Article
- The EMBO Journal (2004) 23, 2235 - 2245
- doi:10.1038/sj.emboj.7600237
Published online: 20 May 2004
Subject Categories:
A novel CDK5-dependent pathway for regulating GSK3 activity and kinesin-driven motility in neurons
Gerardo Morfini1,2, Györgyi Szebenyi3, Hannah Brown2, Harish C Pant2,4, Gustavo Pigino1, Scott DeBoer1, Uwe Beffert5 and Scott T Brady1,2
- Department of Anatomy and Cell Biology, University of Illinois at Chicago, Chicago, IL, USA
- Marine Biological Laboratory, Woods Hole, MA, USA
- Department of Cell Biology and Center for Basic Neuroscience, UT Southwestern, Dallas, TX, USA
- Laboratory of Neurochemistry, NINDS, Bethesda, MD, USA
- Department of Molecular Genetics, UT Southwestern, Dallas, TX, USA
Correspondence to:
Scott T Brady, Anatomy and Cell Biology M/C 512, 808 S Wood St, University of Illinois at Chicago, Chicago, IL 60612, USA. Tel.: +1 312 996 6791; Fax: +1 312 413 0354; E-mail: stbrady@uic.edu
Received 11 November 2003; Accepted 20 April 2004
Abstract
Neuronal transmission of information requires polarized distribution of membrane proteins within axonal compartments. Membrane proteins are synthesized and packaged in membrane-bounded organelles (MBOs) in neuronal cell bodies and later transported to axons by microtubule-dependent motor proteins. Molecular mechanisms underlying targeted delivery of MBOs to discrete axonal subdomains (i.e. nodes of Ranvier or presynaptic terminals) are poorly understood, but regulatory pathways for microtubule motors may be an essential step. In this work, pharmacological, biochemical and in vivo experiments define a novel regulatory pathway for kinesin-driven motility in axons. This pathway involves enzymatic activities of cyclin-dependent kinase 5 (CDK5), protein phosphatase 1 (PP1) and glycogen synthase kinase-3 (GSK3). Inhibition of CDK5 activity in axons leads to activation of GSK3 by PP1, phosphorylation of kinesin light chains by GSK3 and detachment of kinesin from transported cargoes. We propose that regulating the activity and localization of components in this pathway allows nerve cells to target organelle delivery to specific subcellular compartments. Implications of these findings for pathogenesis of neurodegenerative diseases such as Alzheimer's disease are discussed.
Keywords:
- axonal transport,
- CDK5,
- GSK-3,
- kinesin,
- protein phosphatase PP1
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