Phosphorylation of neuronal survival factor MEF2D by glycogen synthase kinase 3beta in neuronal apoptosis.
Glycogen synthase kinase 3beta (GSK3beta) has been identified to play important roles in neuronal death. Evidence from both in vitro and in vivo studies indicates that increased GSK3beta activity contributes to neurodegeneration and to the pathogenesis of Alzheimer disease. But the molecular mechanisms that underlie GSK3beta-mediated neurotoxicity remain poorly understood. We reported here that myocyte enhancer factor 2D (MEF2D), a nuclear transcription factor known to promote neuronal survival, is directly phosphorylated by GSK3beta. Our data showed that phosphorylation of MEF2D by GSK3beta at three specific residues in its transactivation domain inhibits MEF2D transcriptional activity. Withdrawal of neuronal activity in cerebellar granule neurons activated GSK3beta in the nucleus, leading to GSK3beta-dependent inhibition of MEF2 function. This inhibition contributed to GSK3beta-mediated neuronal toxicity. Overexpression of MEF2D mutant that is resistant to GSK3beta inhibition protected cerebellar granule neurons from either GSK3beta activation- or neuronal activity deprivation-induced toxicity. These results identify survival factor MEF2D as a novel downstream effector targeted by GSK3beta and define a molecular link between activation of GSK3beta and neuronal survival machinery which may underlie in part GSK3beta-mediated neurotoxicity.
Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Xuemin
X
Wang
Hua
H
She
Zixu
Z
Mao
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D064326:MEF2 Transcription Factors; D008954:Models, Biological; D018006:Myogenic Regulatory Factors / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism*; D010766:Phosphorylation; D011188:Potassium / Q000378:metabolism; D020033:Protein Isoforms; D017434:Protein Structure, Tertiary; D051381:Rats; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism*; D014162:Transfection
D064326:MEF2 Transcription Factors; C578045:MEF2D protein, rat; D018006:Myogenic Regulatory Factors; D020033:Protein Isoforms; D014157:Transcription Factors; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D011188:Potassium