestown, Massachusetts 02129 and the Department of Physiology, Semmelweis University, H-1444 Budapest, Hungary

The Rho GTPases are critical regulators of the actin cytoskeleton and are required for cell adhesion, migration, and polarity. Among the key Rho regulatory proteins in the context of cell migration are the p190 RhoGAPs (p190A and p190B), which function to modulate Rho signaling in response to integrin engagement. The p190 RhoGAPs undergo complex regulation, including phosphorylation by several identified kinases, interactions with phospholipids, and association with a variety of cellular proteins. Here, we have identified an additional regulatory mechanism unique to p190A RhoGAP that involves priming-dependent phosphorylation by glycogen synthase-3-β (GSK-3β), a kinase previously implicated in establishing cell polarity. We found that p190A-deficient fibroblasts exhibit a defect in directional cell migration reflecting a requirement for GSK-3β-mediated phosphorylation of amino acids in the C-terminal "tail" of p190A. This phosphorylation leads to inhibition of p190A RhoGAP activity in vitro and in vivo. These studies identify p190A as a novel GSK-3β substrate and reveal a mechanism by which GSK-3β contributes to cellular polarization in directionally migrating cells via effects on Rho GTPase activity.

Received for publication, April 3, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grant RO1 CA62142 (to J. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.

¹ Supported by Grant 62221 from the Hungarian Research Fund (OTKA).

² To whom correspondence should be addressed: Massachusetts General Hospital Cancer Center, 149 13th St., Charlestown, MA 02129. Fax: 617-726-7808; E-mail: settleman{at}helix.mgh.harvard.edu.

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