Article
- The EMBO Journal (2007) 26, 635 - 646
- doi:10.1038/sj.emboj.7601523
Published online: 25 January 2007
Subject Category:
Mxi2 promotes stimulus-independent ERK nuclear translocation
Berta Casar1, Victoria Sanz-Moreno1, Mustafa N Yazicioglu2, Javier Rodríguez1, María T Berciano3, Miguel Lafarga3, Melanie H Cobb2 and Piero Crespo1
- Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas (CSIC), Departamento de Biología Molecular, Unidad de Biomedicina CSIC—Universidad de Cantabria, Santander, Spain
- Department of Pharmacology, The University of Texas Southwestern Medical Center, Dallas, TX, USA
- Departamento de Anatomía y Biología Celular, Unidad de Biomedicina CSIC—Universidad de Cantabria, Santander, Spain
Correspondence to:
Piero Crespo, Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas, Departamento de Biología Molecular, Unidad de Biomedicina CSIC—Universidad de Cantabria, Facultad de Medicina, C/Cardenal Herrera Oria s/n., Santander 39011, Spain. Tel.: +34 942 200959; Fax: +34 942 201945; E-mail: pcrespo@iib.uam.es or crespop@unican.es
Received 25 June 2006; Accepted 1 December 2006
Abstract
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
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.
Keywords:
- ERK,
- MAP kinases,
- Mxi2,
- nuclear import,
- p38
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