Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase

Science. 1996 Aug 16;273(5277):959-63. doi: 10.1126/science.273.5277.959.

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

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cell Line
  • Cell Nucleus / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Epidermal Growth Factor / pharmacology
  • Gene Expression Regulation*
  • Growth Substances / pharmacology*
  • Humans
  • Molecular Sequence Data
  • Nerve Growth Factors / pharmacology
  • PC12 Cells
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • Rats
  • Ribosomal Protein S6 Kinases
  • Signal Transduction*
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcriptional Activation
  • Transfection
  • Tumor Cells, Cultured
  • ras Proteins / metabolism

Substances

  • Cyclic AMP Response Element-Binding Protein
  • Growth Substances
  • Nerve Growth Factors
  • Epidermal Growth Factor
  • Protein-Serine-Threonine Kinases
  • Ribosomal Protein S6 Kinases
  • Calcium-Calmodulin-Dependent Protein Kinases
  • ras Proteins
  • Tetradecanoylphorbol Acetate