分泌型人甘氨酰-tRNA 合成酶参与防御 ERK 激活的肿瘤发生。
Secreted human glycyl-tRNA synthetase implicated in defense against ERK-activated tumorigenesis.
机构信息
Medicinal Bioconvergence Research Center, and World Class University Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Technology, Seoul National University, Seoul 151-742, Korea.
出版信息
Proc Natl Acad Sci U S A. 2012 Mar 13;109(11):E640-7. doi: 10.1073/pnas.1200194109. Epub 2012 Feb 15.
Abstract
Although adaptive systems of immunity against tumor initiation and destruction are well investigated, less understood is the role, if any, of endogenous factors that have conventional functions. Here we show that glycyl-tRNA synthetase (GRS), an essential component of the translation apparatus, circulates in serum and can be secreted from macrophages in response to Fas ligand that is released from tumor cells. Through cadherin (CDH)6 (K-cadherin), GRS bound to different ERK-activated tumor cells, and released phosphatase 2A (PP2A) from CDH6. The activated PP2A then suppressed ERK signaling through dephosphorylation of ERK and induced apoptosis. These activities were inhibited by blocking GRS with a soluble fragment of CDH6. With in vivo administration of GRS, growth of tumors with a high level of CDH6 and ERK activation were strongly suppressed. Our results implicate a conventional cytoplasmic enzyme in translation as an intrinsic component of the defense against ERK-activated tumor formation.
摘要
尽管针对肿瘤起始和破坏的适应性免疫系统已得到充分研究，但对于具有常规功能的内源性因素的作用，了解较少。在这里，我们表明甘氨酰-tRNA 合成酶（GRS），一种翻译装置的必需组成部分，在血清中循环，并可以从巨噬细胞中分泌出来，以响应来自肿瘤细胞的 Fas 配体。通过钙粘蛋白（CDH）6（K-钙粘蛋白），GRS 与不同的 ERK 激活的肿瘤细胞结合，并从 CDH6 释放磷酸酶 2A（PP2A）。激活的 PP2A 随后通过去磷酸化 ERK 抑制 ERK 信号传导，并诱导细胞凋亡。这些活性可通过用 CDH6 的可溶性片段阻断 GRS 来抑制。通过体内给予 GRS，高表达 CDH6 和 ERK 激活的肿瘤的生长受到强烈抑制。我们的结果表明，作为针对 ERK 激活的肿瘤形成的固有防御成分的细胞质中常规的酶。
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