Integrin alpha3beta1, a novel receptor for alpha3(IV) noncollagenous domain and a trans-dominant Inhibitor for integrin alphavbeta3.
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.
Borza
Corina M
CM
Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2372. Electronic address: Corina.Borza@vanderbilt.edu.
Pozzi
Ambra
A
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.
Borza
Dorin-Bogdan
DB
Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2372.
Pedchenko
Vadim
V
Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2372.
Hellmark
Thomas
T
Kidney Research Laboratory, Lund University, S-22185 Lund, Sweden.
Hudson
Billy G
BG
Division of Nephrology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-2372. Electronic address: Billy.Hudson@vanderbilt.edu.
Zent
Roy
R
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. Electronic address: Roy.Zent@vanderbilt.edu.
D002448:Cell Adhesion; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039201:Integrin alpha3beta1 / Q000502:physiology*; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D016023:Integrins / Q000378:metabolism; D009389:Neovascularization, Pathologic; D017434:Protein Structure, Tertiary; D011994:Recombinant Proteins / Q000737:chemistry
D039201:Integrin alpha3beta1; D039302:Integrin alphaVbeta3; D016023:Integrins; D011994:Recombinant Proteins