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Mxi2 promotes stimulus-independent ERK nuclear translocation.

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


  • Casar B
  • Sanz-Moreno V
  • Yazicioglu MN
  • Rodríguez J
  • Berciano MT
  • Lafarga M
  • Cobb MH
  • Crespo P


The EMBO journal

Publication Data

February 7, 2007

Associated Grants

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

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