Journal
EMBO JOURNAL
Volume 26, Issue 3, Pages 635-646Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/sj.emboj.7601523
Keywords
ERK; MAP kinases; Mxi2; nuclear import; p38
Categories
Funding
- NIDDK NIH HHS [DK34128, R37 DK034128, R01 DK034128] Funding Source: Medline
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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.
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