MAL/MRTF-A controls migration of non-invasive cells by upregulation of cytoskeleton-associated proteins
MAL/MRTF-A controls migration of non-invasive cells by upregulation of cytoskeleton-associated proteins
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DOI：
10.1242/jcs.092791
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发表时间：
2011-12-15
影响因子：
4
通讯作者：
Posern, Guido
中科院分区：
文献类型：
--
作者：
Leitner, Laura;Shaposhnikov, Dmitry;Posern, Guido
单体肌动蛋白通过抑制血清反应因子（SRF）的转录辅激活因子肌红蛋白相关转录因子（MAL/MRTF）来调节基因表达。许多受影响的基因编码细胞骨架成分。我们分析了肌动蛋白-MAL信号传导和新的靶基因在非侵入性高粘附细胞中的迁移作用。活性MAL的表达会损害成纤维细胞和上皮细胞的迁移，而显性阴性构建体和MAL/MRTF的部分敲除则会增强运动性。敲除三个新表征的G-肌动蛋白调节的MAL靶点，整合素α 5，斑嗜蛋白2（Pkp 2）和FHL 1，增强细胞迁移。所有这三个上调外部刺激通过肌动蛋白-MAL-SRF信号，MAL和SRF诱导招募整合素α 5和Pkp 2基因的顺式调控元件。最后，通过敲低Pkp 2和FHL 1，稳定表达MAL的上皮细胞的迁移减少被部分逆转。我们得出结论，肌动蛋白-MAL途径促进粘附基因的表达，包括整合素α 5，Pkp 2和FHL 1，这是抗运动的非侵入性细胞具有高的基础活动。
Monomeric actin regulates gene expression through serum response factor (SRF) by inhibiting its transcriptional coactivator myocardin-related transcription factor (MAL/MRTF). Many affected genes encode cytoskeletal components. We have analysed the migratory effects of actin-MAL signalling and of new target genes in non-invasive highly adherent cells. Expression of active MAL impaired migration of both fibroblasts and epithelial cells, whereas dominant-negative constructs and partial knockdown of MAL/MRTF enhanced motility. Knockdown of three newly characterised G-actin-regulated MAL targets, integrin alpha 5, plakophilin 2 (Pkp2) and FHL1, enhanced cell migration. All three were upregulated by external stimulation through actin-MAL-SRF signalling, and MAL and SRF were inducibly recruited to cis-regulatory elements of the integrin a5 and Pkp2 genes. Finally, the reduced migration of epithelial cells stably expressing MAL was partially reversed by knockdown of Pkp2 and FHL1. We conclude that the actin-MAL pathway promotes adhesive gene expression, including integrin a5, Pkp2 and FHL1, and that this is anti-motile for non-invasive cells harbouring high basal activity.