Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB

EMBO J. 1998 Aug 3;17(15):4426-41. doi: 10.1093/emboj/17.15.4426.

Abstract

We have identified a novel mitogen- and stress-activated protein kinase (MSK1) that contains two protein kinase domains in a single polypeptide. MSK1 is activated in vitro by MAPK2/ERK2 or SAPK2/p38. Endogenous MSK1 is activated in 293 cells by either growth factor/phorbol ester stimulation, or by exposure to UV radiation, and oxidative and chemical stress. The activation of MSK1 by growth factors/phorbol esters is prevented by PD 98059, which suppresses activation of the MAPK cascade, while the activation of MSK1 by stress stimuli is prevented by SB 203580, a specific inhibitor of SAPK2/p38. In HeLa, PC12 and SK-N-MC cells, PD 98059 and SB 203580 are both required to suppress the activation of MSK1 by TNF, NGF and FGF, respectively, because these agonists activate both the MAPK/ERK and SAPK2/p38 cascades. MSK1 is localized in the nucleus of unstimulated or stimulated cells, and phosphorylates CREB at Ser133 with a Km value far lower than PKA, MAPKAP-K1(p90Rsk) and MAPKAP-K2. The effects of SB 203580, PD 98059 and Ro 318220 on agonist-induced activation of CREB and ATF1 in four cell-lines mirror the effects of these inhibitors on MSK1 activation, and exclude a role for MAPKAP-K1 and MAPKAP-K2/3 in this process. These findings, together with other observations, suggest that MSK1 may mediate the growth-factor and stress-induced activation of CREB.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Activating Transcription Factor 1
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Calcium-Calmodulin-Dependent Protein Kinases / genetics
  • Calcium-Calmodulin-Dependent Protein Kinases / isolation & purification
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Calcium-Calmodulin-Dependent Protein Kinases / physiology*
  • Cell Line
  • Cyclic AMP Response Element-Binding Protein / metabolism*
  • Cyclic AMP Response Element-Binding Protein / radiation effects
  • DNA-Binding Proteins*
  • Enzyme Activation / drug effects
  • Enzyme Activation / radiation effects
  • Epidermal Growth Factor / physiology
  • HeLa Cells
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Kidney
  • Mice
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinases*
  • Molecular Sequence Data
  • PC12 Cells
  • Phosphorylation / radiation effects
  • Precipitin Tests
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / isolation & purification
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein Serine-Threonine Kinases / physiology
  • Rats
  • Ribosomal Protein S6 Kinases / chemistry
  • Ribosomal Protein S6 Kinases / immunology
  • Ribosomal Protein S6 Kinases / metabolism
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Signal Transduction / physiology
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcription Factors / metabolism
  • Transcription Factors / radiation effects
  • Tumor Necrosis Factor-alpha / physiology
  • Ultraviolet Rays
  • p38 Mitogen-Activated Protein Kinases

Substances

  • Activating Transcription Factor 1
  • Atf1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • Intracellular Signaling Peptides and Proteins
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Epidermal Growth Factor
  • MAP-kinase-activated kinase 2
  • Protein Serine-Threonine Kinases
  • RPS6KA4 protein, human
  • Ribosomal Protein S6 Kinases
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Rps6ka4 protein, mouse
  • mitogen and stress-activated protein kinase 1
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Tetradecanoylphorbol Acetate

Associated data

  • GENBANK/AF074393
  • GENBANK/AF074714
  • GENBANK/AF074715