Peptide inhibition of catalytic and noncatalytic activities of matrix metalloproteinase-9 blocks tumor cell migration and invasion.
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.
Björklund
Mikael
M
Department of Biological and Environmental Sciences, Viikinkaari 5D, Viikki Biocenter.
Heikkilä
Pia
P
Koivunen
Erkki
E
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
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