Matrix metalloproteinases (MMPs) regulate fibrin-invasive activity via MT1-MMP-dependent and -independent processes.
Cross-linked fibrin is deposited in tissues surrounding wounds, inflammatory sites, or tumors and serves not only as a supporting substratum for trafficking cells, but also as a structural barrier to invasion. While the plasminogen activator-plasminogen axis provides cells with a powerful fibrinolytic system, plasminogen-deleted animals use alternate proteolytic processes that allow fibrin invasion to proceed normally. Using fibroblasts recovered from wild-type or gene-deleted mice, invasion of three-dimensional fibrin gels proceeded in a matrix metalloproteinase (MMP)-dependent fashion. Consistent with earlier studies supporting a singular role for the membrane-anchored MMP, MT1-MMP, in fibrin-invasive events, fibroblasts from MT1-MMP-null mice displayed an early defect in invasion. However, MT1-MMP-deleted fibroblasts circumvented this early deficiency and exhibited compensatory fibrin-invasive activity. The MT1-MMP-independent process was sensitive to MMP inhibitors that target membrane-anchored MMPs, and further studies identified MT2-MMP and MT3-MMP, but not MT4-MMP, as alternate pro-invasive factors. Given the widespread distribution of MT1-, 2-, and 3-MMP in normal and neoplastic cells, these data identify a subset of membrane-anchored MMPs that operate in an autonomous fashion to drive fibrin-invasive activity.
Hotary
Kevin B
KB
University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, USA.
Yana
Ikuo
I
Sabeh
Farideh
F
Li
Xiao-Yan
XY
Holmbeck
Kenn
K
Birkedal-Hansen
Henning
H
Allen
Edward D
ED
Hiraoka
Nobuaki
N
Weiss
Stephen J
SJ
D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D004285:Dogs; D005337:Fibrin / Q000378:metabolism*; D005342:Fibrinolysis; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D053511:Matrix Metalloproteinase 14; D053517:Matrix Metalloproteinase 15; D053513:Matrix Metalloproteinase 16; D020782:Matrix Metalloproteinases / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D000090023:Metallothionein 3; D051379:Mice; D018345:Mice, Knockout; D014162:Transfection
D000090023:Metallothionein 3; C507096:Mmp14 protein, mouse; C507100:Mmp15 protein, mouse; C507104:Mmp16 protein, mouse; C000715430:Mt3 protein, mouse; D005337:Fibrin; D053517:Matrix Metalloproteinase 15; D053513:Matrix Metalloproteinase 16; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated; D008666:Metalloendopeptidases; D053511:Matrix Metalloproteinase 14