Sef is a spatial regulator for Ras/MAP kinase signaling

Satoru Torii; Morioh Kusakabe; Takuya Yamamoto; Momoko Maekawa; Eisuke Nishida

doi:10.1016/j.devcel.2004.05.019

Sef is a spatial regulator for Ras/MAP kinase signaling

Dev Cell. 2004 Jul;7(1):33-44. doi: 10.1016/j.devcel.2004.05.019.

Authors

Satoru Torii¹, Morioh Kusakabe, Takuya Yamamoto, Momoko Maekawa, Eisuke Nishida

Affiliation

¹ Department of Cell and Developmental Biology, Graduate School of Biostudies, Kyoto University, Sakyo-ku, Kyoto 606-8502, Japan.

PMID: 15239952
DOI: 10.1016/j.devcel.2004.05.019

Abstract

Spatiotemporal control of the Ras/ERK MAP kinase signaling pathway is among the key mechanisms for regulating a wide variety of cellular processes. In this study, we report that human Sef (hSef), a recently identified inhibitor whose action mechanism has not been fully defined, acts as a molecular switch for ERK signaling by specifically blocking ERK nuclear translocation without inhibiting its activity in the cytoplasm. Thus, hSef binds to activated forms of MEK, inhibits the dissociation of the MEK-ERK complex, and blocks nuclear translocation of activated ERK. Consequently, hSef inhibits phosphorylation and activation of the nuclear ERK substrate Elk-1, while it does not affect phosphorylation of the cytoplasmic ERK substrate RSK2. Downregulation of endogenous hSef by hSef siRNA enhances the stimulus-induced ERK nuclear translocation and the activity of Elk-1. These results thus demonstrate that hSef acts as a spatial regulator for ERK signaling by targeting ERK to the cytoplasm.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Active Transport, Cell Nucleus / physiology
Animals
COS Cells
Cell Nucleus / enzymology
Chlorocebus aethiops
Cytoplasm / enzymology
DNA-Binding Proteins / metabolism
HeLa Cells
Humans
MAP Kinase Kinase 1
MAP Kinase Signaling System / physiology*
Mitogen-Activated Protein Kinase Kinases / metabolism*
Mitogen-Activated Protein Kinases / metabolism*
Phosphorylation
Protein Transport / physiology
Proto-Oncogene Proteins / metabolism
Receptors, Interleukin / genetics
Receptors, Interleukin / metabolism*
Ribosomal Protein S6 Kinases, 90-kDa / metabolism
Transcription Factors / metabolism
ets-Domain Protein Elk-1
ras Proteins / metabolism*

Substances

DNA-Binding Proteins
ELK1 protein, human
IL17RD protein, human
Proto-Oncogene Proteins
Receptors, Interleukin
Transcription Factors
ets-Domain Protein Elk-1
Ribosomal Protein S6 Kinases, 90-kDa
ribosomal protein S6 kinase, 90kDa, polypeptide 3
Mitogen-Activated Protein Kinases
MAP Kinase Kinase 1
MAP2K1 protein, human
Mitogen-Activated Protein Kinase Kinases
ras Proteins