Actin dynamics regulate cell behaviour in response to physiological signals. Here we demonstrate a novel role for nuclear actin in inhibiting cell proliferation and migration. We demonstrate that physiological signals that elevate cAMP, which is anti-mitogenic in vascular smooth muscle cells, increases nuclear actin monomer levels. Expression of a nuclear-targeted polymerisation-defective actin mutant (NLS-ActinR62D) inhibited proliferation and migration. Preventing nuclear actin monomer accumulation by enhancing its nuclear export or polymerisation reversed the anti-mitogenic and anti-migratory effects of cAMP. Transcriptomic analysis identified repression of proliferation and migration associated genes regulated by serum response factor (SRF) and TEA Domain (TEAD) transcription factors. Accordingly, NLS-ActinR62D inhibited SRF and TEAD activity and target gene expression, and these effects were reversed by constitutively-active mutants of the TEAD and SRF co-factors YAP, TAZ and MKL1. In summary, intranuclear actin inhibits proliferation and migration by inhibiting YAP-TEAD and MKL-SRF activity. This mechanism explains the anti-mitogenic and anti-migratory properties of physiological signals that elevate cAMP. SUMMARY: McNeill et al show that increased levels of intranuclear actin monomer inhibit cell proliferation and migration by inhibiting MKL1-SRF and YAP/TAZ-TEAD-dependent gene expression. This mechanism mediates the anti-mitogenic and anti-migratory effects of physiological signals that elevate cyclic-AMP.

中文翻译：

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核肌动蛋白通过抑制 SRF 和 TEAD 来调节细胞增殖和迁移。


肌动蛋白动力学调节细胞响应生理信号的行为。在这里，我们证明了核肌动蛋白在抑制细胞增殖和迁移方面的新作用。我们证明，提高 cAMP（血管平滑肌细胞中的抗有丝分裂作用）的生理信号会增加核肌动蛋白单体水平。核靶向聚合缺陷肌动蛋白突变体（NLS-ActinR62D）的表达抑制增殖和迁移。通过增强核输出或聚合来防止核肌动蛋白单体积累，可以逆转 cAMP 的抗有丝分裂和抗迁移作用。转录组分析确定了受血清反应因子 (SRF) 和 TEA 域 (TEAD) 转录因子调节的增殖和迁移相关基因的抑制。因此，NLS-ActinR62D 抑制 SRF 和 TEAD 活性以及靶基因表达，并且这些效应被 TEAD 和 SRF 辅因子 YAP、TAZ 和 MKL1 的组成型活性突变体逆转。总之，核内肌动蛋白通过抑制 YAP-TEAD 和 MKL-SRF 活性来抑制增殖和迁移。这种机制解释了提高 cAMP 的生理信号的抗有丝分裂和抗迁移特性。摘要：McNeill 等人表明，核内肌动蛋白单体水平的增加通过抑制 MKL1-SRF 和 YAP/TAZ-TEAD 依赖性基因表达来抑制细胞增殖和迁移。该机制介导提高环磷酸腺苷的生理信号的抗有丝分裂和抗迁移作用。