Contrasting roles of neuronal Msk1 and Rsk2 in Bad phosphorylation and feedback regulation of Erk signalling.
Activated extracellular-signal-regulated kinase (Erk) phosphorylates and activates downstream kinases including ribosomal S6 kinase 2 (Rsk2/RPS6KA3) and mitogen- and stress-activated kinase 1 (Msk1, RPS6KA5). Rsk2 plays an important role in neuronal plasticity, as patients with Coffin-Lowry syndrome, where Rsk2 is dysfunctional, have impaired cognitive function. However, the relative role of neuronal Rsk2 and Msk1 in activating proteins downstream of Erk is unclear. In PC12 cells and in cortical neurones, the calcium ionophore A23187-induced phosphorylation of Erk, Msk1, Rsk2 and also the Bcl-2-associated death protein (Bad), which protects against neurotoxicity. Specific knockdown of Msk1 with small interfering RNA reduced the ability of A23187 to induce Bad phosphorylation in both PC12 cells and cortical neurones. Conversely, specific knockdown of Rsk2 potentiated Bad phosphorylation following A23187 treatment, and also elevated Erk phosphorylation in both cell types. This indicates that Msk1 rather than Rsk2 mediates neuronal Bad phosphorylation following Ca(2+) influx and implicates Rsk2 in a negative-feedback regulation of Erk activity.
Division of Neuroscience and Biomedical Systems, Institute of Biomedical and Life Sciences, West Medical Building, University of Glasgow, Glasgow, UK.
C J
CJ
Clark
D M
DM
McDade
C T
CT
O'Shaughnessy
B J
BJ
Morris
D000818:Animals; D000001:Calcimycin / Q000494:pharmacology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology; D004622:Embryo, Mammalian; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology*; D005260:Female; D007476:Ionophores / Q000494:pharmacology; D008970:Molecular Weight; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011247:Pregnancy; D034741:RNA, Small Interfering / Q000494:pharmacology; D051381:Rats; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D051025:bcl-Associated Death Protein / Q000378:metabolism*
D007476:Ionophores; D034741:RNA, Small Interfering; D051025:bcl-Associated Death Protein; D000001:Calcimycin; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C116919:mitogen and stress-activated protein kinase 1; C069330:ribosomal protein S6 kinase, 90kDa, polypeptide 3; D048049:Extracellular Signal-Regulated MAP Kinases