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J. Biol. Chem., Vol. 279, Issue 13, 12734-12743, March 26, 2004

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Membrane-type 1 Matrix Metalloproteinase Cytoplasmic Tail-binding Protein-1 Is a New Member of the Cupin Superfamily

A POSSIBLE MULTIFUNCTIONAL PROTEIN ACTING AS AN INVASION SUPPRESSOR DOWN-REGULATED IN TUMORS^*

Takamasa Uekita, Isamu Gotoh, Takeshi Kinoshita¶, Yoshifumi Itoh||, Hiroshi Sato**, Takayuki Shiomi, Yasunori Okada, and Motoharu Seiki

From the Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, ^**Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, and Department of Pathology, School of Medicine, Keio University, Shinjuku-ku, Tokyo 160-0016,-Japan

Membrane-type 1 matrix metalloproteinase (MT1-MMP/MMP-14) is an enzyme that promotes tumor cell invasion in tissues. Although the proteolytic activity of MT1-MMP is indispensable for invasion, it is also regulated by functions of the cytoplasmic tail. In this study we obtained a new human gene whose product binds to the tail sequence in yeast. The product, MTCBP-1, is a 19-kDa protein that belongs to the newly proposed Cupin superfamily composed of proteins with diverse functions. MTCBP-1 expressed in cells formed a complex with MT1-MMP and co-localized at the membrane. It was also detected in both the cytoplasm and nucleus, where MT1-MMP does not exist. In human tumor cell lines MTCBP-1 expression was significantly low compared with non-transformed fibroblasts, and enforced expression of MTCBP-1 inhibited the activity of MT1-MMP in promoting cell migration and invasion. MTCBP-1 showed significant homology to the bacterial aci-reductone dioxygenase, which is an enzyme in methionine metabolism. The C-terminal part of MTCBP-1 is identical to Sip-L, which is reported to be important for human hepatitis C virus replication. Thus, MTCBP-1 may have multiple functions other than the regulation of MT1-MMP, which presumably depends on the subcellular compartment.

Received for publication, September 8, 2003 , and in revised form, December 28, 2003.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) AB158319.

^* This work was supported by the Special Coordination Fund for promoting Science and Technology from the Ministry of Science and Technology of Japan and by a grant-in-aid for Cancer Research from the Ministry of Education, Science, and Culture of Japan. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Growth Factor Division, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045.

^¶ Present address: Center for the Development of Molecular Target Drugs, Cancer Research Institute, Kanazawa University, Kanazawa 920-0934, Japan.

^|| Present address: Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College, 1 Aspenlea Rd., Hammersmith, London W6 8LH, UK.

To whom correspondence should be addressed: Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, 4-6-1 Shirokane-dai, Minato-ku, Tokyo 108-8639, Japan. Tel.: 81-3-5449-5255; Fax: 81-3-5449-5414; E-mail: mseiki{at}ims.u-tokyo.ac.jp.

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