Negative Regulation of the EGFR-MAPK Cascade by Actin-MAL-Mediated Mig6/Errfi-1 Induction
Negative Regulation of the EGFR-MAPK Cascade by Actin-MAL-Mediated Mig6/Errfi-1 Induction
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DOI：
10.1016/j.molcel.2009.07.015
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发表时间：
2009-08-14
期刊：
影响因子：
16
通讯作者：
Posern, Guido
中科院分区：
文献类型：
--
作者：
Descot, Arnaud;Hoffmann, Reinhard;Posern, Guido
我们分析了G-肌动蛋白调节转录组的基因表达分析，使用以前的特点肌动蛋白结合药物。我们发现了许多已知的MAL/MRTF依赖的血清反应因子（SRF）的靶基因，以及其他直接调控的基因。令人惊讶的是，鉴定了几种推定的抗增殖靶基因，包括EGFR家族的负调节因子mig 6/errfi-1。Mig 6诱导通过actin-MAL-SRF信号传导发生，并且MAL可诱导地募集到并激活mig 6启动子元件。脂质激动剂如LPA和S1 P或肌动蛋白药物对Mig 6的上调涉及MAL，并与EGFR、MAPK/Erk和c-fos的活化降低相关。Mig 6耗竭恢复EGFR信号传导并提供增殖优势。MAL的过表达表现出强烈的抗增殖作用，需要SRF结合和反式激活的结构域，这支持MAL对促生长信号的拮抗功能。我们的研究结果表明，存在负作用的转录网络之间的促增殖和抗增殖信号通路向SRF。
We analyzed the G-actin-regulated transcriptome by gene expression analysis using previously characterized actin-binding drugs. We found many known MAL/MRTF-dependent target genes of serum response factor (SRF), as well as additional directly regulated genes. Surprisingly, several putative antiproliferative target genes were identified,, including mig6/errfi-1, a negative regulator of the EGFR family. Mig6 induction occurred through actin-MAL-SRF signaling, and MAL was inducibly recruited to and activated a mig6 promoter element. Upregulation of Mig6 by lipid agonists such as LPA and S1P or actin drugs involved MAL and correlated with decreased activation of EGFR, MAPK/Erk, and c-fos. Mig6 depletion restored EGFR signaling and provided a proliferative advantage. Overexpression of MAL exhibited strong anti proliferative effects requiring the domains for SRF binding and transactivation, which supports antagonistic functions of MAL on growth-promoting signals. Our results show the existence of negatively acting transcriptional networks between pro- and anti proliferative signaling pathways toward SRF.