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Brain‐derived neurotrophic factor stimulates the transcriptional and neuroprotective activity of myocyte‐enhancer factor 2C through an ERK1/2‐RSK2 signaling cascade
Author(s) -
Wang Yupeng,
Liu Lidong,
Xia Zhengui
Publication year - 2007
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/j.1471-4159.2007.04606.x
Subject(s) - mef2c , mef2 , microbiology and biotechnology , biology , phosphorylation , neurotrophin , signal transduction , neurotrophic factors , mapk/erk pathway , brain derived neurotrophic factor , enhancer , transcription factor , biochemistry , receptor , gene
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 brain‐derived 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.