Activation of RSK by UV-light: phosphorylation dynamics and involvement ofthe MAPK pathway

Ribosomal S6 kinases (RSKs) are serine/threonine kinases activated by mitog enic signals through the Mitogen-Activated Protein Kinases/Extracellular Si gnal-Regulated Kinases (MAPK/ERK), RSKs contain two heterologous complete p rotein kinase domains. Phosphorylation by ERK of the C-terminal kinase doma in allows activation of the N-terminal kinase domain, which mediates substr ate phosphorylation, In human, there are three isoforms of RSK (RSK1, RSK2, RSK3), whose functional specificity remains undefined. Importantly, we hav e shown that mutations in the RSK2 gene lead to the Coffin-Lowry syndrome ( CLS), In this study, we characterize two monoclonal antibodies raised again st 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 sig nals, such as UV light, induce phosphorylation and activation of the three RSKs to an extent which is comparable to Epidermal Growth Factor (EGF)-medi ated activation. The use of specific kinase inhibitors indicates that UV-in duced phosphorylation and activation of RSK2 is mediated by the MAPK/ERK pa thway, but that the Stress-Activated Protein Kinase 2 (SAPK2)/p38 pathway i s also involved. These results modify the view of RSKs as kinases restricte d to the mitogenic response and reveal a previously unappreciated role of M APKs in stress induced signaling.