Mitogen- and Stress-Activated Protein Kinase 1 Mediates cAMP Response Element-Binding Protein Phosphorylation and Activation by Neurotrophins

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

Research output: Contribution to journalArticle

162 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 (US)
Pages (from-to)4324-4332
Number of pages9
JournalJournal of Neuroscience
Volume24
Issue number18
DOIs
StatePublished - May 5 2004

Fingerprint

Cyclic AMP Response Element-Binding Protein
Nerve Growth Factors
Phosphorylation
Neurons
Phosphotransferases
MAP Kinase Kinase 1
MAP Kinase Kinase 4
Ribosomal Protein S6 Kinases
Mitogen-Activated Protein Kinase 3
mitogen and stress-activated protein kinase 1
Mitogen-Activated Protein Kinase 1
Brain-Derived Neurotrophic Factor
Knockout Mice
Small Interfering RNA
Genes
Transcription Factors

Keywords

  • Differentiation
  • Nerve growth factor
  • Neurotrophic
  • Nucleus
  • Protein kinase
  • Transcription
  • Transduction

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Mitogen- and Stress-Activated Protein Kinase 1 Mediates cAMP Response Element-Binding Protein Phosphorylation and Activation by Neurotrophins. / Arthur, J. Simon C; Fong, Amy L.; Dwyer, Jami M.; Davare, Monika; Reese, Ed; Obrietan, Karl; Impey, Soren.

In: Journal of Neuroscience, Vol. 24, No. 18, 05.05.2004, p. 4324-4332.

Research output: Contribution to journalArticle

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