title: Type IV collagen α1-chain noncollagenous domain blocks MMP-2 activation both in-vitro and in-vivo.
abstract: α1(IV)NC1 inhibits angiogenesis by regulating MAPK activation, this biological function was partly attributed α1(IV)NC1 binding to α1β1-integrin. However, its potent antiangiogenic activity and the molecular targets of α1(IV)NC1 has not been investigated. In the present study, the regulation of MMP-2 activation by α1(IV)NC1 was evaluated. α1β1-integrin which is required for inhibition of angiogenesis is not playing a role in cellular invasion and inhibition of MMP-2 activation by α1(IV)NC1. We found that α1(IV)NC1 binds the CBD of MMP-2 and forming a stable complex that prevents activation of MMP-2. The antiangiogenic activity of α1(IV)NC1 is mediated, in part, by this binding activity. In addition, up-regulation of TIMP-2 by α1(IV)NC1 led to saturation of MT1-MMP binding sites, which in turn led to inhibition of MMP-2 activation. In-vivo studies using α1-integrin null-mice treated with higher doses of α1(IV)NC1 showed integrin independent inhibition of tumor growth and active-MMP-2, without affecting MMP-9, MMP-7 and angiostatin.
authors.affiliation: 1] Cell Signaling Laboratory, Bioscience Division, Center for Cancer and Metabolism, SRI International, Menlo Park, CA 94025, USA [2] Cell Signaling and Tumor Angiogenesis Laboratory, Department of Genetics, Boys Town National Research Hospital, Omaha, NE 68131, USA.
authors.forename: Yakkanti Akul
authors.initials: YA
authors.lastname: Sudhakar
authors.affiliation: Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, Kingsville, Texas 78363, USA.
authors.forename: Raj Kumar
authors.initials: RK
authors.lastname: Verma
authors.affiliation: Department of Genetics, Osmania University, Hyderabad, AP 500007, India.
authors.forename: Smita C
authors.initials: SC
authors.lastname: Pawar
mesh_terms: D043168:Angiostatins / Q000378:metabolism; D000818:Animals; D024141:Collagen Type IV / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D039423:Integrin alpha1 / Q000235:genetics; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism*; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000188:drug therapy / Q000378:metabolism; D018919:Neovascularization, Physiologic / Q000187:drug effects; D010662:Phenylmercuric Acetate / Q000031:analogs & derivatives / Q000494:pharmacology; D054730:Protein Interaction Domains and Motifs / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000302:isolation & purification / Q000494:pharmacology; D042461:Vascular Endothelial Growth Factor A / Q000494:pharmacology
chemical_list: D024141:Collagen Type IV; D039423:Integrin alpha1; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; C010024:4-aminophenylmercuriacetate; D043168:Angiostatins; D020783:Matrix Metalloproteinase 7; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14; D010662:Phenylmercuric Acetate