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J. Biol. Chem., Vol. 281, Issue 28, 19688-19699, July 14, 2006

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8 Integrin Binds Rho GDP Dissociation Inhibitor-1 and Activates Rac1 to Inhibit Mesangial Cell Myofibroblast Differentiation^*

Sujata Lakhe-Reddy¹, Shenaz Khan¹, Martha Konieczkowski, George Jarad², Karen L. Wu, Louis F. Reichardt, Yoshimi Takai^¶, Leslie A. Bruggeman, Bingcheng Wang^||, John R. Sedor^**, and Jeffrey R. Schelling³

From the Departments of Medicine, ^||Pharmacology, and ^**Physiology and Biophysics, Case Western Reserve University School of Medicine, Rammelkamp Center for Education and Research, MetroHealth Medical Center, Cleveland, Ohio 44109, Departments of Physiology and Biochemistry/Biophysics, University of California, San Francisco and Howard Hughes Medical Institute, San Francisco, California 94143, and ^¶Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan

v8 integrin expression is restricted primarily to kidney, brain, and placenta. Targeted vor 8 deletion is embryonic lethal due to defective placenta and brain angiogenesis, precluding investigation of kidney v8 function. We find that kidney 8 is localized to glomerular mesangial cells, and expression is decreased in mouse models of glomerulosclerosis, suggesting that 8 regulates normal mesangial cell differentiation. To interrogate 8 signaling pathways, yeast two-hybrid and co-precipitation studies demonstrated 8 interaction with Rho guanine nucleotide dissociation inhibitor-1 (GDI). Selective 8 stimulation enhanced 8-GDI interaction as well as Rac1 (but not RhoA) activation and lamellipodia formation. Mesangial cells from itgb8-/- mice backcrossed to a genetic background that permitted survival, or gdi-/- mice, which develop glomerulosclerosis, demonstrated RhoA (but not Rac1) activity and -smooth muscle actin assembly, which characterizes mesangial cell myofibroblast transformation in renal disease. To determine whether Rac1 directly modulates RhoA-associated myofibroblast differentiation, mesangial cells were transduced with inhibitory Rac peptide fused to human immunodeficiency virus-Tat, resulting in enhanced -smooth muscle actin organization. We conclude that the 8 cytosolic tail in mesangial cells organizes a signaling complex that culminates in Rac1 activation to mediate wild-type differentiation, whereas decreased 8 activation shifts mesangial cells toward a RhoA-dependent myofibroblast phenotype.

Received for publication, February 6, 2006 , and in revised form, May 4, 2006.

^* This work was supported by National Institutes of Health Grants P50 DK054178, R01 DK064719, R01 CA092259, R01 CA096533, and R01 DK061395. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ These authors contributed equally to this work.

² Current address: Div. of Nephrology, Washington University, St. Louis, MO 63130.

³ To whom correspondence should be addressed: MetroHealth Medical Center, 2500 MetroHealth Dr., R415, Cleveland, OH. 44109-1998. Tel.: 216-778-4993; E-mail: jeffrey.schelling{at}case.edu.

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