Peptide inhibition of catalytic and noncatalytic activities of matrix metalloproteinase-9 blocks tumor cell migration and invasion

被引:61
作者
Björklund, M
Heikkilä, P
Koivunen, E
机构
[1] Viikki Bioctr, Dept Biol & Environm Sci, Helsinki, Finland
[2] Univ Helsinki, Cent Hosp, Dept Oral & Maxillofacial Dis, Inst Dent, FIN-00014 Helsinki, Finland
关键词
D O I
10.1074/jbc.M401601200
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:29589 / 29597
页数:9
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