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Published 24 December 2001. doi:10.1083/jcb.200108112
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© The Rockefeller University Press, 0021-9525/2001/12/1345 $5.00
The Journal of Cell Biology, Volume 155, Number 7, December 24, 2001 1345-1356

Article

Cytoplasmic tail–dependent internalization of membrane-type 1 matrix metalloproteinase is important for its invasion-promoting activity



Takamasa Uekita1, Yoshifumi Itoh1, Ikuo Yana1, Hiroshi Ohno2 and Motoharu Seiki1

1 Division of Cancer Cell Research, Institute of Medical Science, The University of Tokyo, Tokyo, 108-8639, Japan
2 Division of Molecular Membrane Biology, Cancer Research Institute, Kanazawa University, Kanazawa, 920-0934, Japan

Address correspondence to Motoharu Seiki, Ph.D., Professor, 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

Membrane-type 1 matrix metalloproteinase (MT1-MMP) is an integral membrane proteinase that degrades the pericellular extracellular matrix (ECM) and is expressed in many migratory cells, including invasive cancer cells. MT1-MMP has been shown to localize at the migration edge and to promote cell migration; however, it is not clear how the enzyme is regulated during the migration process. Here, we report that MT1-MMP is internalized from the surface and that this event depends on the sequence of its cytoplasmic tail. Di-leucine (Leu571–572 and Leu578–579) and tyrosine573 residues are important for the internalization, and the µ2 subunit of adaptor protein 2, a component of clathrin-coated pits for membrane protein internalization, was found to bind to the LLY573 sequence. MT1-MMP was internalized predominantly at the adherent edge and was found to colocalize with clathrin-coated vesicles. The mutations that disturb internalization caused accumulation of the enzyme at the adherent edge, though the net proteolytic activity was not affected much. Interestingly, whereas expression of MT1-MMP enhances cell migration and invasion, the internalization-defective mutants failed to promote either activity. These data indicate that dynamic turnover of MT1-MMP at the migration edge by internalization is important for proper enzyme function during cell migration and invasion.

Key Words: MT-MMP; metalloproteinase; internalization; invasion; migration


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