Abstract
The type I insulin-like growth factor receptor (IGF-IR) is known to send two seemingly contradictory signals inducing either cell proliferation or cell differentiation, depending on cell type and/or conditions. H19-7 cells are rat hippocampal neuronal cells immortalized by a temperature-sensitive SV40 large T antigen that grow at 34 degrees C in epidermal growth factor or serum but differentiate at 39 degrees C when induced by basic fibroblast growth factor. At 39 degrees C, expression of the human IGF-IR in H19-7 cells induces an insulin-like growth factor (IGF) I-dependent differentiation. We have investigated the domains of the IGF-IR required for differentiation of H19-7 cells. The tyrosine 950 residue and serines 1280-1283 in the COOH terminus of the receptor are required for IGF-I-induced differentiation at 39 degrees C, although they are dispensable for IGF-I-mediated growth at 34 degrees C. Both domains have to be mutated to inactivate the differentiating function. The inability of these mutant receptors to induce differentiation correlates with mitogen-activated protein kinase activation. In contrast, inhibitors of phosphatidylinositol 3'-kinase have no effect on IGF-I-mediated differentiation of H19-7 cells, although they do inhibit the mitogenic response.
Publication types
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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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Amino Acid Substitution / genetics
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Animals
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Cell Differentiation* / drug effects
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Cell Division / drug effects
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Cell Line
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Enzyme Activation
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Fibroblasts / cytology
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Fibroblasts / drug effects
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Fibroblasts / enzymology
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Fibroblasts / metabolism
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Hippocampus
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Humans
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Insulin Receptor Substrate Proteins
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Insulin-Like Growth Factor I / antagonists & inhibitors
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Insulin-Like Growth Factor I / pharmacology
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MAP Kinase Signaling System* / drug effects
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Mice
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Mutation / genetics
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Neurons / cytology*
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Neurons / drug effects
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Neurons / enzymology
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Neurons / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoproteins / metabolism
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Phosphorylation / drug effects
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Proteins / metabolism
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Rats
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Receptor, IGF Type 1 / chemistry
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Receptor, IGF Type 1 / genetics
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Receptor, IGF Type 1 / metabolism*
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Shc Signaling Adaptor Proteins
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Src Homology 2 Domain-Containing, Transforming Protein 1
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Temperature
Substances
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Adaptor Proteins, Signal Transducing
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Adaptor Proteins, Vesicular Transport
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IRS1 protein, human
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Insulin Receptor Substrate Proteins
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Irs1 protein, mouse
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Irs1 protein, rat
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Phosphoinositide-3 Kinase Inhibitors
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Phosphoproteins
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Proteins
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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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Shc1 protein, rat
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Src Homology 2 Domain-Containing, Transforming Protein 1
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Insulin-Like Growth Factor I
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Receptor, IGF Type 1
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Mitogen-Activated Protein Kinases
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Mitogen-Activated Protein Kinase Kinases