p190RhoGAP is the convergence point of adhesion signals from alpha 5 beta 1 integrin and syndecan-4.
The fibronectin receptors alpha(5)beta(1) 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 alpha(5)beta(1) integrin and syndecan-4. Matrix-induced tyrosine phosphorylation of p190RhoGAP is stimulated solely by engagement of alpha(5)beta(1) 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 alpha 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 alpha(5)beta(1) integrin and syndecan-4. This molecular mechanism explains the cooperation between extracellular matrix receptors during cell adhesion.
Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, England, UK.
Mark D
MD
Bass
Mark R
MR
Morgan
Kirsty A
KA
Roach
Jeffrey
J
Settleman
Andrew B
AB
Goryachev
Martin J
MJ
Humphries
D000818:Animals; D002448:Cell Adhesion; D002462:Cell Membrane; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology / Q000201:enzymology; D005353:Fibronectins / Q000378:metabolism; D022001:Focal Adhesions / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism*; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D051379:Mice; D011485:Protein Binding; D051571:Protein Kinase C-alpha / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D053671:Syndecan-4 / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism
C513041:Arhgap35 protein, mouse; D004268:DNA-Binding Proteins; D005353:Fibronectins; D020690:GTPase-Activating Proteins; D039081:Integrin alpha5beta1; D012097:Repressor Proteins; D053671:Syndecan-4; D051571:Protein Kinase C-alpha; D020742:rhoA GTP-Binding Protein