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Originally published as MBC in Press, 10.1091/mbc.E03-12-0917 on March 16, 2005

Vol. 16, Issue 5, 2458-2469, May 2005

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The Unique N-Terminus of R-Ras Is Required for Rac Activation and Precise Regulation of Cell Migration

Stephen P. Holly * {dagger}, Mark K. Larson * {ddagger}, and Leslie V. Parise * {dagger} §

* Department of Pharmacology, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; {dagger} Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599; and § Carolina Cardiovascular Biology Center, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599

Submitted December 22, 2003; Accepted March 1, 2005
Monitoring Editor: Mark Ginsberg

The Ras family GTPase, R-Ras, elicits important integrin-dependent cellular behaviors such as adhesion, spreading and migration. While oncogenic Ras GTPases and R-Ras share extensive sequence homology, R-Ras induces a distinct set of cellular behaviors. To explore the structural basis for these differences, we asked whether the unique N-terminal 26 amino acid extension of R-Ras was responsible for R-Ras–specific signaling events. Using a 32D mouse myeloid cell line, we show that full-length R-Ras activates Rac and induces Rac-dependent cell spreading. In contrast, truncated R-Ras lacking its first 26 amino acids fails to activate Rac, resulting in reduced cell spreading. Truncated R-Ras also stimulates more {beta}3 integrin-dependent cell migration than full-length R-Ras, suggesting that the N-terminus may negatively regulate cell movement. However, neither the subcellular localization of R-Ras nor its effects on cell adhesion are affected by the presence or absence of the N-terminus. These results indicate that the N-terminus of R-Ras positively regulates specific R-Ras functions such as Rac activation and cell spreading but negatively regulates R-Ras–mediated cell migration.

This article was published online ahead of print in MBC in Press (http://www.molbiolcell.org/cgi/doi/10.1091/mbc.E03-12-0917) on March 16, 2005.

{ddagger} Present address: Institute for Biomedical Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.

Address correspondence to: Leslie V. Parise (parise{at}med.unc.edu).




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