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Mxi2 promotes stimulus-independent ERK nuclear translocation.

The EMBO journal | Feb 7, 2007

http://www.ncbi.nlm.nih.gov/pubmed/17255949

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 p38alpha 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.

Pubmed ID: 17255949 RIS Download

Mesh terms: Active Transport, Cell Nucleus | Animals | Cell Line | Cell Nucleus | Cercopithecus aethiops | Dogs | Fluorescent Antibody Technique | Humans | Immunoblotting | Immunoprecipitation | Intracellular Signaling Peptides and Proteins | Mitogen-Activated Protein Kinase 14 | Mitogen-Activated Protein Kinase 3 | Models, Biological | Nuclear Pore Complex Proteins | Phosphoproteins | RNA Interference

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Associated grants

  • Agency: NIDDK NIH HHS, Id: DK34128
  • Agency: NIDDK NIH HHS, Id: R37 DK034128

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