Borza Corina M, Pozzi Ambra, Borza Dorin-Bogdan, Pedchenko Vadim, Hellmark Thomas, Hudson Billy G, Zent Roy
Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2372.
Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2372; Department of Research Medicine, Veterans Affairs Hospital, Nashville, Tennessee 37232-2372.
J Biol Chem. 2006 Jul 28;281(30):20932-20939. doi: 10.1074/jbc.M601147200. Epub 2006 May 26.
Exogenous soluble human alpha3 noncollagenous (NC1) domain of collagen IV inhibits angiogenesis and tumor growth. These biological functions are attributed to the binding of alpha3NC1 to integrin alphavbeta3. However, in some tumor cells that express integrin alphavbeta3, the alpha3NC1 domain does not inhibit proliferation, suggesting that integrin alphavbeta3 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 alpha3NC1 domain in cells lacking alphavbeta3 integrin. In these cells, soluble alpha3NC1 bound integrin alpha3beta1; however, unlike alphavbeta3, alpha3beta1 integrin did not mediate cell adhesion to immobilized alpha3NC1 domain. Interestingly, in cells lacking integrin alpha3beta1, adhesion to the alpha3NC1 domain was enhanced due to activation of integrin alphavbeta3. These findings indicate that integrin alpha3beta1 is a receptor for the alpha3NC1 domain and transdominantly inhibits integrin alphavbeta3 activation. Thus integrin alpha3beta1, in conjunction with integrin alphavbeta3, modulates cellular responses to the alpha3NC1 domain, which may be pivotal in the mechanism underpinning its anti-angiogenic and anti-tumorigenic activities.
外源性可溶性人IV型胶原α3非胶原（NC1）结构域可抑制血管生成和肿瘤生长。这些生物学功能归因于α3NC1与整合素αvβ3的结合。然而，在一些表达整合素αvβ3的肿瘤细胞中，α3NC1结构域并不抑制增殖，这表明整合素αvβ3的表达不足以介导该结构域的抗肿瘤活性。因此，在本研究中，我们在缺乏αvβ3整合素的细胞中寻找可溶性α3NC1结构域的新型结合受体。在这些细胞中，可溶性α3NC1与整合素α3β1结合；然而，与αvβ3不同，α3β1整合素并不介导细胞与固定化α3NC1结构域的黏附。有趣的是，在缺乏整合素α3β1的细胞中，由于整合素αvβ3的激活，对α3NC1结构域的黏附增强。这些发现表明整合素α3β1是α3NC1结构域的受体，并反式抑制整合素αvβ3的激活。因此，整合素α3β1与整合素αvβ3共同调节细胞对α3NC1结构域的反应，这可能在其抗血管生成和抗肿瘤活性的机制中起关键作用。
