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First published online 26 May 2009
doi: 10.1242/jcs.041632

Journal of Cell Science 122, 2043-2054 (2009)
Published by The Company of Biologists 2009
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Research Article

Integrin {alpha}9β1 mediates enhanced cell migration through nitric oxide synthase activity regulated by Src tyrosine kinase

Shiv K. Gupta and Nicholas E. Vlahakis*

Thoracic Disease Research Unit, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, MN 55905, USA

* Author for correspondence (e-mail: vlahakis.nicholas{at}mayo.edu)

Accepted 4 March 2009

Integrins are important mediators of cell adhesion and migration, which in turn are essential for diverse biological functions, including wound healing and cancer metastasis. The integrin {alpha}9β1 is expressed on numerous mammalian tissues and can mediate accelerated cell migration. As the molecular signaling mechanisms that transduce this effect are poorly defined, we investigated the pathways by which activated integrin {alpha}9β1 signals migration. We found for the first time that specific ligation of integrin {alpha}9β1 rapidly activates Src tyrosine kinase, with concomitant tyrosine phosphorylation of p130Cas and activation of Rac-1. Furthermore, activation of integrin {alpha}9β1 also enhanced NO production through activation of inducible nitric oxide synthase (iNOS). Inhibition of Src tyrosine kinase or NOS decreased integrin-{alpha}9β1-dependent cell migration. Src appeared to function most proximal in the signaling cascade, in a FAK-independent manner to facilitate iNOS activation and NO-dependent cell migration. The cytoplasmic domain of integrin {alpha}9 was crucial for integrin-{alpha}9β1-induced Src activation, subsequent signaling events and cell migration. When taken together, our results describe a novel and unique mechanism of coordinated interactions of the integrin {alpha}9 cytoplasmic domain, Src tyrosine kinase and iNOS to transduce integrin-{alpha}9β1-mediated cell migration.

Key words: Adhesion receptor, Cell migration, Integrin, Nitric oxide


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