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Membrane-Type Matrix Metalloproteinase 1 Is a Gelatinolytic Enzyme and Is Secreted in a Complex with Tissue Inhibitor of Metalloproteinases 2¹

Departments of Molecular Immunology and Pathology [K. I., E. O., Y. O.], Surgery [H. N.], and Virology and Oncology [H. S., M. S.], Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920; Fuji Chemical Industries Ltd., Takaoka, Toyama 933 [E. O., T. A.]; and Department of Chemistry, Fukui Medical School, Fukui 910-11 [Y. F.], Japan

The processing mechanism and gelatinolytic activity of the membranetype matrix metalloproteinase 1 (MT-MMP-1) were examined by expressing in COS-1 cells a deletion mutant of MT-MMP-1 lacking the transmembrane domain (MT1) and its site-directed mutant with a furinresistant sequence in the propeptide domain (mutant MT1). MT1, but not mutant MT1, was processed to an active form and exhibited gelatinolytic activity as seen using gelatin zymography. MT1 isolated in a complex form with tissue inhibitor of metalloproteinases 2 (TIMP-2) from the stable transfectants demonstrated the NH₂-terminal sequence of Ala¹¹³-IIe-Gln-Gly-Leu, indicating cleavage at one amino acid down-stream from the furin recognition sequence. The MT1/TIMP-2 complex formed a ternary complex with proMMP-2 through the COOH termini of TIMP-2 and proMMP-2. A human breast carcinoma cell line (MDA-MB-231 cells) also secreted MT-MMP-1 into culture media, which was purified in a complex form with TIMP-2 and showed gelatinolytic activity as seen using zymography. These results demonstrate for the first time that MT-MMP-1 is a gelatinolytic enzyme and secreted from cells in a complex with TIMP-2, which can form a ternary complex of MT-MMP-1/TIMP-2/proMMP-2.

¹ Supported by a Grant-in-Aid from the Ministry of Education, Science, and Culture of Japan (Y. O.).

² Recipient of Research Fellowship from the Japan Society for the Promotion of Science for Young Scientists.

³ To whom requests for reprints should be addressed. Phone: 81-762-34-4507; Fax: 81-762-34-4508; E-mail: yasokada@kenroku.ipc.kanazawa-u.ac.jp.

Received 3/ 4/96. Accepted 4/30/96.

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