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Molecular and Cellular Biology, May 2007, p. 3313-3326, Vol. 27, No. 9
0270-7306/07/$08.00+0     doi:10.1128/MCB.01476-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Integrin {alpha}1ß1 Controls Reactive Oxygen Species Synthesis by Negatively Regulating Epidermal Growth Factor Receptor-Mediated Rac Activation{triangledown}

Xiwu Chen,1 Tristin D. Abair,1,2 Maria R. Ibanez,1 Yan Su,1 Mark R. Frey,4 Rebecca S. Dise,3,4 D. Brent Polk,3,4 Amar B. Singh,1 Raymond C. Harris,1,3,5 Roy Zent,1,2,3,5 and Ambra Pozzi1,2,5*

Division of Nephrology, Department of Medicine,1 Departments of Cancer Biology,2 Cell Biology,3 Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee 37232,4 Department of Experimental Medicine, Veterans Affairs Hospital, Nashville, Tennessee 372325

Received 9 August 2006/ Returned for modification 14 November 2006/ Accepted 21 February 2007

Integrins control many cell functions, including generation of reactive oxygen species (ROS) and regulation of collagen synthesis. Mesangial cells, found in the glomerulus of the kidney, are able to produce large amounts of ROS via the NADPH oxidase. We previously demonstrated that integrin {alpha}1-null mice develop worse fibrosis than wild-type mice following glomerular injury and this is due, in part, to excessive ROS production by {alpha}1-null mesangial cells. In the present studies, we describe the mechanism whereby integrin {alpha}1-null mesangial cells produce excessive ROS. Integrin {alpha}1-null mesangial cells have constitutively increased basal levels of activated Rac1, which result in its increased translocation to the cell membrane, excessive ROS production, and consequent collagen IV deposition. Basal Rac1 activation is a direct consequence of ligand-independent increased epidermal growth factor receptor (EGFR) phosphorylation in {alpha}1-null mesangial cells. Thus, our study demonstrates that integrin {alpha}1ß1-EGFR cross talk is a key step in negatively regulating Rac1 activation, ROS production, and excessive collagen synthesis, which is a hallmark of diseases characterized by irreversible fibrosis.

* Corresponding author. Mailing address: Medical Center North, B3109, Department of Medicine, Division of Nephrology, Vanderbilt University, Nashville, TN 37232. Phone: (615) 322-4637. Fax: (615) 322-4690. E-mail: ambra.pozzi{at}vanderbilt.edu

{triangledown} Published ahead of print on 5 March 2007.

Molecular and Cellular Biology, May 2007, p. 3313-3326, Vol. 27, No. 9
0270-7306/07/$08.00+0     doi:10.1128/MCB.01476-06
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



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