Coupling of the RAS-MAPK Pathway to Gene Activation by RSK2, a Growth Factor-Regulated CREB Kinase

• Published in: Science (American Association for the Advancement of Science) 1996-08, Vol.273 (5277), p.959-963
• Main Authors: Xing, Jun, Ginty, David D., Greenberg, Michael E.
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Animals; Antibodies; Antigen antibody complex; Biological and medical sciences; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cell cycle, cell proliferation; Cell growth; Cell Line; Cell Nucleus - metabolism; Cell physiology; COS cells; Cyclic adenosine monophosphate; Cyclic adenylic acid; Cyclic AMP Response Element-Binding Protein - metabolism; Epidermal Growth Factor - pharmacology; Fear of Success; Fractions; Fundamental and applied biological sciences. Psychology; Gels; Gene Expression Regulation; Genes; Genetic regulation; Genetic vectors; Growth factors; Growth Substances - pharmacology; Humans; Individualized Instruction; K562 cells; Logical Thinking; Mobility; Molecular and cellular biology; Molecular Sequence Data; Nerve Growth Factors - pharmacology; Neurology; PC12 Cells; Phosphorylation; Protein-Serine-Threonine Kinases - metabolism; Proteins; ras Proteins - metabolism; Rats; Ribosomal Protein S6 Kinases; Signal Transduction; Tetradecanoylphorbol Acetate - pharmacology; Transcription factors; Transcriptional Activation; Transfection; Tumor Cells, Cultured
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.273.5277.959

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.