Glycobiology and Extracellular Matrices
Integrin α3β1, a Novel Receptor for α3(IV) Noncollagenous Domain and a Trans-dominant Inhibitor for Integrin αvβ3*

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Exogenous soluble human α3 noncollagenous (NC1) domain of collagen IV inhibits angiogenesis and tumor growth. These biological functions are attributed to the binding of α3NC1 to integrin αvβ3. However, in some tumor cells that express integrin αvβ3, the α3NC1 domain does not inhibit proliferation, suggesting that integrin αvβ3 expression is not sufficient to mediate the anti-tumorigenic activity of this domain. Therefore, in the present study, we searched for novel binding receptors for the soluble α3NC1 domain in cells lacking αvβ3 integrin. In these cells, soluble α3NC1 bound integrin α3β1; however, unlike αvβ3, α3β1 integrin did not mediate cell adhesion to immobilized α3NC1 domain. Interestingly, in cells lacking integrin α3β1, adhesion to the α3NC1 domain was enhanced due to activation of integrin αvβ3. These findings indicate that integrin α3β1 is a receptor for the α3NC1 domain and transdominantly inhibits integrin αvβ3 activation. Thus integrin α3β1, in conjunction with integrin αvβ3, modulates cellular responses to the α3NC1 domain, which may be pivotal in the mechanism underpinning its anti-angiogenic and anti-tumorigenic activities.

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This work was supported by National Institutes of Health Grants P01 DK65123 (to B. G. H., R. Z., A. P., and D.-B. B.) and 4R37 DK18381 (to B. G. H.); National Research Service Awards 5F32 DK065375 (to C. M. B.), R01-DK074359 (to A. P.), R01-CA94849 (to A. P.), and RO1-DK 69921 (to R. Z.); and by an Advanced Career Development and Merit award from the Department of Veterans Affairs (to R. Z.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.