TY - JOUR
T1 - Matrix metalloproteinases (MMPs) regulate fibrin-invasive activity via MT1-MMP-dependent and -independent processes
AU - Hotary, Kevin B
AU - Yana, Ikuo
AU - Sabeh, Farideh
AU - Li, Xiao-Yan
AU - Holmbeck, Kenn
AU - Birkedal-Hansen, Henning
AU - Allen, Edward D
AU - Hiraoka, Nobuaki
AU - Weiss, Stephen J
PY - 2002/2/4
Y1 - 2002/2/4
N2 - 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.
AB - 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.
KW - Animals
KW - CHO Cells
KW - Cell Line
KW - Cricetinae
KW - Dogs
KW - Fibrin/metabolism
KW - Fibrinolysis
KW - Fibroblasts/cytology
KW - Matrix Metalloproteinase 14
KW - Matrix Metalloproteinase 15
KW - Matrix Metalloproteinase 16
KW - Matrix Metalloproteinases/metabolism
KW - Matrix Metalloproteinases, Membrane-Associated
KW - Metalloendopeptidases/deficiency
KW - Mice
KW - Mice, Knockout
KW - Transfection
M3 - Journal article
C2 - 11828004
SN - 0022-1007
VL - 195
SP - 295
EP - 308
JO - The Journal of Experimental Medicine
JF - The Journal of Experimental Medicine
IS - 3
ER -