DA-Raf1, a competent intrinsic dominant-negative antagonist of the Ras-ERK pathway, is required for myogenic differentiation

J Cell Biol. 2007 Jun 4;177(5):781-93. doi: 10.1083/jcb.200703195. Epub 2007 May 29.


Ras activates Raf, leading to the extracellular-regulated kinase (ERK)-mitogen-activated protein kinase pathway, which is involved in a variety of cellular, physiological, and pathological responses. Thus, regulators of this Ras-Raf interaction play crucial roles in these responses. In this study, we report a novel regulator of the Ras-Raf interaction named DA-Raf1. DA-Raf1 is a splicing isoform of A-Raf with a wider tissue distribution than A-Raf. It contains the Ras-binding domain but lacks the kinase domain, which is responsible for activation of the ERK pathway. As inferred from its structure, DA-Raf1 bound to activated Ras as well as M-Ras and interfered with the ERK pathway. The Ras-ERK pathway is essential for the negative regulation of myogenic differentiation induced by growth factors. DA-Raf1 served as a positive regulator of myogenic differentiation by inducing cell cycle arrest, the expression of myogenin and other muscle-specific proteins, and myotube formation. These results imply that DA-Raf1 is the first identified competent, intrinsic, dominant-negative antagonist of the Ras-ERK pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alternative Splicing
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cell Cycle
  • Cell Differentiation*
  • Cells, Cultured
  • Extracellular Signal-Regulated MAP Kinases / antagonists & inhibitors
  • Humans
  • MAP Kinase Signaling System / physiology*
  • Mice
  • Molecular Sequence Data
  • Monomeric GTP-Binding Proteins / metabolism
  • Muscle Development / physiology
  • Muscle Fibers, Skeletal / cytology*
  • Muscle Fibers, Skeletal / enzymology*
  • Myogenin / metabolism
  • Protein Isoforms / chemistry
  • Protein Isoforms / metabolism
  • Protein Isoforms / physiology
  • Proto-Oncogene Proteins A-raf / chemistry
  • Proto-Oncogene Proteins A-raf / metabolism
  • Proto-Oncogene Proteins A-raf / physiology*
  • Rats
  • ras Proteins


  • Myogenin
  • Protein Isoforms
  • DA-Raf1 protein, mouse
  • Proto-Oncogene Proteins A-raf
  • Extracellular Signal-Regulated MAP Kinases
  • Mras protein, mouse
  • Monomeric GTP-Binding Proteins
  • ras Proteins

Associated data

  • GENBANK/AB158252
  • GENBANK/AB158253
  • GENBANK/AB158254