ERF nuclear shuttling, a continuous monitor of Erk activity that links it to cell cycle progression
ERF nuclear shuttling, a continuous monitor of Erk activity that links it to cell cycle progression
复制标题
DOI：
10.1128/mcb.24.3.1206-1218.2004
复制
发表时间：
2004-02-01
影响因子：
5.3
通讯作者：
Mavrothalassitis, G
中科院分区：
文献类型：
--
作者：
Le Gallic, L;Virgilio, L;Mavrothalassitis, G
Ets结构域转录抑制因子ERF是受体酪氨酸激酶/Ras/Erk通路的效应者，已被认为是由ERK依赖的磷酸化的亚细胞定位调节的，能够抑制细胞增殖和ras诱导的肿瘤发生。在这里，我们分析了ERF的磷酸化对核进出口的影响，其磷酸化和去磷酸化的时间与其亚细胞定位的关系，ERK活性，以及ERF诱导的细胞周期停滞的要求。我们的发现表明，ERF在细胞核和细胞质之间持续穿梭，并且ERF的磷酸化和去磷酸化都发生在细胞核内。虽然核进口不受磷酸化的影响，但ERF的核输出和细胞质释放需要多位点的磷酸化和去磷酸化。ERF出口依赖于CRM1，尽管ERF没有可检测到的核出口信号。ERF的磷酸化和输出与核内ERK活性水平相关。非磷酸化ERF诱导的细胞周期停滞需要野生型视网膜母细胞瘤蛋白，并可被细胞周期蛋白的过表达所抑制。这些数据表明，ERF可能是一个非常敏感和稳定的ERK活性传感器，可以通过G，影响细胞周期进程，在Ras/Erk途径和细胞增殖之间提供另一种联系。
The ets domain transcriptional repressor ERF is an effector of the receptor tyrosine kinase/Ras/Erk pathway, which, it has been suggested, is regulated by subcellular localization as a result of Erk-dependent phosphorylation and is capable of suppressing cell proliferation and ras-induced tumorigenicity. Here, we analyze the effect of ERF phosphorylation on nuclear import and export, the timing of its phosphorylation and dephosphorylation in relation to its subcellular location, Erk activity, and the requirements for ERF-induced cell cycle arrest. Our findings indicate that ERF continuously shuttles between the nucleus and the cytoplasm and that both phosphorylation and dephosphorylation of ERF occur within the nucleus. While nuclear import is not affected by phosphorylation, ERF nuclear export and cytoplasmic release require multisite phosphorylation and dephosphorylation. ERF export is CRM1 dependent, although ERF does not have a detectable nuclear export signal. ERF phosphorylation and export correlate with the levels of nuclear Erk activity. The cell cycle arrest induced by nonphosphorylated ERF requires the wild-type retinoblastoma protein and can be suppressed by overexpression of cyclin. These data suggest that ERF may be a very sensitive and constant sensor of Erk activity that can affect cell cycle progression through G,, providing another link between the Ras/Erk pathway and cellular proliferation.