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Integrin α9β1 mediates enhanced cell migration through nitric oxide synthase activity regulated by Src tyrosine kinase
Shiv K. Gupta, Nicholas E. Vlahakis


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 α9β1 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 α9β1 signals migration. We found for the first time that specific ligation of integrin α9β1 rapidly activates Src tyrosine kinase, with concomitant tyrosine phosphorylation of p130Cas and activation of Rac-1. Furthermore, activation of integrin α9β1 also enhanced NO production through activation of inducible nitric oxide synthase (iNOS). Inhibition of Src tyrosine kinase or NOS decreased integrin-α9β1-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 α9 was crucial for integrin-α9β1-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 α9 cytoplasmic domain, Src tyrosine kinase and iNOS to transduce integrin-α9β1-mediated cell migration.


  • Supplementary material available online at

  • We thank Dean Sheppard (Lung Biology Center, UCSF, CA) for critical reading of this manuscript, the generous gift of cell lines and antibody (Y9A2) used in this study. We also thank Amha Atakilit for helpful suggestions and technical help. This work was supported by the NIH grant 1K08 HL076455-01A2 and Mayo Foundation Scholar Award to N.E.V. Deposited in PMC for release after 12 months.

  • Accepted March 4, 2009.
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