Tissue inhibitor of metalloproteinases-2 binding to membrane-type 1 matrix metalloproteinase induces MAPK activation and cell growth by a non-proteolytic mechanism
Tissue inhibitor of metalloproteinases-2 binding to membrane-type 1 matrix metalloproteinase induces MAPK activation and cell growth by a non-proteolytic mechanism
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DOI：
10.1074/jbc.m705492200
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发表时间：
2008-01-04
影响因子：
4.8
通讯作者：
Mignatti, Paolo
中科院分区：
文献类型：
--
作者：
D'Alessio, Silvia;Ferrari, Giovanni;Mignatti, Paolo
膜型1基质金属蛋白酶（MT1-MMP）是一种具有胞质短结构域和胞外催化结构域的跨膜蛋白酶，通过胞外或跨膜蛋白的蛋白水解降解控制多种生理和病理过程。MT1-MMP与其生理蛋白抑制剂组织金属蛋白酶抑制剂-2 （TIMP-2）在细胞膜上形成复合体。本研究表明，除了胞外蛋白水解外，MT1-MMP和TIMP-2还通过非蛋白水解机制控制细胞增殖和迁移。TIMP-2结合MT1-MMP通过不需要蛋白水解活性的机制诱导ERK1/2的激活，并由MT1-MMP的细胞质尾部介导。mt1 - mmp介导的ERK1/2激活在体外独立于细胞外基质蛋白水解的情况下上调细胞迁移和增殖。蛋白水解无活性的MT1-MMP在体内促进肿瘤生长，而缺乏细胞质尾部的蛋白水解活性MT1-MMP则没有这种作用。这些发现说明了MT1-MMP-TIMP-2相互作用的新作用，它通过独立于细胞外基质降解的机制控制细胞功能。
Membrane-type 1 matrix metalloproteinase (MT1-MMP), a transmembrane proteinase with a short cytoplasmic domain and an extracellular catalytic domain, controls a variety of physiological and pathological processes through the proteolytic degradation of extracellular or transmembrane proteins. MT1-MMP forms a complex on the cell membrane with its physiological protein inhibitor, tissue inhibitor of metalloproteinases-2 (TIMP-2). Here we show that, in addition to extracellular proteolysis, MT1-MMP and TIMP-2 control cell proliferation and migration through a non-proteolytic mechanism. TIMP-2 binding to MT1-MMP induces activation of ERK1/2 by a mechanism that does not require the proteolytic activity and is mediated by the cytoplasmic tail of MT1-MMP. MT1-MMP-mediated activation of ERK1/2 up-regulates cell migration and proliferation in vitro independently of extracellular matrix proteolysis. Proteolytically inactive MT1-MMP promotes tumor growth in vivo, whereas proteolytically active MT1-MMP devoid of cytoplasmic tail does not have this effect. These findings illustrate a novel role for MT1-MMP-TIMP-2 interaction, which controls cell functions by a mechanism independent of extracellular matrix degradation.