Membrane-type 1 matrix metalloproteinase modulates focal adhesion stability and cell migration.
Membrane-type 1 matrix metalloproteinase (MT1-MMP) plays an important role in extracellular matrix-induced cell migration and the activation of extracellular signal-regulated kinase (ERK). We showed here that transfection of the MT1-MMP gene into HeLa cells promoted fibronectin-induced cell migration, which was accompanied by fibronectin degradation and reduction of stable focal adhesions, which function as anchors for actin-stress fibers. MT1-MMP expression attenuated integrin clustering that was induced by adhesion of cells to fibronectin. The attenuation of integrin clustering was abrogated by MT1-MMP inhibition with a synthetic MMP inhibitor, BB94. When cultured on fibronectin, HT1080 cells, which endogenously express MT1-MMP, showed so-called motile morphology with well-organized focal adhesion formation, well-oriented actin-stress fiber formation, and the lysis of fibronectin through trails of cell migration. Inhibition of endogenous MT1-MMP by BB94 treatment or expression of the MT1-MMP carboxyl-terminal domain, which negatively regulates MT1-MMP activity, resulted in the suppression of fibronectin lysis and cell migration. BB94 treatment promoted stable focal adhesion formation concomitant with enhanced phosphorylation of tyrosine 397 of focal adhesion kinase (FAK) and reduced ERK activation. These results suggest that lysis of the extracellular matrix by MT1-MMP promotes focal adhesion turnover and subsequent ERK activation, which in turn stimulates cell migration.
Department of Molecular Virology and Oncology, Cancer Research Institute, Kanazawa University, 13-1 Takara-machi, Kanazawa 920-0934, Japan. ttakino@kenroku.kanazawa-u.ac.jp
Takahisa
T
Takino
Yumi
Y
Watanabe
Miyuki
M
Matsui
Hisashi
H
Miyamori
Tomoya
T
Kudo
Motoharu
M
Seiki
Hiroshi
H
Sato
D008841:Actin Cytoskeleton / Q000378:metabolism; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005109:Extracellular Matrix / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000187:drug effects / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism* / Q000494:pharmacology; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000187:drug effects / Q000378:metabolism; D022001:Focal Adhesions / Q000187:drug effects / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D016023:Integrins / Q000187:drug effects / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D053504:Matrix Metalloproteinases, Membrane-Associated; D010766:Phosphorylation / Q000187:drug effects; D017434:Protein Structure, Tertiary / Q000502:physiology; D022502:Stress Fibers / Q000378:metabolism; D014162:Transfection
D004791:Enzyme Inhibitors; D005353:Fibronectins; D016023:Integrins; D061965:Matrix Metalloproteinase Inhibitors; D051416:Focal Adhesion Protein-Tyrosine Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D020782:Matrix Metalloproteinases; D053504:Matrix Metalloproteinases, Membrane-Associated