National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China.
Oncogene. 2012 Jan 19;31(3):306-21. doi: 10.1038/onc.2011.244. Epub 2011 Jul 4.
Tumor cell migration is a well-orchestrated multistep process that drives cancer development and metastasis. Previous data indicated that CD146 expression correlates with malignant progression and metastatic potential of human melanoma cells. However, the exact molecular mechanism of how CD146 promotes melanoma cell migration still remains poorly understood. Here, we report that CD146 physically interacts with actin-linking ezrin-radixin-moesin (ERM) proteins and recruits ERM proteins to cell protrusions, promoting the formation and elongation of microvilli. Moreover, CD146-promoted melanoma cell migration is linked to RhoA activation and ERM phosphorylation. CD146 recruits Rho guanine nucleotide dissociation inhibitory factors 1 (RhoGDI1) through ERM proteins and thus sequesters RhoGDI1 from RhoA, which leads to upregulated RhoA activity and increased melanoma cell motility. CD146-activated RhoA also promotes further ERM phosphorylation and activation through Rho-phosphatidylinositol-4-phosphate-5-kinase-phosphatidylinositol 4,5-biphosphate pathway, which reinforces CD146/ERM association. Thus, our results provide a mechanistic basis to understand the role of CD146 in regulating human melanoma cell motility.
肿瘤细胞迁移是一个经过精心协调的多步骤过程，推动了癌症的发展和转移。先前的数据表明，CD146 的表达与人类黑色素瘤细胞的恶性进展和转移潜能相关。然而，CD146 如何促进黑色素瘤细胞迁移的确切分子机制仍知之甚少。在这里，我们报告 CD146 与肌动蛋白连接蛋白 ezrin-radixin-moesin (ERM) 蛋白发生物理相互作用，并将 ERM 蛋白募集到细胞突起中，促进微绒毛的形成和伸长。此外，CD146 促进黑色素瘤细胞迁移与 RhoA 的激活和 ERM 的磷酸化有关。CD146 通过 ERM 蛋白招募 Rho 鸟嘌呤核苷酸解离抑制因子 1 (RhoGDI1)，从而将 RhoGDI1 从 RhoA 上隔离出来，导致 RhoA 活性上调和黑色素瘤细胞迁移能力增强。CD146 激活的 RhoA 还通过 Rho-磷脂酰肌醇-4-磷酸-5-激酶-磷酸磷脂酰肌醇 4,5-二磷酸途径进一步促进 ERM 的磷酸化和激活，从而加强 CD146/ERM 的结合。因此，我们的研究结果为理解 CD146 在调节人类黑色素瘤细胞迁移中的作用提供了机制基础。
