Activation of RSK by UV-light: phosphorylation dynamics and involvement of the MAPK pathway.
Ribosomal S6 kinases (RSKs) are serine/threonine kinases activated by mitogenic signals through the Mitogen-Activated Protein Kinases/Extracellular Signal-Regulated Kinases (MAPK/ERK). RSKs contain two heterologous complete protein kinase domains. Phosphorylation by ERK of the C-terminal kinase domain allows activation of the N-terminal kinase domain, which mediates substrate phosphorylation. In human, there are three isoforms of RSK (RSK1, RSK2, RSK3), whose functional specificity remains undefined. Importantly, we have shown that mutations in the RSK2 gene lead to the Coffin-Lowry syndrome (CLS). In this study, we characterize two monoclonal antibodies raised against phosphorylated forms of the N- and C-terminal domain of RSK2 (P-S227 and P-T577, respectively). Using these two antibodies, we show that stress signals, such as UV light, induce phosphorylation and activation of the three RSKs to an extent which is comparable to Epidermal Growth Factor (EGF)-mediated activation. The use of specific kinase inhibitors indicates that UV-induced phosphorylation and activation of RSK2 is mediated by the MAPK/ERK pathway, but that the Stress-Activated Protein Kinase 2 (SAPK2)/p38 pathway is also involved. These results modify the view of RSKs as kinases restricted to the mitogenic response and reveal a previously unappreciated role of MAPKs in stress induced signaling. Oncogene (2000) 19, 4221 - 4229
Mérienne
K
K
Institut de Génétique et de Biologie Moléculaire et Cellulaire CNRS, INSERM, ULP, Strasbourg, France.
Jacquot
S
S
Zeniou
M
M
Pannetier
S
S
Sassone-Corsi
P
P
Hanauer
A
A
D016475:3T3 Cells / Q000201:enzymology / Q000528:radiation effects; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D019556:COS Cells / Q000201:enzymology / Q000528:radiation effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005347:Fibroblasts / Q000201:enzymology / Q000528:radiation effects; D006801:Humans; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism / Q000528:radiation effects*; D020935:MAP Kinase Signaling System / Q000502:physiology / Q000528:radiation effects*; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D008969:Molecular Sequence Data; D010766:Phosphorylation / Q000528:radiation effects; D011499:Protein Processing, Post-Translational / Q000528:radiation effects*; D017434:Protein Structure, Tertiary; D019893:Ribosomal Protein S6 Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000528:radiation effects*; D013312:Stress, Physiological / Q000503:physiopathology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014466:Ultraviolet Rays; D048051:p38 Mitogen-Activated Protein Kinases
D000911:Antibodies, Monoclonal; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D004815:Epidermal Growth Factor; D019893:Ribosomal Protein S6 Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate