Inhibition of Arginyltransferase 1 Induces Transcriptional Activity of Myocardin-related Transcription Factor A (MRTF-A) and Promotes Directional Migration
Inhibition of Arginyltransferase 1 Induces Transcriptional Activity of Myocardin-related Transcription Factor A (MRTF-A) and Promotes Directional Migration
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DOI：
10.1074/jbc.m114.578674
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发表时间：
2014-12-19
影响因子：
4.8
通讯作者：
Posern, Guido
中科院分区：
文献类型：
--
作者：
Eisenach, Patricia A.;Schikora, Franziska;Posern, Guido
心肌素相关转录因子 A (MRTF-A/MAL/MKL1/BSAC) 可响应 Rho-肌动蛋白信号通路调节血清反应因子 (SRF) 依赖性靶基因的表达。 MRTF-A 的过度表达或激活会影响细胞的形状、迁移和侵袭，并导致人类恶性肿瘤，包括癌症。在这项研究中，我们报告说，抑制精氨酰转移酶 1 (ATE1)（一种介导转录后蛋白精氨酰化的酶）足以增加 MCF-7 人乳腺癌细胞中的 MRTF-A 活性，而不受外部生长因子刺激的影响。此外，沉默或抑制ATE1会破坏E-钙粘蛋白介导的细胞间接触，增强富含肌动蛋白的突起的形成，并增加粘着斑的数量，随后导致趋化迁移增加。尽管精氨酸化肌动蛋白对 MRTF-A 的影响没有差异，但在 ATE1 抑制后 MRTF-A 激活之前，E-钙粘蛋白和 F-肌动蛋白重组的快速丧失。相反，异位 ATE1 表达足以使 MRTF-A 失活，无论是在静息细胞中还是在具有外源激活的 RhoA-肌动蛋白途径的细胞中。在这项研究中，我们提供了蛋白质精氨酸化和 MRTF-A 活性之间的关键联系，并将 ATE1 置于心肌素相关转录因子的上游。
Myocardin-related transcription factor A (MRTF-A/MAL/MKL1/BSAC) regulates the expression of serum-response factor (SRF)-dependent target genes in response to the Rho-actin signaling pathway. Overexpression or activation of MRTF-A affects shape, migration, and invasion of cells and contributes to human malignancies, including cancer. In this study, we report that inhibition of arginyltransferase 1 (ATE1), an enzyme mediating post-transcriptional protein arginylation, is sufficient to increase MRTF-A activity in MCF-7 human breast carcinoma cells independently of external growth factor stimuli. In addition, silencing or inhibiting ATE1 disrupted E-cadherin-mediated cell-cell contacts, enhanced formation of actin-rich protrusions, and increased the number of focal adhesions, subsequently leading to elevated chemotactic migration. Although arginylated actin did not differentially affect MRTF-A, a rapid loss of E-cadherin and F-actin reorganization preceded MRTF-A activation upon ATE1 inhibition. Conversely, ectopic ATE1 expression was sufficient to render MRTF-A inactive, both in resting cells and in cells with exogenously activated RhoA-actin pathways. In this study, we provide a critical link between protein arginylation and MRTF-A activity and place ATE1 upstream of myocardin-related transcription factor.