![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
|
|
|
|
|
||
A more recent version of this article appeared on November 1, 2006
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Submitted on February 14, 2006
Revised on August 4, 2006
Accepted on August 31, 2006
||
*Department of Molecular Biophysics and Biochemistry, Interdepartmental Neuroscience Program, and ||Department of Neurobiology, Yale University, New Haven, CT 06520; Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129
Monitoring Editor: Anne Ridley
The Rho family GTPases RhoA (Rho), Rac1, and Cdc42 are essential effectors of integrin-mediated cell attachment and spreading. Rho activity, which promotes formation of focal adhesions and actin stress fibers, is inhibited upon initial cell attachment to allow sampling of the new adhesive environment. The Abl-related gene (Arg) tyrosine kinase mediates adhesion-dependent inhibition of Rho through phosphorylation and activation of the Rho inhibitor p190RhoGAP-A (p190). p190 phosphorylation promotes its binding to p120RasGAP (p120). Here, we elucidate the mechanism by which p120 binding regulates p190 activation following adhesion. We show that p190 requires its p120-binding domain to undergo Arg-dependent activation in vivo. However, p120 binding does not activate p190RhoGAP activity in vitro. Instead, activation of p190 requires recruitment to the cell periphery. Integrin-mediated adhesion promotes relocalization of p190 and p120 to the cell periphery in wild type fibroblasts, but not in arg-/- fibroblasts. A dominant-negative p120 fragment blocks p190:p120 complex formation, prevents activation of p190 by adhesion, and disrupts the adhesion-dependent recruitment of p190 to the cell periphery. Our results demonstrate that integrin signaling through Arg activates p190 by promoting its association with p120, resulting in recruitment of p190 to the cell periphery where it inhibits Rho.
These authors contributed equally to this work.
Address correspondence to:
Anthony J. Koleske (anthony.koleske{at}yale.edu)
This article has been cited by other articles:
|
|
 |
|
  W. Jiang, M. Betson, R. Mulloy, R. Foster, M. Levay, E. Ligeti, and J. Settleman p190A RhoGAP Is a Glycogen Synthase Kinase-3-{beta} Substrate Required for Polarized Cell Migration J. Biol. Chem., July 25, 2008; 283(30): 20978 - 20988. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. D. Bass, M. R. Morgan, K. A. Roach, J. Settleman, A. B. Goryachev, and M. J. Humphries p190RhoGAP is the convergence point of adhesion signals from {alpha}5{beta}1 integrin and syndecan-4 J. Cell Biol., June 16, 2008; 181(6): 1013 - 1026. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. K. Sfakianos, A. Eisman, S. L. Gourley, W. D. Bradley, A. J. Scheetz, J. Settleman, J. R. Taylor, C. A. Greer, A. Williamson, and A. J. Koleske Inhibition of Rho via Arg and p190RhoGAP in the Postnatal Mouse Hippocampus Regulates Dendritic Spine Maturation, Synapse and Dendrite Stability, and Behavior J. Neurosci., October 10, 2007; 27(41): 10982 - 10992. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. G. Peacock, A. L. Miller, W. D. Bradley, O. C. Rodriguez, D. J. Webb, and A. J. Koleske The Abl-related Gene Tyrosine Kinase Acts through p190RhoGAP to Inhibit Actomyosin Contractility and Regulate Focal Adhesion Dynamics upon Adhesion to Fibronectin Mol. Biol. Cell, October 1, 2007; 18(10): 3860 - 3872. [Abstract] [Full Text] [PDF]
|
|
