ABSTRACT

Matrix metalloproteinase 7 (MMP-7) has been purified as an inactive zymogen of M 28,000 (proMMP-7) from the culture medium of CaR-1 human rectal carcinoma cells. The NH-terminal sequence of proMMP-7 is Lys-Pro-Lys-Pro-Gln-Glu, which is identical to that of matrilysin. The zymogen is activated by 4-aminophenylmercuric acetate (APMA), yielding an intermediate form of M 21,000 and an active species of M 19,000 which shows the new NH-terminal sequence of Tyr-Ser-Leu-Phe-Pro-Asn-Ser. Although trypsin fully activates the zymogen, the activation rate by plasmin or leukocyte elastase is confined to 50%. ProMMP-7 can be activated by MMP-3 (stromelysin 1) to its full activity in a single-step mechanism and generates the same NH terminus obtained by APMA activation, whereas MMP-1 (tissue collagenase), MMP-2 (gelatinase A), and MMP-9 (gelatinase B) do not have such an effect. On the other hand, proMMP-1 is activated by MMP-7 to an activity similar to that obtained by APMA and the activation by MMP-7 is enhanced up to 6.5-fold in the presence of APMA. This enhanced activity is donated by specific cleavage at the Gln-Phe bond of proMMP-1. MMP-7 can also activate proMMP-9 up to 50% of the full activity with a new NH terminus of Leu-Arg-Thr-(Asn)-Leu. Incubation of proMMP-2 or proMMP-3 with MMP-7 results in no activation of these proMMPs. MMP-7 degrades type IV collagen, laminin-1, fibronectin, proteoglycan, type I gelatin, and insoluble elastin. These results suggest that in vivo MMP-7 may play a role in degradation of extracellular matrix macromolecules in concert with MMP-1, -3, and -9 under pathological conditions.

FOOTNOTES

*

This work was supported by Grant-in-aid 05670167 from the ministry of Education, Science and Culture of Japan (to Y. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked ``advertisement'' in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§

To whom correspondence should be addressed: Dept. of Molecular Immunology and Pathology, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920, Japan. Tel.: 81-762-34-4507; Fax: 81-762-34-4508.

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The abbreviations used are: MMPs, matrix metalloproteinases; proMMP, corresponding zymogen form; APMA, 4-aminophenylmercuric acetate; DIFP, diisopropyl fluorophosphate; PAGE, polyacrylamide gel electrophoresis; TIMP, tissue inhibitor of metalloproteinases; Cm-Tf, carboxymethylated transferrin.

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K. Imai, A. Kimura, I. Nakanishi, and Y. Okada, unpublished data.

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