Negative regulation of the EGFR-MAPK cascade by actin-MAL-mediated Mig6/Errfi-1 induction

Mol Cell. 2009 Aug 14;35(3):291-304. doi: 10.1016/j.molcel.2009.07.015.

Abstract

We analyzed the G-actin-regulated transcriptome by gene expression analysis using previously characterized actin-binding drugs. We found many known MAL/MRTF-dependent target genes of serum response factor (SRF), as well as additional directly regulated genes. Surprisingly, several putative antiproliferative target genes were identified, including mig6/errfi-1, a negative regulator of the EGFR family. Mig6 induction occurred through actin-MAL-SRF signaling, and MAL was inducibly recruited to and activated a mig6 promoter element. Upregulation of Mig6 by lipid agonists such as LPA and S1P or actin drugs involved MAL and correlated with decreased activation of EGFR, MAPK/Erk, and c-fos. Mig6 depletion restored EGFR signaling and provided a proliferative advantage. Overexpression of MAL exhibited strong antiproliferative effects requiring the domains for SRF binding and transactivation, which supports antagonistic functions of MAL on growth-promoting signals. Our results show the existence of negatively acting transcriptional networks between pro- and antiproliferative signaling pathways toward SRF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / physiology*
  • Adaptor Proteins, Signal Transducing / physiology*
  • Animals
  • Bridged Bicyclo Compounds, Heterocyclic / pharmacology
  • Cell Line
  • Cell Proliferation
  • Cycloheximide / pharmacology
  • Cytochalasin D / pharmacology
  • ErbB Receptors / metabolism*
  • Gene Expression Profiling
  • Gene Expression Regulation
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • MAP Kinase Signaling System* / drug effects
  • Membrane Transport Proteins / physiology*
  • Mice
  • Myelin Proteins / physiology*
  • Myelin and Lymphocyte-Associated Proteolipid Proteins
  • Nucleic Acid Synthesis Inhibitors / pharmacology
  • Proteolipids / physiology*
  • RNA, Messenger / metabolism
  • Thiazolidines / pharmacology
  • Tumor Suppressor Proteins

Substances

  • Actins
  • Adaptor Proteins, Signal Transducing
  • Bridged Bicyclo Compounds, Heterocyclic
  • Errfi1 protein, mouse
  • Intracellular Signaling Peptides and Proteins
  • Ligands
  • MAL protein, human
  • MIG-6 protein, human
  • Mal protein, mouse
  • Membrane Transport Proteins
  • Myelin Proteins
  • Myelin and Lymphocyte-Associated Proteolipid Proteins
  • Nucleic Acid Synthesis Inhibitors
  • Proteolipids
  • RNA, Messenger
  • Thiazolidines
  • Tumor Suppressor Proteins
  • Cytochalasin D
  • Cycloheximide
  • ErbB Receptors
  • latrunculin B

Associated data

  • GEO/GSE17105