Dimerization is essential for HAb18G/CD147 promoting tumor invasion via MAPK pathway
Dimerization is essential for HAb18G/CD147 promoting tumor invasion via MAPK pathway
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二聚化对于 HAb18G/CD147 通过 MAPK 途径促进肿瘤侵袭至关重要
DOI：
10.1016/j.bbrc.2012.02.049
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发表时间：
2012-03-16
影响因子：
3.1
通讯作者：
Yu, Xiao-Ling
中科院分区：
文献类型：
--
作者：
Cui, Hong-Yong;Guo, Tao;Yu, Xiao-Ling
HAb 18 G/CD 147是免疫球蛋白超家族（IgSF）的一种跨膜糖蛋白，与多种肿瘤的侵袭和转移有关。HAb 18 G/CD 147胞外域的晶体结构表明其在晶体中可形成同源二聚体。然而，HAb 18 G/CD 147二聚化的功能意义仍不清楚。在本研究中，在晶体结构的指导下，我们进行了广泛的突变和功能研究，以确定残基的二聚化和分子功能的HAb 18 G/CD 147的关键。纯化了14种突变体，并评价了它们在溶液和活细胞中形成二聚体的能力。随后的功能验证显示，K63 E和S193 A突变体，破坏了CD 147在溶液和活细胞中的二聚化，在肿瘤细胞中对MAPK活化、MMP 2诱导和侵袭性显示出明显的显性负效应。总之，本研究提供了突变和功能证据，首次证明了CD 147二聚化的功能重要性及其与肿瘤细胞侵袭和转移的直接相关性。(C)2012 Elsevier Inc. All rights reserved.
HAb18G/CD147 is a transrnembrane glycoprotein of the immunoglobulin superfamily (IgSF) and is reported to be correlated with invasion and metastasis of many cancers. The crystal structure of HAb18G/CD147 ectodomain has shown that it can form homodimers in crystal. However, the functional significance of HAb18G/CD147 dimerization remains unclear. In the present study, guided by the crystal structure, we performed extensive mutational and functional studies to identify residues critical for dimerization and molecular function of HAb18G/CD147. Fourteen mutants were purified and evaluated for their ability to form dimers in solution and in living cells. Subsequent functional validation revealed that K63E and S193A mutants, which disrupted CD147 dimerization both in solution and in living cells, showed clearly dominant-negative effects on MAPK activation, MMP2 induction and invasiveness in tumor cells. Taken together, the present study provides mutational and functional evidences demonstrating for the first time the functional importance of CD147 dimerization and its direct correlation with invasion and metastasis of tumor cells. (C) 2012 Elsevier Inc. All rights reserved.