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Molecular and Cellular Biology, September 1998, p. 5567-5578, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Ras-GAP Controls Rho-Mediated Cytoskeletal Reorganization through Its SH3 Domain

Véronique Leblanc,* Bruno Tocque,dagger and Isabelle Delumeau

Rhône-Poulenc Rorer Central Research, Gene Medicine Department, Centre de Recherche de Vitry Alfortville, 94403 Vitry sur Seine, France

Received 16 March 1998/Returned for modification 23 April 1998/Accepted 23 June 1998

Proteins of the Ras superfamily, Ras, Rac, Rho, and Cdc42, control the remodelling of the cortical actin cytoskeleton following growth factor stimulation. A major regulator of Ras, Ras-GAP, contains several structural motifs, including an SH3 domain and two SH2 domains, and there is evidence that they harbor a signalling function. We have previously described a monoclonal antibody to the SH3 domain of Ras-GAP which blocks Ras signalling in Xenopus oocytes. We now show that microinjection of this antibody into Swiss 3T3 cells prevents the formation of actin stress fibers stimulated by growth factors or activated Ras, but not membrane ruffling. This inhibition is bypassed by coinjection of activated Rho, suggesting that the Ras-GAP SH3 domain is necessary for endogenous Rho activation. In agreement, the antibody blocks lysophosphatidic acid-induced neurite retraction in differentiated PC12 cells. Furthermore, we demonstrate that microinjection of full-length Ras-GAP triggers stress fiber polymerization in fibroblasts in an SH3-dependent manner, strongly suggesting an effector function besides its role as a Ras downregulator. These results support the idea that Ras-GAP connects the Ras and Rho pathways and, therefore, regulates the actin cytoskeleton through a mechanism which probably does not involve p190 Rho-GAP.

* Corresponding author. Mailing address: ExonHit Therapeutics, 65 Bld Massena, 75013 Paris, France. Phone: 331 53 94 77 00. Fax: 331 53 94 77 07. E-mail: veronique.leblanc{at}exonhit.com.

dagger Present address: ExonHit Therapeutics, 75013 Paris, France.

Molecular and Cellular Biology, September 1998, p. 5567-5578, Vol. 18, No. 9
0270-7306/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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