Article abstract
Nature Structural & Molecular Biology 16, 1026 - 1035 (2009)
Published online: 20 September 2009 | doi:10.1038/nsmb.1656
Phosphoproteomics reveals new ERK MAP kinase targets and links ERK to nucleoporin-mediated nuclear transport
Hidetaka Kosako1,2, Nozomi Yamaguchi1,3, Chizuru Aranami4, Masato Ushiyama1,5, Shingo Kose6, Naoko Imamoto6, Hisaaki Taniguchi2, Eisuke Nishida7 & Seisuke Hattori1,4
Abstract
Many extracellular signal–regulated kinase (ERK) mitogen-activated protein (MAP) kinase substrates have been identified, but the diversity of ERK-mediated processes suggests the existence of additional targets. Using a phosphoproteomic approach combining the steroid receptor fusion system, IMAC, 2D-DIGE and phosphomotif-specific antibodies, we detected 38 proteins showing reproducible phosphorylation changes between ERK-activated and ERK-inhibited samples, including 24 new candidate ERK targets. ERK directly phosphorylated at least 13 proteins in vitro. Of these, Nup50 was verified as a bona fide ERK substrate. Notably, ERK phosphorylation of the FG repeat region of Nup50 reduced its affinity for importin-
family proteins, importin- and transportin. Other FG nucleoporins showed a similar functional change after ERK-mediated phosphorylation. Nuclear migration of importin- and transportin was impaired in ERK-activated, digitonin-permeabilized cells, as a result of ERK phosphorylation of Nup50. Thus, we propose that ERK phosphorylates various nucleoporins to regulate nucleocytoplasmic transport.
- Division of Cellular Proteomics (BML), Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
- Division of Disease Proteomics, Institute for Enzyme Research, The University of Tokushima, Tokushima, Japan.
- RD Center, BML, Inc., Saitama, Japan.
- Department of Biochemistry, School of Pharmaceutical Sciences, Kitasato University, Tokyo, Japan.
- GE Healthcare Bio-Sciences KK, Tokyo, Japan.
- Cellular Dynamics Laboratory, Advanced Science Institute, RIKEN, Saitama, Japan.
- Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Kyoto, Japan.
Correspondence to: Hidetaka Kosako1,2 e-mail: kosako@ier.tokushima-u.ac.jp
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