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Vol. 12, Issue 9, 2711-2720, September 2001
Department of Cell and Developmental Biology and Lineberger
Comprehensive Cancer Center, University of North Carolina, Chapel Hill,
North Carolina 27599
The binding of extracellular matrix proteins to integrins
triggers rearrangements in the actin cytoskeleton by regulating the Rho
family of small GTPases. The signaling events that mediate changes in
the activity of Rho proteins in response to the extracellular matrix
remain largely unknown. We have demonstrated in previous studies that
integrin signaling transiently suppresses RhoA activity through
stimulation of p190RhoGAP. Here, we investigated the biological significance of adhesion-dependent RhoA inactivation by manipulating p190RhoGAP signaling in Rat1 fibroblasts. The inhibition of RhoA activity that is induced transiently by adhesion was antagonized by
expression of dominant negative p190RhoGAP. This resulted in impaired
cell spreading on a fibronectin substrate, reduced cell protrusion, and
premature assembly of stress fibers. Conversely, overexpression of
p190RhoGAP augmented cell spreading. Dominant negative p190RhoGAP
elevated RhoA activity in cells on fibronectin and inhibited migration,
whereas overexpression of the wild-type GAP decreased RhoA activity,
promoted the formation of membrane protrusions, and enhanced motility.
Cells expressing dominant negative p190RhoGAP, but not control cells or
cells overexpressing the wild-type GAP, were unable to establish
polarity in the direction of migration. Taken together, these data
demonstrate that integrin-triggered RhoA inhibition by
p190RhoGAP enhances spreading and migration by regulating cell
protrusion and polarity.
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 D. GRATZINGER, S. CANOSA, B. ENGELHARDT, and J. A. MADRI Platelet endothelial cell adhesion molecule-1 modulates endothelial cell motility through the small G-protein Rho FASEB J, August 1, 2003; 17(11): 1458 - 1469. [Abstract] [Full Text] [PDF]
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J. Zhai, H. Lin, Z. Nie, J. Wu, R. Canete-Soler, W. W. Schlaepfer, and D. D. Schlaepfer Direct Interaction of Focal Adhesion Kinase with p190RhoGEF J. Biol. Chem., June 27, 2003; 278(27): 24865 - 24873. [Abstract] [Full Text] [PDF]
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I. D. Coghill, S. Brown, D. L. Cottle, M. J. McGrath, P. A. Robinson, H. H. Nandurkar, J. M. Dyson, and C. A. Mitchell FHL3 Is an Actin-binding Protein That Regulates {alpha}-Actinin-mediated Actin Bundling: FHL3 LOCALIZES TO ACTIN STRESS FIBERS AND ENHANCES CELL SPREADING AND STRESS FIBER DISASSEMBLY J. Biol. Chem., June 20, 2003; 278(26): 24139 - 24152. [Abstract] [Full Text] [PDF]
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K. A. DeMali and K. Burridge Coupling membrane protrusion and cell adhesion J. Cell Sci., June 15, 2003; 116(12): 2389 - 2397. [Abstract] [Full Text] [PDF]
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 A. Masszi, C. Di Ciano, G. Sirokmany, W. T. Arthur, O. D. Rotstein, J. Wang, C. A. G. McCulloch, L. Rosivall, I. Mucsi, and A. Kapus Central role for Rho in TGF-beta 1-induced alpha -smooth muscle actin expression during epithelial-mesenchymal transition Am J Physiol Renal Physiol, May 1, 2003; 284(5): F911 - F924. [Abstract] [Full Text] [PDF]
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T. Wakatsuki, R. B. Wysolmerski, and E. L. Elson Mechanics of cell spreading: role of myosin II J. Cell Sci., April 15, 2003; 116(8): 1617 - 1625. [Abstract] [Full Text] [PDF]
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N. K. Noren, W. T. Arthur, and K. Burridge Cadherin Engagement Inhibits RhoA via p190RhoGAP J. Biol. Chem., April 11, 2003; 278(16): 13615 - 13618. [Abstract] [Full Text] [PDF]
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R. A. Worthylake and K. Burridge RhoA and ROCK Promote Migration by Limiting Membrane Protrusions J. Biol. Chem., April 4, 2003; 278(15): 13578 - 13584. [Abstract] [Full Text] [PDF]
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J. C. Hodge, J. Bub, S. Kaul, A. Kajdacsy-Balla, and P. F. Lindholm Requirement of RhoA Activity for Increased Nuclear Factor {kappa}B Activity and PC-3 Human Prostate Cancer Cell Invasion Cancer Res., March 15, 2003; 63(6): 1359 - 1364. [Abstract] [Full Text] [PDF]
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R. M. Wolf, N. Draghi, X. Liang, C. Dai, L. Uhrbom, C. Eklof, B. Westermark, E. C. Holland, and M. D. Resh p190RhoGAP can act to inhibit PDGF-induced gliomas in mice: a putative tumor suppressor encoded on human Chromosome 19q13.3 Genes & Dev., February 15, 2003; 17(4): 476 - 487. [Abstract] [Full Text] [PDF]
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B. Butler, M. P. Williams, and S. D. Blystone Ligand-dependent Activation of Integrin alpha vbeta 3 J. Biol. Chem., February 7, 2003; 278(7): 5264 - 5270. [Abstract] [Full Text] [PDF]
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A. S. Maddox and K. Burridge RhoA is required for cortical retraction and rigidity during mitotic cell rounding J. Cell Biol., January 21, 2003; 160(2): 255 - 265. [Abstract] [Full Text] [PDF]
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L. Zeng, X. Si, W.-P. Yu, H. T. Le, K. P. Ng, R. M.H. Teng, K. Ryan, D. Z.-M. Wang, S. Ponniah, and C. J. Pallen PTP{alpha} regulates integrin-stimulated FAK autophosphorylation and cytoskeletal rearrangement in cell spreading and migration J. Cell Biol., January 2, 2003; 160(1): 137 - 146. [Abstract] [Full Text] [PDF]
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H.-B. Guo, I. Lee, M. Kamar, S. K. Akiyama, and M. Pierce Aberrant N-Glycosylation of {beta}1 Integrin Causes Reduced {alpha}5{beta}1 Integrin Clustering and Stimulates Cell Migration Cancer Res., December 1, 2002; 62(23): 6837 - 6845. [Abstract] [Full Text] [PDF]
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A. Tsubouchi, J. Sakakura, R. Yagi, Y. Mazaki, E. Schaefer, H. Yano, and H. Sabe Localized suppression of RhoA activity by Tyr31/118-phosphorylated paxillin in cell adhesion and migration J. Cell Biol., November 25, 2002; 159(4): 673 - 683. [Abstract] [Full Text] [PDF]
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A. L. Berrier, R. Martinez, G. M. Bokoch, and S. E. LaFlamme The integrin {beta} tail is required and sufficient to regulate adhesion signaling to Rac1 J. Cell Sci., November 15, 2002; 115(22): 4285 - 4291. [Abstract] [Full Text] [PDF]
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J. M. Dunty and M. D. Schaller The N Termini of Focal Adhesion Kinase Family Members Regulate Substrate Phosphorylation, Localization, and Cell Morphology J. Biol. Chem., November 15, 2002; 277(47): 45644 - 45654. [Abstract] [Full Text] [PDF]
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W. T. Arthur, S. M. Ellerbroek, C. J. Der, K. Burridge, and K. Wennerberg XPLN, a Guanine Nucleotide Exchange Factor for RhoA and RhoB, But Not RhoC J. Biol. Chem., November 1, 2002; 277(45): 42964 - 42972. [Abstract] [Full Text] [PDF]
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 Y. Chang, B. Ceacareanu, M. Dixit, N. Sreejayan, and A. Hassid Nitric Oxide-Induced Motility in Aortic Smooth Muscle Cells: Role of Protein Tyrosine Phosphatase SHP-2 and GTP-Binding Protein Rho Circ. Res., September 6, 2002; 91(5): 390 - 397. [Abstract] [Full Text] [PDF]
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T. Tsuji, T. Ishizaki, M. Okamoto, C. Higashida, K. Kimura, T. Furuyashiki, Y. Arakawa, R. B. Birge, T. Nakamoto, H. Hirai, et al. ROCK and mDia1 antagonize in Rho-dependent Rac activation in Swiss 3T3 fibroblasts J. Cell Biol., May 28, 2002; 157(5): 819 - 830. [Abstract] [Full Text] [PDF]
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