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First published online 4 January 2005
doi: 10.1242/jcs.01625

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SH3 domain of spectrin participates in the activation of Rac in specialized calpain-induced integrin signaling complexes

¹ Joseph J. Jacobs Center for Thrombosis and Vascular Biology, Department of Molecular Cardiology, The Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA
² Laboratory for Proteolytic Neuroscience, RIKEN Brain Science Institute, 2-1 Hiroshwa, Wako-shi Saitama 351-01, Japan
³ Department of Physiology and Biophysics, School of Medicine, Case Western Reserve University, Cleveland, OH 44106, USA

^* Author for correspondence (e-mail: foxj{at}ccf.org)

Accepted 2 November 2004

In this study, we used cultured cells spreading on ß3 integrin substrates to examine the possibility that spectrin is involved in signal transduction. Spectrin clustered with specialized calpain-induced ß3 integrin signaling complexes that mediate the initial attachment of cells and initiate Rac activation and lamellipodia extension. It was absent from focal complexes and focal adhesions, the integrin complexes that mediate adhesion in lamellipodia and fully spread cells. Spectrin contains a Src homology (SH3) domain of unknown function. Cells overexpressing this domain adhered and calpain-induced integrin signaling complexes formed. However, Rac activation, lamellipodia extension and cell spreading were inhibited. Spreading was restored by overexpression of constitutively active Rac. These studies point to a previously unrecognized role for spectrin and its SH3 domain in initiating Rac activation in the specialized integrin clusters that initiate cell adhesion and spreading. Thus, spectrin may have a pivotal role in initiating integrin-induced physiological and pathological events such as development, proliferation, cell survival, wound healing, metastasis and atherosclerosis.

Key words: Spectrin, SH3 domain, Cell spreading, ß3 integrin, Calpain, Rac activation

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