MCRIP1, an ERK substrate, mediates ERK-induced gene silencing during epithelial-mesenchymal transition by regulating the co-repressor CtBP

Mol Cell. 2015 Apr 2;58(1):35-46. doi: 10.1016/j.molcel.2015.01.023. Epub 2015 Feb 26.

Authors

Kenji Ichikawa¹, Yuji Kubota², Takanori Nakamura², Jane S Weng³, Taichiro Tomida⁴, Haruo Saito⁵, Mutsuhiro Takekawa⁶

Affiliations

¹ Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan; Department of Cell Signaling and Molecular Medicine, Research Institute of Environmental Medicine, Nagoya University, Chikusa-ku, Nagoya 464-8601, Japan; Division of Molecular Cell Signaling, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan; Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan.
² Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan; Department of Cell Signaling and Molecular Medicine, Research Institute of Environmental Medicine, Nagoya University, Chikusa-ku, Nagoya 464-8601, Japan.
³ Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
⁴ Division of Molecular Cell Signaling, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
⁵ Division of Molecular Cell Signaling, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan; Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: h-saito@ims.u-tokyo.ac.jp.
⁶ Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan; Department of Cell Signaling and Molecular Medicine, Research Institute of Environmental Medicine, Nagoya University, Chikusa-ku, Nagoya 464-8601, Japan; Department of Biophysics and Biochemistry, Graduate School of Science, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan. Electronic address: takekawa@ims.u-tokyo.ac.jp.

PMID: 25728771
DOI: 10.1016/j.molcel.2015.01.023

Abstract

The ERK pathway not only upregulates growth-promoting genes, but also downregulates anti-proliferative and tumor-suppressive genes. In particular, ERK signaling contributes to repression of the E-cadherin gene during epithelial-mesenchymal transition (EMT). The CtBP transcriptional co-repressor is also involved in gene silencing of E-cadherin. However, the functional relationship between ERK signaling and CtBP is unknown. Here, we identified an ERK substrate, designated MCRIP1, which bridges ERK signaling and CtBP-mediated gene silencing. CtBP is recruited to promoter elements of target genes by interacting with the DNA-binding transcriptional repressor ZEB1. We found that MCRIP1 binds to CtBP, thereby competitively inhibiting CtBP-ZEB1 interaction. When phosphorylated by ERK, MCRIP1 dissociates from CtBP, allowing CtBP to interact with ZEB1. In this manner, the CtBP co-repressor complex is recruited to, and silences, the E-cadherin promoter by inducing chromatin modifications. Our findings reveal a molecular mechanism underlying ERK-induced epigenetic gene silencing during EMT and its dysregulation in cancer.

Publication types

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

MeSH terms

Alcohol Oxidoreductases / genetics*
Alcohol Oxidoreductases / metabolism
Amino Acid Sequence
Cadherins / genetics*
Cadherins / metabolism
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / metabolism
Epigenesis, Genetic*
Epithelial-Mesenchymal Transition / genetics*
Extracellular Signal-Regulated MAP Kinases / genetics*
Extracellular Signal-Regulated MAP Kinases / metabolism
Gene Silencing
HEK293 Cells
Homeodomain Proteins / genetics
Homeodomain Proteins / metabolism
Humans
Molecular Sequence Data
Phosphorylation
Plasmids / chemistry
Promoter Regions, Genetic
Recombinant Proteins / genetics
Recombinant Proteins / metabolism
Saccharomyces cerevisiae / genetics
Saccharomyces cerevisiae / metabolism
Sequence Alignment
Signal Transduction
Transcription Factors / genetics
Transcription Factors / metabolism
Transfection
Two-Hybrid System Techniques
Zinc Finger E-box-Binding Homeobox 1

Substances

Cadherins
DNA-Binding Proteins
Homeodomain Proteins
Recombinant Proteins
Transcription Factors
ZEB1 protein, human
Zinc Finger E-box-Binding Homeobox 1
Alcohol Oxidoreductases
C-terminal binding protein
Extracellular Signal-Regulated MAP Kinases