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© The Rockefeller University Press, 0021-9525/2000//685 $5.00
The Journal of Cell Biology, Volume 151, Number 3, , 2000 685-696

Evidence That β3 Integrin-Induced Rac Activation Involves the Calpain-Dependent Formation of Integrin Clusters That Are Distinct from the Focal Complexes and Focal Adhesions That Form as Rac and Rhoa Become Active

^a Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, The Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195
^b Department of Pharmacology, The University of Illinois, College of Medicine, Chicago, Illinois 60612
^c Muscle Biology Group, University of Arizona, Tucson, Arizona 85721
^d Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, Wako-shi Saitama 351-01, Japan
^e Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106
Joseph J. Jacobs Center for Thrombosis and Vascular Biology, (NB 50), The Lerner Research Institute, Cleveland Clinic Foundation, 9500 Euclid Ave., Cleveland, OH 44195.(216) 445-2051(216) 445-3874

Interaction of integrins with the extracellular matrix leads to transmission of signals, cytoskeletal reorganizations, and changes in cell behavior. While many signaling molecules are known to be activated within Rac-induced focal complexes or Rho-induced focal adhesions, the way in which integrin-mediated adhesion leads to activation of Rac and Rho is not known. In the present study, we identified clusters of integrin that formed upstream of Rac activation. These clusters contained a Rac-binding protein(s) and appeared to be involved in Rac activation. The integrin clusters contained calpain and calpain-cleaved β3 integrin, while the focal complexes and focal adhesions that formed once Rac and Rho were activated did not. Moreover, the integrin clusters were dependent on calpain for their formation. In contrast, while Rac- and Rho-GTPases were dependent on calpain for their activation, formation of focal complexes and focal adhesions by constitutively active Rac or Rho, respectively, occurred even when calpain inhibitors were present. Taken together, these data are consistent with a model in which integrin-induced Rac activation requires the formation of integrin clusters. The clusters form in a calpain-dependent manner, contain calpain, calpain-cleaved integrin, and a Rac binding protein(s). Once Rac is activated, other integrin signaling complexes are formed by a calpain-independent mechanism(s).

Key Words: cell spreading • β3 integrin • calpain • integrin clusters • Rac activation

© 2000 The Rockefeller University Press

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