Miyamori Hisashi

Sato Hiroshi

Seiki M.

Takino Takahisa

Watanabe Y.

Yoshioka Katsuji

Kanazawa University Repository for Academic Resources

―  ― 18Membrane-Type 1 Matrix Metalloproteinase Regulates Collagen-dependent Mitogen-Activated Protein/Extracellular Signal-Related Kinase Activation and Cell Migration  T. Takino, H. Miyamori, Y. Watanabe, K.Yoshioka1, M. Seiki2 and Hiroshi Sato (1Dept. Cell Cycle Regulation, Cancer Res. Inst. Kanazawa Univ., 2Dept. Cancer Cell Research, Inst. of Medical Science, University of Tokyo)  Mitogen-activated protein kinase (MAPK)-extracellular signal-related kinase (ERK) kinase 1 (MEK1)/ERK signaling has been implicated in regulation of tumor cell invasion and metastasis. Migration of HT1080 cells on type I collagen was suppressed by matrix metalloproteinase (MMP) inhibitors BB94 and tissue inhibitor of metalloproteinase (TIMP)-2 but not by TIMP-1. TIMP-2-specific inhibition suggests that membrane type-1 MMP (MT1-MMP) is involved in it. Activation of ERK was induced in HT1080 cells adhered on dishes coated with type I collagen, which was inhibited by BB94. MMP-2 processing in HT1080 cells, which was also stimulated by cultivation on type I collagen was inhibited by a MEK inhibitor PD98059. Expression of constitutively active form of MEK1 promoted MMP-2 processing concomitant with the increase of MT1-MMP level, suggesting that MT1-MMP is regulated by MEK/ERK signaling. In addition, expression of hemopexin-like domain of MT1-MMP in HT1080 cells interfered with MMP-2 processing, ERK activation and cell migration, implying that the enzymatic activity of MT1-MMP is involved in collagen-induced ERK activation which results in enhanced cell migration. Thus, adhesion of HT1080 cells to type I collagen induces MT1-MMP-dependent ERK activation, which in turn causes increase of MT1-MMP level and subsequent cell migration.  Fig. 1.  MT1-MMP is involved in cell migration.  HT1080 cells cultured in serum-free DMEM containing DMSO (Control), BB94 (1 µM), PD98059 (25 µM), recombinant TIMP-1 or TIMP-2 (10 µg/ml) and HT1080 cells transfected with MT1-MMP or CA-MEK were examined for migration on type I collagen. Error bars indicate S.D. for at least 30 cells per condition. Asterisk, P < 0.01 versus control.  

Membrane-Type 1 Matrix Metalloproteinase Regulates Collagen-dependent Mitogen-Activated Protein/Extracellular Signal-Related Kinase Activation and Cell Migration

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Membrane-Type 1 Matrix Metalloproteinase Regulates Collagen-dependent Mitogen-Activated Protein/Extracellular Signal-Related Kinase Activation and Cell Migration

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