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The Journal of Neuroscience, May 5, 2004, 24(18):4324-4332; doi:10.1523/JNEUROSCI.5227-03.2004
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Cellular/Molecular
Mitogen- and Stress-Activated Protein Kinase 1 Mediates cAMP Response Element-Binding Protein Phosphorylation and Activation by Neurotrophins
J. Simon, C. Arthur,1 Amy L. Fong,2 Jami M. Dwyer,2 Monika Davare,2 Ed Reese,2 Karl Obrietan,3 andSoren Impey2 1Medical Research Council Protein Phosphorylation Unit, MSI/WTB Complex, School of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, United Kingdom, 2The Vollum Institute, Oregon Health Sciences University, Portland, Oregon 97201, and 3Department of Neuroscience, Ohio State University, Columbus, Ohio 43210
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.
Key words: differentiation; neurotrophic; nerve growth factor; nucleus; protein kinase; transcription; transduction
Received Nov 26, 2003; revised February 27, 2004; accepted March 11, 2004.
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