title: Peptide inhibition of catalytic and noncatalytic activities of matrix metalloproteinase-9 blocks tumor cell migration and invasion.
abstract: Migration of invasive cells appears to be dependent on matrix metalloproteinases (MMPs) anchored on the cell surface through integrins. We have previously demonstrated an interaction between the integrin alpha-subunit I domain and the catalytic domain of MMP-9. We now show that there is also an interaction between the integrin beta subunit and MMP-9. Using phage display, we have developed MMP-9 inhibitors that bind either to the MMP-9 catalytic domain, the collagen binding domain, or the C-terminal hemopexin-like domain. The C-terminal domain-binding peptide mimics an activation epitope in the stalk of the integrin beta chain and inhibits the association of MMP-9 C-terminal domain with alpha(V)beta(5) integrin. Unlike other MMP-9 binding peptides, it does not directly inhibit catalytic activity of MMP-9, but still prevents proenzyme activation and cell migration in vitro and tumor xenograft growth in vivo. We also find an association between MMP-9 and urokinase-plasminogen activator receptor and find that urokinase-plasminogen activator receptor is cleaved by MMP-9. Collectively, we have defined molecular details for several interactions mediated by the different MMP-9 domains.
authors.affiliation: Department of Biological and Environmental Sciences, Viikinkaari 5D, Viikki Biocenter.
authors.forename: Mikael
authors.initials: M
authors.lastname: Björklund
authors.forename: Pia
authors.initials: P
authors.lastname: Heikkilä
authors.forename: Erkki
authors.initials: E
authors.lastname: Koivunen
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D020134:Catalytic Domain; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D019281:Dimerization; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000378:metabolism*; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016023:Integrins / Q000235:genetics / Q000378:metabolism; D016177:Macrophage-1 Antigen / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D010455:Peptides / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D011956:Receptors, Cell Surface / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D019030:Receptors, Vitronectin / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D014183:Transplantation, Heterologous; D019096:Vitronectin / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D005353:Fibronectins; D016023:Integrins; D016177:Macrophage-1 Antigen; D061965:Matrix Metalloproteinase Inhibitors; C524898:PLAUR protein, human; D010455:Peptides; C524899:Plaur protein, mouse; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D019030:Receptors, Vitronectin; D019096:Vitronectin; C064660:integrin alphaVbeta5; D020780:Matrix Metalloproteinase 9