ERK2 but not ERK1 induces epithelial-to-mesenchymal transformation via DEF motif-dependent signaling events

Mol Cell. 2010 Apr 9;38(1):114-27. doi: 10.1016/j.molcel.2010.02.020.

Abstract

Hyperactivation of Ras-ERK1/2 signaling is critical to the development of many human malignancies, but little is known regarding the specific contribution of ERK1 or ERK2 to oncogenic processes. We demonstrate that ERK2 but not ERK1 signaling is necessary for Ras-induced epithelial-to-mesenchymal transformation (EMT). Further, ERK2 but not ERK1 overexpression is sufficient to induce EMT. Many ERK1/2-interacting proteins contain amino acid motifs, e.g., DEF or D-motifs, which regulate docking with ERK1/2. Remarkably, ERK2 signaling to DEF motif-containing targets is required to induce EMT and correlates with increased migration, invasion, and survival. Importantly, the late-response gene product Fra1 is necessary for Ras- and ERK2-induced EMT through upregulation of ZEB1/2 proteins. Thus, an apparent critical role for ERK2 DEF motif signaling during tumorigenesis is the regulation of Fra1 and the subsequent induction of ZEB1/2, suggesting a potential therapeutic target for Ras-regulated tumorigenesis.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Amino Acid Motifs*
  • Biomarkers / metabolism
  • Cell Differentiation / physiology*
  • Cell Line, Tumor
  • Cell Movement / physiology
  • Epithelial Cells / cytology
  • Epithelial Cells / physiology
  • Homeodomain Proteins / genetics
  • Homeodomain Proteins / metabolism
  • Humans
  • Mitogen-Activated Protein Kinase 1 / genetics
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3 / genetics
  • Mitogen-Activated Protein Kinase 3 / metabolism*
  • Mutation
  • Proto-Oncogene Proteins c-fos / genetics
  • Proto-Oncogene Proteins c-fos / metabolism
  • RNA Interference
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Signal Transduction / physiology*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Zinc Finger E-box Binding Homeobox 2
  • Zinc Finger E-box-Binding Homeobox 1
  • ras Proteins / genetics
  • ras Proteins / metabolism

Substances

  • Biomarkers
  • Homeodomain Proteins
  • Proto-Oncogene Proteins c-fos
  • Repressor Proteins
  • Transcription Factors
  • ZEB1 protein, human
  • ZEB2 protein, human
  • Zinc Finger E-box Binding Homeobox 2
  • Zinc Finger E-box-Binding Homeobox 1
  • fos-related antigen 1
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • ras Proteins