Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase.
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.
Xing
J
J
Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA.
Ginty
D D
DD
Greenberg
M E
ME
D000595:Amino Acid Sequence; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005786:Gene Expression Regulation; D006133:Growth Substances / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D009414:Nerve Growth Factors / Q000494:pharmacology; D016716:PC12 Cells; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051381:Rats; D019893:Ribosomal Protein S6 Kinases; D015398:Signal Transduction; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015533:Transcriptional Activation; D014162:Transfection; D014407:Tumor Cells, Cultured; D018631:ras Proteins / Q000378:metabolism
D017362:Cyclic AMP Response Element-Binding Protein; D006133:Growth Substances; D009414:Nerve Growth Factors; D004815:Epidermal Growth Factor; D017346:Protein Serine-Threonine Kinases; D019893:Ribosomal Protein S6 Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D018631:ras Proteins; D013755:Tetradecanoylphorbol Acetate