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First published online 31 October 2006
doi: 10.1242/jcs.03237

Journal of Cell Science 119, 4650-4666 (2006)
Published by The Company of Biologists 2006
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Research Article

ARAP2 effects on the actin cytoskeleton are dependent on Arf6-specific GTPase-activating-protein activity and binding to RhoA-GTP

Hye-Young Yoon1, Koichi Miura1,*, E. Jebb Cuthbert2, Kathryn Kay Davis2, Bijan Ahvazi3, James E. Casanova2 and Paul A. Randazzo1,{ddagger}

1 Laboratory of Cellular Oncology, Center for Cancer Research, National Cancer Institute, Department of Health and Human Services, Building 37, Bethesda, MD 20892, USA
2 Department of Microbiology, University of Virginia at Charlottesville, School of Medicine, Charlottesville, VA, USA
3 X-Ray Crystallography Facility, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Disease, National Institutes of Health, Bethesda, MD, USA

{ddagger} Author for correspondence (e-mail: randazzo{at}helix.nih.gov)

Accepted 31 August 2006

ARAP2 is a protein that contains both ArfGAP and RhoGAP domains. We found that it is a phosphatidylinositol (3,4,5)-trisphosphate-dependent Arf6 GAP that binds RhoA-GTP but lacks RhoGAP activity. In agreement with the hypothesis that ARAP2 mediates effects of RhoA, endogenous ARAP2 associated with focal adhesions (FAs) and reduction of ARAP2 expression, by RNAi, resulted in fewer FAs and actin stress fibers (SFs). In cells with reduced levels of endogenous ARAP2, FAs and SFs could be restored with wild-type recombinant ARAP2 but not mutants lacking ArfGAP or Rho-binding activity. Constitutively active Arf6 also caused a loss of SFs. The Rho effector ROK{alpha} was ineffective in restoring FAs. Conversely, overexpression of ARAP2 did not restore SFs in cells treated with a ROK inhibitor but induced punctate accumulations of paxillin. We conclude that ARAP2 is an Arf6GAP that functions downstream of RhoA to regulate focal adhesion dynamics.

Key words: Actin, Rho, Arf, GTPase-activating protein




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