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J. Biol. Chem. 281 (37): 27317-27326

© 2006 by The American Society for Biochemistry and Molecular Biology, Inc.

Cell Migration and Signaling Specificity Is Determined by the Phosphatidylserine Recognition Motif of Rac1*

Formula

Carla V. Finkielstein{ddagger}, Michael Overduin§, , and Daniel G. S. Capelluto1

Departments of {ddagger}Biological Sciences and Chemistry, Virginia Polytechnic Institute and State University, Blacksburg, Virginia 24061 and the §CR-UK Institute for Cancer Studies, School of Medicine, University of Birmingham, Birmingham B15 2TT, United Kingdom

Abstract: The Rho guanosine triphosphatases (GTPases) control cell shape and motility and are frequently overexpressed during malignant growth. These proteins act as molecular switches cycling between active GTP- and inactive GDP-bound forms. Despite being membrane anchored via their isoprenylated C termini, Rho GTPases rapidly translocate between membrane and cytosolic compartments. Here, we show that the Rho GTPase Rac1 preferentially interacts with phosphatidylserine (PS)-containing bilayers through its polybasic motif (PBM). Rac1 isoprenylation contributes to membrane avidity but is not critical for PS recognition. The similar protein Cdc42 (cell division cycle 42), however, only associates with PS when prenylated. Conversely, other Rho GTPases such as Rac2, Rac3, and RhoA do not bind to PS even when they are prenylated. Cell stimulation with PS induces translocation of Rac1 toward the plasma membrane and stimulates GTP loading, membrane ruffling, and filopodia formation. This stimulation also promotes Cdc42 activation and phosphorylation of mitogen-activated protein kinase through Rac1/PS signaling. Consequently, the PBM specifically directs Rac1 to effect cytoskeletal rearrangement and cell migration by selective membrane phospholipid targeting.

Received for publication June 9, 2006. Revision received July 17, 2006.

* This work was supported by grants from the National Institutes of Health (to M. O. and David Jones), the Wellcome Trust (to M. O.), American Heart Association Grant 0665363U and Jeffress Memorial Trust Grant 06-0383-08 (to C. V. F.), Cancer League of Colorado Grant 2-5-52423, American Cancer Society ISG Grant 2-5-63252I, the Concern Foundation (to D. G. S. C.), and the University of Colorado Health Sciences Center's DNA Sequencing, Biophysics, Cell Culture and NMR Facilities. 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.


Formula

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

1 To whom correspondence should be addressed. Tel.: 540-231-0974; Fax: 540-231-3255; E-mail: capellut{at}vt.edu.

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