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.
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
EMBO J.
Date: Feb. 07, 2007
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