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Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan

Membrane type-1 matrix metalloproteinase (MT1-MMP) is a proinvasive protease that regulates various cellular functions as evidenced by myriad defects in different types of cells and tissues in MT1-MMP-deficient (MT1^–/–) mice. Here we demonstrate that MT1^–/– mice exhibit fewer infiltrating macrophages into sites of inflammation. MT1^–/– macrophages exhibited a reduced ability to invade reconstituted basement membrane (Matrigel) and invasion by wild type (WT) macrophages was inhibited by a synthetic MMP inhibitor (BB94) to a level similar to that of MT1^–/– cells. The rate of migration of MT1^–/– macrophages was also low compared to that of the WT cells and re-expression of MT1-MMP in MT1^–/– macrophages reconstituted their migratory activity. Unexpectedly, however, BB94 did not inhibit the migration of WT macrophages. The migration-boosting activity of MT1-MMP is retained in a mutant that lacks most of the extracellular portion including the catalytic and hemopexin-like domains. In contrast, deletion of the cytoplasmic (CP) tail abolished the activity completely. Thus, we have demonstrated that MT1-MMP regulates macrophages via its invasion-promoting protease activity as well as its CP-dependent non-proteolytic activity to boost cell migration.

^* Correspondence: mseiki{at}ims.u-tokyo.ac.jp

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