A Mediator of Rho-dependent Invasion Moonlights as a Methionine Salvage Enzyme
A Mediator of Rho-dependent Invasion Moonlights as a Methionine Salvage Enzyme
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DOI：
10.1074/mcp.m900178-mcp200
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发表时间：
2009-10-01
影响因子：
7
通讯作者：
Ahn, Natalie G.
中科院分区：
文献类型：
--
作者：
Kabuyama, Yukihito;Litman, Elizabeth S.;Ahn, Natalie G.
RhoA控制与癌症表型相关的细胞形态和侵袭性的变化。不同阶段的黑色素瘤细胞系显示，在转移性来源的细胞中，RhoA被选择性地激活。我们描述了一种功能蛋白质组学策略来识别受RhoA调控的蛋白质，并报告了一种以前未确定的人类蛋白质，名为“RhoA依赖侵袭的介体(MRDI)”，它由RhoA的结构性激活在转移细胞中诱导并促进细胞侵袭。在人类黑色素瘤中，MRDI的定位与分期相关，表现为胞核定位于色素痣和早期肿瘤，胞浆定位于晚期肿瘤的胞膜强化。与其促进细胞侵袭的作用一致，MRDI定位于培养细胞的细胞突起和前沿膜上，是细胞运动、粘着斑激酶酪氨酸磷酸化和肌动蛋白应激纤维调节所必需的。出乎意料的是，MRDI具有异构酶的功能，可以将S-腺苷蛋氨酸分解代谢产物5-甲基核糖-1-磷酸转化为5-甲基核酮糖-1-磷酸。从S-腺苷蛋氨酸中回收蛋氨酸需要MRDI的酶功能，但与其在细胞侵袭中的功能不同。因此，信号转导途径用来控制细胞运动的机制是从具有古老氨基酸代谢功能的蛋白质进化而来的。《分子与细胞蛋白质组学》8：2308-2320,2009。
RhoA controls changes in cell morphology and invasion associated with cancer phenotypes. Cell lines derived from melanoma tumors at varying stages revealed that RhoA is selectively activated in cells of metastatic origin. We describe a functional proteomics strategy to identify proteins regulated by RhoA and report a previously uncharacterized human protein, named "mediator of RhoA-dependent invasion (MRDI)," that is induced in metastatic cells by constitutive RhoA activation and promotes cell invasion. In human melanomas, MRDI localization correlated with stage, showing nuclear localization in nevi and early stage tumors and cytoplasmic localization with plasma membrane accentuation in late stage tumors. Consistent with its role in promoting cell invasion, MRDI localized to cell protrusions and leading edge membranes in cultured cells and was required for cell motility, tyrosine phosphorylation of focal adhesion kinase, and modulation of actin stress fibers. Unexpectedly MRDI had enzymatic function as an isomerase that converts the S-adenosylmethionine catabolite 5-methylribose 1-phosphate into 5-methylribulose 1-phosphate. The enzymatic function of MRDI was required for methionine salvage from S-adenosylmethionine but distinct from its function in cell invasion. Thus, mechanisms used by signal transduction pathways to control cell movement have evolved from proteins with ancient function in amino acid metabolism. Molecular & Cellular Proteomics 8: 2308-2320, 2009.