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First published online 7 March 2006
doi: 10.1242/jcs.02842
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Research Article |
1 The Burnham Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA
2 Pathology Department, University of California San Diego, La Jolla, CA 92093, USA
3 Université René Descartes, Centre Biomédical des Saints-Pères, UMR7060 CNRS 75270 Paris CEDEX 06, France
* Author for correspondence (e-mail: elenap{at}burnham.org)
Accepted 19 December 2005
Eph receptor tyrosine kinases regulate the spatial organization of cells within tissues. Central to this function is their ability to modulate cell shape and movement in response to stimulation by the ephrin ligands. The EphB2 receptor was reported to inhibit cell-matrix adhesion by phosphorylating tyrosine 66 in the effector domain of R-Ras, a Ras family protein known to regulate cell adhesion and motility. Here, we further characterize the role of R-Ras downstream of both EphA and EphB receptors. Our data show that besides inhibiting R-Ras function through phosphorylation, Eph receptors can reduce R-Ras activity through the GTPase-activating protein, p120RasGAP. By using R-Ras mutants that cannot be inactivated by p120RasGAP and/or cannot be phosphorylated at tyrosine 66, we show that the two forms of R-Ras negative regulation - through increased GTP hydrolysis and phosphorylation - differentially contribute to various ephrin-mediated responses. Retraction of the COS cell periphery depends only on R-Ras inactivation through p120RasGAP. By contrast, both reduced R-Ras GTP levels and tyrosine 66 phosphorylation contribute to the ephrin inhibitory effects on COS cell migration and to ephrin-dependent growth cone collapse in primary neurons. Therefore, Eph receptors can regulate R-Ras in two different ways to achieve cell repulsion.
Key words: Ephrin, GTPase-activating protein, P120RasGAP, Cell retraction, Cell motility, Growth cone collapse
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