Cell-surface-associated tissue transglutaminase is a target of MMP-2 proteolysis
Cell-surface-associated tissue transglutaminase is a target of MMP-2 proteolysis
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DOI：
10.1021/bi049266z
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发表时间：
2004-09-21
期刊：
影响因子：
2.9
通讯作者：
Strongin, AY
中科院分区：
文献类型：
--
作者：
Belkin, AM;Zemskov, EA;Strongin, AY
MT 1-MMP是膜型金属蛋白酶亚家族的原型成员，是一种侵袭促进蛋白酶和MMP-2的激活剂。此外，MT 1-MMP蛋白水解调节细胞表面粘附/信号受体的功能，包括组织转氨酶（tTG）。已知tTG可作为β 1/β 3整联蛋白的粘附辅助受体，也是一种催化蛋白质交联和多胺与蛋白质结合的酶。在这里，我们报告说，MMP-2，与MT 1-MMP协同发挥作用，水解细胞表面相关的tTG，从而进一步促进MMP-2的激活剂启动的效果。反过来，tTG优先与MMP-2的活化中间体结合。该事件降低MMP-2成熟的速率并保护tTG免受MMP-2的蛋白水解。我们的细胞培养、体外实验和计算机模拟表明MMP-2的催化结构域与tTG的核心酶结构域II直接相关（Kd = 380 nM）。结构域II的后续切割消除了tTG的受体和酶活性。我们的数据阐明了涉及MT 1-MMP/MMP-2蛋白酶串联体在细胞受体调节中的协调相互作用，并解释了存在于正常组织/肿瘤边界的广泛tTG蛋白水解的潜在生化机制。我们的研究结果还表明，肿瘤，表达功能活性的MT 1-MMP，因此，激活可溶性MMP-2，可以有助于降解的tTG表达在邻近的宿主细胞。tTG在肿瘤和正常组织之间的界面处的粘附和酶活性的丧失将减少细胞-基质相互作用并抑制基质交联，从而引起宿主细胞粘附和运动的多种病理改变。
MT1-MMP, a prototypic member of a membrane-type metalloproteinase subfamily, is an invasion promoting protease and an activator of MMP-2. In addition, MT1-MMP proteolysis regulates the functionality of cell-surface adhesion/signaling receptors including tissue transglutaminase (tTG). tTG is known to serve as an adhesion coreceptor for beta1/beta3 integrins and as an enzyme that catalyzes the cross-linking of proteins and the conjugation of polyamines to proteins. Here, we report that MMP-2, functioning in concert with MT1-MMP, hydrolyzes cell-surface-associated tTG, thereby further promoting the effect initiated by the activator of MMP-2. tTG, in return, preferentially associates with the activation intermediate of MMP-2. This event decreases the rate of MMP-2 maturation and protects tTG against proteolysis by MMP-2. Our cell culture, in vitro experiments, and in silico modeling indicate that the catalytic domain of MMP-2 directly associates with the core enzymatic domain II of tTG (the K-d = 380 nM). The follow-up cleavage of the domain II eliminates both the receptor and the enzymatic activity of tTG. Our data illuminate the coordinated interplay involving the MT1-MMP/MMP-2 protease tandem in the regulation of the cell receptors and explain the underlying biochemical mechanisms of the extensive tTG proteolysis that exists at the normal tissue/tumor boundary. Our findings also suggest that neoplasms, which express functionally active MT1-MMP and, therefore, activate soluble MMP-2, can contribute to the degradation of tTG expressed in neighboring host cells. The loss of adhesive and enzymatic activities of tTG at the interface between tumor and normal tissue will decrease cell-matrix interactions and inhibit matrix cross-linking, causing multiple pathological alterations in host cell adhesion and locomotion.