Abstract
A signaling pathway has been elucidated whereby growth factors activate the transcription factor cyclic adenosine monophosphate response element-binding protein (CREB), a critical regulator of immediate early gene transcription. Growth factor-stimulated CREB phosphorylation at serine-133 is mediated by the RAS-mitogen-activated protein kinase (MAPK) pathway. MAPK activates CREB kinase, which in turn phosphorylates and activates CREB. Purification, sequencing, and biochemical characterization of CREB kinase revealed that it is identical to a member of the pp90(RSK) family, RSK2. RSK2 was shown to mediate growth factor induction of CREB serine-133 phosphorylation both in vitro and in vivo. These findings identify a cellular function for RSK2 and define a mechanism whereby growth factor signals mediated by RAS and MAPK are transmitted to the nucleus to activate gene expression.
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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Amino Acid Sequence
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Animals
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Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
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Cell Line
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Cell Nucleus / metabolism
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Cyclic AMP Response Element-Binding Protein / metabolism*
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Epidermal Growth Factor / pharmacology
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Gene Expression Regulation*
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Growth Substances / pharmacology*
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Humans
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Molecular Sequence Data
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Nerve Growth Factors / pharmacology
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PC12 Cells
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Phosphorylation
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Protein Serine-Threonine Kinases / metabolism*
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Rats
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Ribosomal Protein S6 Kinases
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Signal Transduction*
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Tetradecanoylphorbol Acetate / pharmacology
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Transcriptional Activation
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Transfection
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Tumor Cells, Cultured
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ras Proteins / metabolism
Substances
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Cyclic AMP Response Element-Binding Protein
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Growth Substances
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Nerve Growth Factors
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Epidermal Growth Factor
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Protein Serine-Threonine Kinases
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Ribosomal Protein S6 Kinases
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Calcium-Calmodulin-Dependent Protein Kinases
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ras Proteins
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Tetradecanoylphorbol Acetate