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 RIS Download
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