Cytoplasmic tail of MT1-MMP regulates macrophage motility independently from its protease activity.
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.
Division of Cancer Cell Research, Institute of Medical Science, University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Takeharu
T
Sakamoto
Motoharu
M
Seiki
D000818:Animals; D002465:Cell Movement / Q000187:drug effects; D003593:Cytoplasm / Q000378:metabolism*; D008264:Macrophages / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology*; D053511:Matrix Metalloproteinase 14 / Q000172:deficiency / Q000378:metabolism*; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D018345:Mice, Knockout; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000494:pharmacology; D013876:Thiophenes / Q000494:pharmacology
D061965:Matrix Metalloproteinase Inhibitors; C507096:Mmp14 protein, mouse; D013876:Thiophenes; D010649:Phenylalanine; C080985:batimastat; D053511:Matrix Metalloproteinase 14