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

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.

Pubmed ID: 9687510


  • Deak M
  • Clifton AD
  • Lucocq LM
  • Alessi DR


The EMBO journal

Publication Data

August 3, 1998

Associated Grants

  • Agency: Wellcome Trust, Id:

Mesh Terms

  • Activating Transcription Factor 1
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Cell Line
  • Cyclic AMP Response Element-Binding Protein
  • DNA-Binding Proteins
  • Enzyme Activation
  • Epidermal Growth Factor
  • 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
  • Precipitin Tests
  • Protein-Serine-Threonine Kinases
  • Rats
  • Ribosomal Protein S6 Kinases
  • Ribosomal Protein S6 Kinases, 90-kDa
  • Signal Transduction
  • Tetradecanoylphorbol Acetate
  • Transcription Factors
  • Tumor Necrosis Factor-alpha
  • Ultraviolet Rays
  • p38 Mitogen-Activated Protein Kinases