Erythropoietin activates Raf1 by an Shc-independent pathway in CTLL-EPO-R cells

Blood. 1997 Jan 1;89(1):55-64.


Stimulation of the erythropoietin receptor (EPO-R) or the interleukin-2 receptor (IL-2-R) by their respective ligands has been reported to activate tyrosine phosphorylation of the cytoplasmic protein, Shc. We have recently characterized a cell line, CTLL-EPO-R, that contains functional cell-surface receptors for both EPO and IL-2. Although stimulation with IL-2 or IL-15 resulted in the rapid, dose-dependent tyrosine phosphorylation of Shc, stimulation with EPO failed to activate Shc. EPO, IL-2, and IL-15 activated the tyrosine phosphorylation of the adaptor protein, Shp2, and the association of Shp2/Grb2/cytokine receptor complexes. In addition, EPO, IL-2, and IL-15 activated Raf1 and ERK2, demonstrating that the Raf1/MEK/MAP kinase pathway was activated. These results indicate that multiple biochemical pathways are capable of conferring a mitogenic signal in CTLL-EPO-R. EPO can activate the Raf1/MEK/MAP kinase pathway via Shc-dependent or Shc-independent pathways, and Shc activation is not required for EPO-dependent cell growth in CTLL-EPO-R.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Adaptor Proteins, Vesicular Transport*
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Cattle
  • Cell Division / drug effects
  • Cell Line
  • Enzyme Activation
  • Erythropoietin / pharmacology*
  • GRB2 Adaptor Protein
  • Humans
  • Interleukin-15 / physiology
  • Interleukin-2 / physiology
  • Mice
  • Phosphorylation
  • Protein Kinases / metabolism*
  • Protein Processing, Post-Translational / drug effects*
  • Protein Serine-Threonine Kinases / metabolism*
  • Proteins / metabolism
  • Proteins / physiology
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-raf
  • Receptors, Erythropoietin / drug effects*
  • Receptors, Erythropoietin / physiology
  • Receptors, Interleukin-2 / drug effects
  • Receptors, Interleukin-2 / physiology
  • Shc Signaling Adaptor Proteins
  • Signal Transduction / drug effects*
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • T-Lymphocytes, Cytotoxic / drug effects*
  • T-Lymphocytes, Cytotoxic / metabolism


  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Grb2 protein, mouse
  • Interleukin-15
  • Interleukin-2
  • Proteins
  • Proto-Oncogene Proteins
  • Receptors, Erythropoietin
  • Receptors, Interleukin-2
  • SHC1 protein, human
  • Shc Signaling Adaptor Proteins
  • Shc1 protein, mouse
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Erythropoietin
  • Protein Kinases
  • Protein Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-raf
  • Calcium-Calmodulin-Dependent Protein Kinases