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Molecular and Cellular Biology, May 2000, p. 3685-3694, Vol. 20, No. 10
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

ADP-Ribosylation Factor 6 Regulates Actin Cytoskeleton Remodeling in Coordination with Rac1 and RhoA

Rita L. Boshans,1 Stacey Szanto,1 Linda van Aelst,2 and Crislyn D'Souza-Schorey1,3,*

Department of Biological Sciences1 and Walther Cancer Institute,3 University of Notre Dame, Notre Dame, Indiana, and Cold Spring Harbor Laboratory, Cold Spring Harbor, New York2

Received 6 October 1999/Returned for modification 16 November 1999/Accepted 22 February 2000

In this study, we have documented an essential role for ADP-ribosylation factor 6 (ARF6) in cell surface remodeling in response to physiological stimulus and in the down regulation of stress fiber formation. We demonstrate that the G-protein-coupled receptor agonist bombesin triggers the redistribution of ARF6- and Rac1-containing endosomal vesicles to the cell surface. This membrane redistribution was accompanied by cortical actin rearrangements and was inhibited by dominant negative ARF6, implying that bombesin is a physiological trigger of ARF6 activation. Furthermore, these studies provide a new model for bombesin-induced Rac1 activation that involves ARF6-regulated endosomal recycling. The bombesin-elicited translocation of vesicular ARF6 was mimicked by activated Galpha q and was partially inhibited by expression of RGS2, which down regulates Gq function. This suggests that Gq functions as an upstream regulator of ARF6 activation. The ARF6-induced peripheral cytoskeletal rearrangements were accompanied by a depletion of stress fibers. Moreover, cells expressing activated ARF6 resisted the formation of stress fibers induced by lysophosphatidic acid. We show that the ARF6-dependent inhibition of stress fiber formation was due to an inhibition of RhoA activation and was overcome by expression of a constitutively active RhoA mutant. The latter observations demonstrate that activation of ARF6 down regulates Rho signaling. Our findings underscore the potential roles of ARF6, Rac1, and RhoA in the coordinated regulation of cytoskeletal remodeling.

* Corresponding author. Mailing address: Department of Biological Sciences, Galvin Life Science Building, University of Notre Dame, Notre Dame, IN 46556-0369. Phone: (219) 631-3735. Fax: (219) 631-7413. E-mail: D'Souza-Schorey.1{at}nd.edu.

Molecular and Cellular Biology, May 2000, p. 3685-3694, Vol. 20, No. 10
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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