MCRIP1, an ERK substrate, mediates ERK-induced gene silencing during epithelial-mesenchymal transition by regulating the co-repressor CtBP.
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.
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.
Kenji
K
Ichikawa
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.
Yuji
Y
Kubota
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.
Takanori
T
Nakamura
Division of Cell Signaling and Molecular Medicine, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Jane S
JS
Weng
Division of Molecular Cell Signaling, Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo 108-8639, Japan.
Taichiro
T
Tomida
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.
Haruo
H
Saito
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.
Mutsuhiro
M
Takekawa
D000429:Alcohol Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D044127:Epigenesis, Genetic; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics* / Q000378:metabolism; D020868:Gene Silencing; D057809:HEK293 Cells; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D010766:Phosphorylation; D010957:Plasmids / Q000737:chemistry; D011401:Promoter Regions, Genetic; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014162:Transfection; D020798:Two-Hybrid System Techniques; D000071799:Zinc Finger E-box-Binding Homeobox 1
D015820:Cadherins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein; D048049:Extracellular Signal-Regulated MAP Kinases