The p35/Cdk5 kinase is a neuron-specific Rac effector that inhibits Pak1 activity

Nature. 1998 Sep 10;395(6698):194-8. doi: 10.1038/26034.

Abstract

Cyclin-dependent kinase 5 (Cdk5) and its neuron-specific regulator p35 are essential for neuronal migration and for the laminar configuration of the cerebral cortex. In addition, p35/Cdk5 kinase concentrates at the leading edges of axonal growth cones and regulates neurite outgrowth in cortical neurons in culture. The Rho family of small GTPases is implicated in a range of cellular functions, including cell migration and neurite outgrowth. Here we show that the p35/Cdk5 kinase co-localizes with Rac in neuronal growth cones. Furthermore, p35 associates directly with Rac in a GTP-dependent manner. Another Rac effector, Pak1 kinase, is also present in the Rac-p35/Cdk5 complexes and co-localizes with p35/Cdk5 and Rac at neuronal peripheries. The active p35/Cdk5 kinase causes Pak1 hyperphosphorylation in a Rac-dependent manner, which results in down-regulation of Pak1 kinase activity. Because the Rho family of GTPases and the Pak kinases are implicated in actin polymerization, the modification of Pak1, imposed by the p35/Cdk5 kinase, is likely to have an impact on the dynamics of the reorganization of the actin cytoskeleton in neurons, thus promoting neuronal migration and neurite outgrowth.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • COS Cells
  • Cell Membrane / metabolism
  • Cyclin-Dependent Kinase 5
  • Cyclin-Dependent Kinases*
  • Enzyme Inhibitors / metabolism
  • GTP Phosphohydrolases / metabolism
  • GTP-Binding Proteins / metabolism*
  • Histones / metabolism
  • Nerve Tissue Proteins / metabolism*
  • Neurites / enzymology
  • Neurons / enzymology*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism*
  • Signal Transduction
  • Transfection
  • p21-Activated Kinases
  • rac GTP-Binding Proteins

Substances

  • Enzyme Inhibitors
  • Histones
  • Nerve Tissue Proteins
  • neuronal Cdk5 activator (p25-p35)
  • Cyclin-Dependent Kinase 5
  • Protein-Serine-Threonine Kinases
  • p21-Activated Kinases
  • Cyclin-Dependent Kinases
  • GTP Phosphohydrolases
  • GTP-Binding Proteins
  • rac GTP-Binding Proteins