Abstract
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
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing*
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Adaptor Proteins, Vesicular Transport*
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Animals
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism
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Cattle
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Cell Division / drug effects
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Cell Line
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Enzyme Activation
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Erythropoietin / pharmacology*
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GRB2 Adaptor Protein
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Humans
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Interleukin-15 / physiology
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Interleukin-2 / physiology
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Mice
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Phosphorylation
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Protein Kinases / metabolism*
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Protein Processing, Post-Translational / drug effects*
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Protein Serine-Threonine Kinases / metabolism*
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Proteins / metabolism
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Proteins / physiology
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Proto-Oncogene Proteins / metabolism*
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Proto-Oncogene Proteins c-raf
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Receptors, Erythropoietin / drug effects*
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Receptors, Erythropoietin / physiology
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Receptors, Interleukin-2 / drug effects
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Receptors, Interleukin-2 / physiology
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Shc Signaling Adaptor Proteins
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Signal Transduction / drug effects*
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Src Homology 2 Domain-Containing, Transforming Protein 1
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T-Lymphocytes, Cytotoxic / drug effects*
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T-Lymphocytes, Cytotoxic / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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GRB2 Adaptor Protein
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GRB2 protein, human
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Grb2 protein, mouse
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Interleukin-15
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Interleukin-2
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Proteins
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Proto-Oncogene Proteins
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Receptors, Erythropoietin
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Receptors, Interleukin-2
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SHC1 protein, human
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Shc Signaling Adaptor Proteins
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Shc1 protein, mouse
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Src Homology 2 Domain-Containing, Transforming Protein 1
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Erythropoietin
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Protein Kinases
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-raf
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Calcium-Calmodulin-Dependent Protein Kinases