Mxi2 promotes stimulus-independent ERK nuclear translocation

被引:38
作者
Casar, Berta
Sanz-Moreno, Victoria
Yazicioglu, Mustafa N.
Rodriguez, Javier
Berciano, Maria T.
Lafarga, Miguel
Cobb, Melanie H.
Crespo, Piero
机构
[1] Univ Cantabria, CSIC, Unidad Biomed, Fac Med,Inst Invest Biomed,Dept Biol Mol, Santander 39011, Spain
[2] Univ Texas, SW Med Ctr, Dept Pharmacol, Dallas, TX 75230 USA
[3] Univ Cantabria, CSIC, Unidad Biomed, Dept Anat & Biol Celular, Santander 39011, Spain
关键词
ERK; MAP kinases; Mxi2; nuclear import; p38;
D O I
10.1038/sj.emboj.7601523
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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.
引用
收藏
页码:635 / 646
页数:12
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