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p190RhoGAP is the convergence point of adhesion signals from ₅β₁ integrin and syndecan-4

¹ Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, England, UK
² Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, MA 02129
³ Centre for Systems Biology, School of Biological Sciences, University of Edinburgh, Edinburgh EH9 3JR, Scotland, UK

Correspondence to Martin J. Humphries: martin.humphries{at}manchester.ac.uk

The fibronectin receptors ₅β₁ integrin and syndecan-4 cocluster in focal adhesions and coordinate cell migration by making individual contributions to the suppression of RhoA activity during matrix engagement. p190Rho–guanosine triphosphatase–activating protein (GAP) is known to inhibit RhoA during the early stages of cell spreading in an Src-dependent manner. This paper dissects the mechanisms of p190RhoGAP regulation and distinguishes the contributions of ₅β₁ integrin and syndecan-4. Matrix-induced tyrosine phosphorylation of p190RhoGAP is stimulated solely by engagement of ₅β₁ integrin and is independent of syndecan-4. Parallel engagement of syndecan-4 causes redistribution of the tyrosine-phosphorylated pool of p190RhoGAP between membrane and cytosolic fractions by a mechanism that requires direct activation of protein kinase C by syndecan-4. Activation of both pathways is necessary for the efficient regulation of RhoA and, as a consequence, focal adhesion formation. Accordingly, we identify p190RhoGAP as the convergence point for adhesive signals mediated by ₅β₁ integrin and syndecan-4. This molecular mechanism explains the cooperation between extracellular matrix receptors during cell adhesion.

Abbreviations used in this paper: BIM-1, bisindolylmaleimide 1; GAG, glycoaminoglycan; GAP, GTPase-activating protein; GEF, guanine nucleotide exchange factor; MEF, mouse embryonic fibroblast; p190-A, p190RhoGAP-A; TrX, Triton X-100.

© 2008 Bass et al. This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.jcb.org/misc/terms.shtml). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 3.0 Unported license, as described at http://creativecommons.org/licenses/by-nc-sa/3.0/).

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