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.
Casar
Berta
B
Instituto de Investigaciones Biomédicas, Consejo Superior de Investigaciones Científicas (CSIC), Departamento de Biología Molecular, Unidad de Biomedicina CSIC--Universidad de Cantabria, Santander, Spain.
Sanz-Moreno
Victoria
V
Yazicioglu
Mustafa N
MN
Rodríguez
Javier
J
Berciano
María T
MT
Lafarga
Miguel
M
Cobb
Melanie H
MH
Crespo
Piero
P
D021581:Active Transport, Cell Nucleus / Q000502:physiology; D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism* / Q000502:physiology; D002522:Chlorocebus aethiops; D004285:Dogs; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D048308:Mitogen-Activated Protein Kinase 14 / Q000235:genetics / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism* / Q000502:physiology; D008954:Models, Biological; D028861:Nuclear Pore Complex Proteins / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D034622:RNA Interference
D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D028861:Nuclear Pore Complex Proteins; C092039:PEA15 protein, human; D010750:Phosphoproteins; D048308:Mitogen-Activated Protein Kinase 14; D048052:Mitogen-Activated Protein Kinase 3