Molecular dissection of the structural machinery underlying the tissue-invasive activity of membrane type-1 matrix metalloproteinase
Molecular dissection of the structural machinery underlying the tissue-invasive activity of membrane type-1 matrix metalloproteinase
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DOI：
10.1091/mbc.e08-01-0016
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发表时间：
2008-08-01
影响因子：
3.3
通讯作者：
Weiss, Stephen J.
中科院分区：
文献类型：
--
作者：
Li, Xiao-Yan;Ota, Ichiro;Weiss, Stephen J.
膜1型基质金属蛋白酶（MT 1-MMP）通过由I型胶原或纤维蛋白主导的三维（3-D）细胞外基质（ECM）屏障驱动细胞侵袭。主要基于其在二维培养条件下对细胞功能的影响的分析，MT 1-MMP被分类为多功能分子，其具有1）结构上不同的N-末端催化结构域; 2）调节底物识别以及构象的C-末端血红素结合蛋白结构域;和3）其胞质尾部控制蛋白酶运输和信号级联的I型跨膜结构域。然而，在体外或体内通过3-D ECM屏障辅助细胞运输的MT 1-MMP结构域在很大程度上仍然不确定。在此，我们证明，胶原蛋白的侵袭活性并不严格限于催化，血红素结合蛋白，跨膜，或胞质结构域序列的MT 1-MMP。事实上，即使是分泌的胶原酶支持入侵时，拴系到细胞表面的MT 1-MMP血红素结合蛋白，跨膜，和胞质尾部结构域的情况下。相比之下，MT 1-MMP支持纤维蛋白侵袭活性的能力与胶原溶解潜力不同，或者，它需要MT-MMP催化结构域和血红素结合蛋白结构域的特异性参与。因此，MT 1-MMP的组织侵入性质出乎意料地嵌入不同但简约的序列中，所述序列用于将必需的基质降解活性拴系到迁移细胞的表面。
Membrane type-1 matrix metalloproteinase (MT1-MMP) drives cell invasion through three-dimensional (3-D) extracellular matrix (ECM) barriers dominated by type I collagen or fibrin. Based largely on analyses of its impact on cell function under two-dimensional culture conditions, MT1-MMP is categorized as a multifunctional molecule with 1) a structurally distinct, N-terminal catalytic domain; 2) a C-terminal hemopexin domain that regulates substrate recognition as well as conformation; and 3) a type I transmembrane domain whose cytosolic tail controls protease trafficking and signaling cascades. The MT1-MMP domains that subserve cell trafficking through 3-D ECM barriers in vitro or in vivo, however, remain largely undefined. Herein, we demonstrate that collagen-invasive activity is not confined strictly to the catalytic, hemopexin, transmembrane, or cytosolic domain sequences of MT1-MMP. Indeed, even a secreted collagenase supports invasion when tethered to the cell surface in the absence of the MT1-MMP hemopexin, transmembrane, and cytosolic tail domains. By contrast, the ability of MT1-MMP to support fibrin-invasive activity diverges from collagenolytic potential, and alternatively, it requires the specific participation of MT-MMP catalytic and hemopexin domains. Hence, the tissue-invasive properties of MT1-MMP are unexpectedly embedded within distinct, but parsimonious, sequences that serve to tether the requisite matrix-degradative activity to the surface of migrating cells.