β-Arrestin 1 inhibits the GAP function of ARHGAP21 so as to promote the activation of RhoA following angiotensin II type 1A receptor stimulation

Anthony, D.F., Sin, Y.Y., Vadrevu, S., Advant, N., Day, J.P., Byrne, A.M., Lynch, M.J., Milligan, G. , Houslay, M.D. and Baillie, G.S. (2011) β-Arrestin 1 inhibits the GAP function of ARHGAP21 so as to promote the activation of RhoA following angiotensin II type 1A receptor stimulation. Molecular and Cellular Biology, 31(5), pp. 1066-1075. (doi:10.1128/MCB.00883-10) (PMID:21173159) (PMCID:PMC3067824)

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Abstract

Activation of the small GTPase RhoA following angiotensin II stimulation is known to result in actin reorganization and stress fiber formation. Full activation of RhoA, by angiotensin II, depends on the scaffolding protein β-arrestin 1, although the mechanism behind its involvement remains elusive. Here we uncover a novel partner and function for β-arrestin 1, namely, in binding to ARHGAP21 (also known as ARHGAP10), a known effector of RhoA activity, whose GTPase-activating protein (GAP) function it inhibits. Using yeast two-hybrid screening, a peptide array, in vitro binding studies, truncation analyses, and coimmunoprecipitation techniques, we show that β-arrestin 1 binds directly to ARHGAP21 in a region that transects the RhoA effector GAP domain. Moreover, we show that the level of a complex containing β-arrestin 1 and ARHGAP21 is dynamically increased following angiotensin stimulation and that the kinetics of this interaction modulates the temporal activation of RhoA. Using information gleaned from a peptide array, we developed a cell-permeant peptide that serves to inhibit the interaction of these proteins. Using this peptide, we demonstrate that disruption of the β-arrestin 1/ARHGAP21 complex results in a more active ARHGAP21, leading to less-efficient signaling via the angiotensin II type 1A receptor and, thereby, attenuation of stimulated stress fiber formation.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Milligan, Professor Graeme and Sin, Dr Yuan Yan and Advant, Miss Noopur and Baillie, Professor George and Houslay, Professor Miles and Anthony, Dr Diana
Authors: Anthony, D.F., Sin, Y.Y., Vadrevu, S., Advant, N., Day, J.P., Byrne, A.M., Lynch, M.J., Milligan, G., Houslay, M.D., and Baillie, G.S.
College/School:College of Medical Veterinary and Life Sciences > Institute of Molecular Cell and Systems Biology
College of Medical Veterinary and Life Sciences > Institute of Neuroscience and Psychology
College of Medical Veterinary and Life Sciences > Institute of Cardiovascular and Medical Sciences
Journal Name:Molecular and Cellular Biology
Publisher:American Society for Microbiology
ISSN:0270-7306
ISSN (Online):1067-8824
Published Online:20 December 2010

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
438301Phosphodiesterase-4 isoforms - intracellular targeting, regulation and potential therapeutic targetsMiles HouslayMedical Research Council (MRC)G0600765Institute of Neuroscience and Psychology
432501Transatlantic networks of excellence in cardiovascular diseaseMiles HouslayFoundation Leducq (LEDUCQ-VIL)06 CVD 02Institute of Neuroscience and Psychology