Journal
JOURNAL OF NEUROCHEMISTRY
Volume 102, Issue 3, Pages 957-966Publisher
BLACKWELL PUBLISHING
DOI: 10.1111/j.1471-4159.2007.04606.x
Keywords
apoptosis; brain-derived neurotrophic factor; cortical neurons; extracellular signal-regulated kinase 1/2; myocyte-enhancer factor 2C; ribosomal S6 kinase 2
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Funding
- NIA NIH HHS [AG19193] Funding Source: Medline
- NIEHS NIH HHS [ES012215] Funding Source: Medline
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Neurotrophin activation of myocyte-enhancer factor (MEF) 2C is one of the strongest pro-survival signaling pathways in developing neurons. To date, neurotrophin stimulation of MEF2C has been largely attributed to its direct phosphorylation by extracellular signal- regulated kinase (ERK) 5. Because MEF2C is not directly phosphorylated by ERK1/2 in vitro, it is generally assumed that the ERK1/2 signaling cascade does not regulate MEF2C. Surprisingly, we discovered that ERK1/2 are required for both the transcriptional and neuroprotective activity of MEF2C in cortical neurons stimulated by brainderived neurotrophic factor. ERK1/2 stimulation of MEF2C is mediated by p90 ribosomal S6 kinase 2 (RSK2), a Ser/Thr protein kinase downstream of ERK1/2. RSK2 strongly phosphorylates purified recombinant MEF2C protein in vitro. Furthermore, RSK2 can directly phosphorylate MEF2C on S192, a consensus RSK2-phosphorylation site located in the transactivation domain of MEF2C. Substitution of S192 with a non-phosphorylatable alanine diminishes both the transcriptional and neuroprotective activity of MEF2C to an extent similar to mutation on S387, an established activating phosphorylation site. Together, our data identifies ERK1/2-RSK2 signaling as a novel mechanism by which neurotrophins activate MEF2C and promote neuronal survival.
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