Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology (original) (raw)

Nature volume 442, pages 814–817 (2006)Cite this article

Abstract

WAVE1—the Wiskott–Aldrich syndrome protein (WASP)-family verprolin homologous protein 1—is a key regulator of actin-dependent morphological processes1 in mammals, through its ability to activate the actin-related protein (Arp2/3) complex. Here we show that WAVE1 is phosphorylated at multiple sites by cyclin-dependent kinase 5 (Cdk5) both in vitro and in intact mouse neurons. Phosphorylation of WAVE1 by Cdk5 inhibits its ability to regulate Arp2/3 complex-dependent actin polymerization. Loss of WAVE1 function in vivo or in cultured neurons results in a decrease in mature dendritic spines. Expression of a dephosphorylation-mimic mutant of WAVE1 reverses this loss of WAVE1 function in spine morphology, but expression of a phosphorylation-mimic mutant does not. Cyclic AMP (cAMP) signalling reduces phosphorylation of the Cdk5 sites in WAVE1, and increases spine density in a WAVE1-dependent manner. Our data suggest that phosphorylation/dephosphorylation of WAVE1 in neurons has an important role in the formation of the filamentous actin cytoskeleton, and thus in the regulation of dendritic spine morphology.

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Acknowledgements

We thank W.-B. Gan for assisting us with the DiI staining method; L.-H. Tsai for providing P35 cDNA; A. Yamamoto for Nap1 cDNA; and P. Aspenström for N-WASP antibody. We also thank T. D. Pollard for suggestions. This work was supported by the postdoctoral fellowship programme of the Korea Science & Engineering Foundation (KOSEF) (to J.Y.S.), and funding from the F.M. Kirby foundation (to P.G.), the Picower Foundation (to P.G.), the National Institute of Mental Health, the National Institute of Drug Abuse and the National Institute on Aging (to A.C.N. and P.G.). Author Contributions Y.K., J.Y.S., I.C. and K.-W.L. performed experiments; J.M.H. and A.M.K. assisted in experiments; J.-H.A., S.P.K., A.S., B.B. and J.D.S. provided reagents; J.B.P. and S.H.R. performed MALDI-TOF mass spectrometry; Y.K., A.C.N. and P.G. designed experiments and wrote the manuscript.

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Authors and Affiliations

  1. Laboratory of Molecular and Cellular Neuroscience, The Rockefeller University, 1230 York Avenue, New York, 10021, New York, USA
    Yong Kim, Jee Young Sung, Ilaria Ceglia, Ko-Woon Lee, Jung-Hyuck Ahn, Jonathan M. Halford, Amie M. Kim, Angus C. Nairn & Paul Greengard
  2. Discovery Neurosciences, Wyeth Research, New Jersey, 08543, Princeton, USA
    Seung P. Kwak
  3. Division of Molecular and Life Sciences, Pohang University of Science and Technology, 790-784, Pohang, Korea
    Jong Bae Park & Sung Ho Ryu
  4. Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, BP 10142, 67404, Illkirch cedex, France
    Annette Schenck & Barbara Bardoni
  5. Howard Hughes Medical Institute, Vollum Institute, 3181 Sam Jackson Park Road, Oregon, 97239-3098, Portland, USA
    John D. Scott
  6. Department of Psychiatry, Yale University School of Medicine, 34 Park Street, New Haven, Connecticut, 06508, USA
    Angus C. Nairn

Authors

  1. Yong Kim
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  2. Jee Young Sung
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  3. Ilaria Ceglia
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  4. Ko-Woon Lee
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  5. Jung-Hyuck Ahn
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  6. Jonathan M. Halford
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  7. Amie M. Kim
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  8. Seung P. Kwak
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  9. Jong Bae Park
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  10. Sung Ho Ryu
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  11. Annette Schenck
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  12. Barbara Bardoni
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  13. John D. Scott
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  14. Angus C. Nairn
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  15. Paul Greengard
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Correspondence toPaul Greengard.

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Supplementary information

Supplementary Notes

This file contains Supplementary Figures and Legends 1–7, Supplementary Table 1 and Supplementary Methods. The Supplementary Figures show the interaction of P35 with the WAVE complex, phosphorylation of WAVE1, actin polymerization catalyzed by WAVE1 and Cdk5 activity in striatal slices following forskolin treatment. The Supplementary Table provides stoichiometry of phosphorylation of WAVE1. The Supplementary Methods provide technical details of experimental methods used in this study. (PDF 622 kb)

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Kim, Y., Sung, J., Ceglia, I. et al. Phosphorylation of WAVE1 regulates actin polymerization and dendritic spine morphology.Nature 442, 814–817 (2006). https://doi.org/10.1038/nature04976

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