Membrane type 1 matrix metalloproteinase regulates collagen-dependent mitogen-activated protein/extracellular signal-related kinase activation and cell migration
Membrane type 1 matrix metalloproteinase regulates collagen-dependent mitogen-activated protein/extracellular signal-related kinase activation and cell migration
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DOI：
10.1158/0008-5472.can-03-1843
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发表时间：
2004-02-01
期刊：
影响因子：
11.2
通讯作者：
Sato, H
中科院分区：
文献类型：
--
作者：
Takino, T;Miyamori, H;Sato, H
丝裂原激活蛋白激酶-细胞外信号相关激酶 (ERK) 激酶 1 (MEK1)/ERK 信号传导参与肿瘤细胞侵袭和转移的调节。 HT1080 细胞在 I 型胶原上的迁移受到基质金属蛋白酶 (MMP) 抑制剂 BB94 和金属蛋白酶组织抑制剂 (TIMP)-2 的抑制，但不受 TIMP-L TIMP-2 特异性抑制的抑制，表明膜 1 型 MMP (MT1-MMP) 可能参与了这一过程。粘附在涂有 I 型胶原蛋白的培养皿上的 HT1080 细胞会诱导 ERK 激活，而 BB94 会抑制这种激活。 HT1080 细胞中的 MMP-2 加工也受到 I 型胶原培养的刺激，但受到 MEK 抑制剂 PD98059 的抑制。 MEK1 组成型活性形式的表达促进了 MMP-2 加工，同时 MT1-MMP 水平增加，表明 MT1-MMP 受 MEK/ERK 信号传导调节。此外，HT1080细胞中MT1-MMP的血红素结合蛋白样结构域的表达干扰MMP-2加工、ERK激活和细胞迁移，这意味着MT1-MMP的酶活性参与胶原诱导的ERK激活，从而增强细胞迁移。因此，HT1080 细胞与 I 型胶原的粘附诱导 MT1-MMP 依赖性 ERK 激活，进而导致 MT1-MMP 水平增加和随后的细胞迁移。
Mitogen-activated protein kinase-extracellular signal-related kinase (ERK) kinase 1 (MEK1)/ERK signaling has been implicated in the regulation of tumor cell invasion and metastasis. Migration of HT1080 cells on type I collagen was suppressed by the matrix metalloproteinase (MMP) inhibitors BB94 and tissue inhibitor of metalloproteinase (TIMP)-2 but not by TIMP-L TIMP-2-specific inhibition suggests that membrane type 1 MMP (MT1-MMP) is likely involved in this process. Activation of ERK was induced in HT1080 cells adhered on dishes coated with type I collagen, and this was inhibited by BB94. MMP-2 processing in HT1080 cells, which also was stimulated by cultivation on type I collagen, was inhibited by MEK inhibitor PD98059. Expression of a constitutively active form of MEK1 promoted MMP-2 processing concomitant with the increase of MT1-MMP levels, suggesting that MT1-MMP is regulated by MEK/ERK signaling. In addition, expression of the 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 an increase in MT1-MMP levels and subsequent cell migration.