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.
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
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
EMBO J.
Date: Aug. 03, 1998
PubMed ID: 9687510
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