Mitogen- and stress-activated protein kinase 1 mediates cAMP response element-binding protein phosphorylation and activation by neurotrophins

Simon Arthur, Amy L. Fong, Jami M. Dwyer, Monika Davare, Ed Reese, Karl Obrietan, Soren Impey

    Research output: Contribution to journalArticle

    168 Citations (Scopus)

    Abstract

    Activation of the transcription factor cAMP response element-binding protein (CREB) by neurotrophins is believed to regulate the survival, differentiation, and maturation of neurons in the CNS and PNS. Although phosphorylation of Ser133 is critical for the expression of CREB-regulated genes, the identity of neurotrophin-regulated Ser133 kinases has remained controversial. We show here that neurotrophin-induced CREB phosphorylation in CNS neurons depends exclusively on the extracellular signal-regulated kinase 1/2-activated kinase mitogen- and stress-activated protein kinase 1 (MSK1). Small interfering RNA directed against ribosomal S6 kinase 1 (RSK1) and RSK2 reduced phosphorylation of a RSK substrate but did not effect CREB-dependent transcription. However, expression of a selective inhibitory MSK1 mutant markedly attenuated BDNF-stimulated CREB phosphorylation and CREB-mediated transcription. Moreover, the ability of neurotrophins to stimulate CREB phosphorylation was abolished in CNS neurons from MSK1 knock-out mice. Consistent with a role for MSK1 in Ser133 phosphorylation, neurotrophin-induced expression of CREB-regulated genes was attenuated in MSK-deficient neurons. These results indicate that MSK1 is the major neurotrophin-activated Ser133 kinase in CNS neurons.
    Original languageEnglish
    Pages (from-to)4324-4332
    Number of pages9
    JournalJournal of Neuroscience
    Volume24
    Issue number18
    DOIs
    Publication statusPublished - 5 May 2004

    Keywords

    • Animals
    • Humans
    • Transcription, Genetic
    • Mice
    • RNA, Small Interfering
    • Nerve Growth Factors
    • Cyclic AMP Response Element-Binding Protein
    • Fibroblasts
    • Mice, Knockout
    • Rats
    • Cerebral Cortex
    • Phosphorylation
    • Genes, Dominant
    • Cells, Cultured
    • Neurons
    • Ribosomal Protein S6 Kinases, 90-kDa
    • Mitogen-Activated Protein Kinases
    • Mutation
    • Signal Transduction

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