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J. Cell Biol., Volume 145, Number 4, May 17, 1999 889-897

A Molecular Mechanism of Integrin Crosstalk: alpha vbeta 3 Suppression of Calcium/Calmodulin-dependent Protein Kinase II Regulates alpha 5beta 1 Function

Scott D. Blystone,* Suzanne E. Slater,Dagger Matthew P. Williams,* Michael T. Crow,§ and Eric J. Brownparallel

* Department of Anatomy and Cell Biology, State University of New York, Health Science Center at Syracuse, Syracuse, New York 13210; Dagger  Department of Medicine, Infectious Diseases Division, Washington University School of Medicine, St. Louis, Missouri, 63110; § Vascular Biology Unit, Laboratory of Cardiovascular Science, Gerontology Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224; and parallel  Program in Microbial Pathogenesis and Host Defense, University of California, San Francisco, California 94143

Many cells express more than one integrin receptor for extracellular matrix, and in vivo these receptors may be simultaneously engaged. Ligation of one integrin may influence the behavior of others on the cell, a phenomenon we have called integrin crosstalk. Ligation of the integrin alpha vbeta 3 inhibits both phagocytosis and migration mediated by alpha 5beta 1 on the same cell, and the beta 3 cytoplasmic tail is necessary and sufficient for this regulation of alpha 5beta 1. Ligation of alpha 5beta 1 activates the calcium- and calmodulin-dependent protein kinase II (CamKII). This activation is required for alpha 5beta 1-mediated phagocytosis and migration. Simultaneous ligation of alpha vbeta 3 or expression of a chimeric molecule with a free beta 3 cytoplasmic tail prevents alpha 5beta 1-mediated activation of CamKII. Expression of a constitutively active CamKII restores alpha 5beta 1 functions blocked by alpha vbeta 3-initiated integrin crosstalk. Thus, alpha vbeta 3 inhibition of alpha 5beta 1 activation of CamKII is required for its role in integrin crosstalk. Structure-function analysis of the beta 3 cytoplasmic tail demonstrates a requirement for Ser752 in beta 3-mediated suppression of CamKII activation, while crosstalk is independent of Tyr747 and Tyr759, implicating Ser752, but not beta 3 tyrosine phosphorylation in initiation of the alpha vbeta 3 signal for integrin crosstalk.

Key words: integrin;  vitronectin;  kinase;  cross- talk;  signaling


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