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© The Rockefeller University Press, 0021-9525/1999//889 $5.00
The Journal of Cell Biology, Volume 145, Number 4, , 1999 889-897

Regular Articles

A Molecular Mechanism of Integrin Crosstalk: {alpha}vβ3 Suppression of Calcium/Calmodulin-dependent Protein Kinase II Regulates {alpha}5β1 Function



Scott D. Blystone*, Suzanne E. Slater{ddagger}, Matthew P. Williams*, Michael T. Crow§, and Eric J. Brown||

* Department of Anatomy and Cell Biology, State University of New York, Health Science Center at Syracuse, Syracuse, New York 13210; {ddagger} 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 || 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}vβ3 inhibits both phagocytosis and migration mediated by {alpha}5β1 on the same cell, and the β3 cytoplasmic tail is necessary and sufficient for this regulation of {alpha}5β1. Ligation of {alpha}5β1 activates the calcium- and calmodulin-dependent protein kinase II (CamKII). This activation is required for {alpha}5β1-mediated phagocytosis and migration. Simultaneous ligation of {alpha}vβ3 or expression of a chimeric molecule with a free β3 cytoplasmic tail prevents {alpha}5β1-mediated activation of CamKII. Expression of a constitutively active CamKII restores {alpha}5β1 functions blocked by {alpha}vβ3-initiated integrin crosstalk. Thus, {alpha}vβ3 inhibition of {alpha}5β1 activation of CamKII is required for its role in integrin crosstalk. Structure-function analysis of the β3 cytoplasmic tail demonstrates a requirement for Ser752 in β3-mediated suppression of CamKII activation, while crosstalk is independent of Tyr747 and Tyr759, implicating Ser752, but not β3 tyrosine phosphorylation in initiation of the {alpha}vβ3 signal for integrin crosstalk.

Key Words: integrin • vitronectin • kinase • cross- talk • signaling

Abbreviations used in this paper: CamKII, calcium/calmodulin-dependent protein kinase II; FN, fibronectin; IMDM, Iscove's Modified Eagle's Medium; LIBS, ligand-induced binding site; MLCK, myosin light chain kinase; VN, vitronectin.

S.D. Blystone is an investigator of the Arthritis Foundation. This work was supported by grants AI24674 and GM38330 from the National Institutes of Health to E.J. Brown. During these studies, S.D. Blystone was a recipient of NRSA AI08990-02 and a grant from the Lucille P. Markey Foundation.


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