Mxi2 promotes stimulus-independent ERK nuclear translocation
Mxi2 promotes stimulus-independent ERK nuclear translocation
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DOI：
10.1038/sj.emboj.7601523
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发表时间：
2007-02-07
期刊：
影响因子：
11.4
通讯作者：
Crespo, Piero
中科院分区：
文献类型：
--
作者：
Casar, Berta;Sanz-Moreno, Victoria;Crespo, Piero
ERK 1/2 MAP激酶的空间调节是确保其信号的保真度和特异性的基本但基本上未被揭示的机制。Mxi 2是具有结合ERK 1/2的能力的p38 α同种型。在此，我们表明Mxi 2对ERK 1/2核质分布具有深远的影响，促进它们在细胞核中的积累。通过RNAi下调内源性Mxi 2导致细胞核中ERK 1/2的显著减少，伴随着细胞增殖的显著下降。我们证明，Mxi 2的功能，在核穿梭的ERK 1/2的磷酸化和未磷酸化的形式，在没有刺激的情况下，通过增强核积累。该过程需要两种蛋白质的直接相互作用和Mxi 2与核孔蛋白中的ERK结合位点的高亲和力结合。在这方面，Mxi 2与PEA 15拮抗作用，将其从ERK 1/2复合物中置换。这些结果表明Mxi 2是ERK 1/2的关键空间调节因子，并揭示了ERK核输入的前所未有的刺激非依赖性机制。
Spatial regulation of ERK1/2 MAP kinases is an essential yet largely unveiled mechanism for ensuring the fidelity and specificity of their signals. Mxi2 is a p38 alpha isoform with the ability to bind ERK1/2. Herein we show that Mxi2 has profound effects on ERK1/2 nucleocytoplasmic distribution, promoting their accumulation in the nucleus. Downregulation of endogenous Mxi2 by RNAi causes a marked reduction of ERK1/2 in the nucleus, accompanied by a pronounced decline in cellular proliferation. We demonstrate that Mxi2 functions in nuclear shuttling of ERK1/2 by enhancing the nuclear accumulation of both phosphorylated and unphosphorylated forms in the absence of stimulation. This process requires the direct interaction of both proteins and a high-affinity binding of Mxi2 to ERK-binding sites in nucleoporins, In this respect, Mxi2 acts antagonistically to PEA15, displacing it from ERK1/2 complexes. These results point to Mxi2 as a key spatial regulator for ERK1/2 and disclose an unprecedented stimulus-independent mechanism for ERK nuclear import.