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.


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


  • 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