title: The p35/Cdk5 kinase is a neuron-specific Rac effector that inhibits Pak1 activity.
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.
authors.affiliation: Howard Hughes Medical Institute and Department of Pathology, Children's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: M
authors.initials: M
authors.lastname: Nikolic
authors.forename: M M
authors.initials: MM
authors.lastname: Chou
authors.forename: W
authors.initials: W
authors.lastname: Lu
authors.forename: B J
authors.initials: BJ
authors.lastname: Mayer
authors.forename: L H
authors.initials: LH
authors.lastname: Tsai
mesh_terms: D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000378:metabolism; D051360:Cyclin-Dependent Kinase 5; D018844:Cyclin-Dependent Kinases; D004791:Enzyme Inhibitors / Q000378:metabolism; D020558:GTP Phosphohydrolases / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D016501:Neurites / Q000201:enzymology; D009474:Neurons / Q000201:enzymology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D054462:p21-Activated Kinases; D020744:rac GTP-Binding Proteins
chemical_list: D004791:Enzyme Inhibitors; D006657:Histones; D009419:Nerve Tissue Proteins; C089495:neuronal Cdk5 activator (p25-p35); D051360:Cyclin-Dependent Kinase 5; D017346:Protein Serine-Threonine Kinases; D054462:p21-Activated Kinases; D018844:Cyclin-Dependent Kinases; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins