Abstract
Cyclin-dependent kinase 5 (Cdk5) and its neuron-specific regulator p35 (refs 1–4) are essential for neuronal migration and for the laminar configuration of the cerebral cortex5,6,7. In addition, p35/Cdk5 kinase concentrates at the leading edges of axonal growth cones and regulates neurite outgrowth in cortical neurons in culture8. The Rho family of small GTPases is implicated in a range of cellular functions, including cell migration and neurite outgrowth9,10,11,12,13. 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 kinase14,15, 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 downregulation of Pak1 kinase activity. Because the Rho family of GTPases and the Pak kinases are implicated in actin polymerization16,17,18, 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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 51 print issues and online access
$199.00 per year
only $3.90 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Lew, J.et al. Neuronal cdc-2-like kinase is a complex of cyclin-dependent kinase 5 and a novel brain-specific regulatory subunit. Nature 371, 423–425 (1994).
Tsai, L.-H., Delalle, I., Caviness, V. S. J, Chae, T. & Harlow, E. p35 is a neural-specific regulatory subunit of cyclin-dependent kinase 5. Nature 371, 419–423 (1994).
Delalle, I., Bhide, P. G., Caviness, V. S. J & Tsai, L.-H. Temporal and spatial patterns of expression ofp35, a regulatory subunit of cyclin-dependent kinase 5, in the nervous system of the mouse. J.Neurocytol. 26, 283–296 (1997).
Tomizawa, K.et al. Localization and developmental changes in the neuron-specific cyclin-dependent kinase 5 activator (p35nck5a) in the rat brain. Neuroscience 74, 519–529 (1996).
Chae, T.et al. Mice lacking p35, a neuronal specific activator of Cdk5, display cortical lamination defects, seizures, and adult lethality. Neuron 18, 29–42 (1997).
Ohshima, T.et al. Targeted disruption of the cyclin-dependent kinase 5 gene results in abnormal corticogenesis, neuronal pathology and perinatal death. Proc. Natl Acad. Sci. USA 93, 11173–11178 (1996).
Kwon, Y. T. K. & Tsai, L.-H. Anovel disruption of cortical development in p35−/− mice distinct from reeler. J. Comp. Neurol. 395, 510–522 (1998).
Nikolic, M., Dudek, H., Kwon, Y. T., Ramos, Y. F. & Tsai, L.-H. The cdk5/p35 kinase is essential for neurite outgrowth during neuronal differentiation. Genes Dev. 10, 816–825 (1996).
Luo, L., Liao, Y. J., Jan, L. Y. & Jan, Y. N. Distinct morphogenetic functions of similar small GTPases: Drosophila Drac1 is involved in axonal outgrowth and myoblast fusion. Genes Dev. 8, 1787–1802 (1994).
Luo, L.et al. Differential effects of the Rac GTPase on Purkinje cell axons and dendritic trunks and spines. Nature 379, 837–840 (1996).
Kozma, R., Sarner, S., Ahmed, S. & Lim, L. Rho family GTPases and neuronal growth cone remodeling: relationship between increased complexity induced by Cdc42Hs, Rac1, and acetylcholine and collapse induced by RhoA and lysophosphatidic acid. Mol. Cell. Biol. 17, 1201–1211 (1997).
Threadgill, R., Bobb, K. & Ghosh, A. Regulation of dendritic growth and remodeling by Rho, Rac, and Cdc42. Neuron 19, 625–634 (1997).
Zipkin, I. D., Kindt, R. M. & Kenyon, C. J. Role of a new Rho family member in cell migration and axon guidance in C. elegans. Cell 90, 883–894 (1997).
Lim, L., Manser, E., Leung, T. & Hall, C. Regulation of phosphorylation pathways by p21 GTPases. The p21 Ras-related Rho subfamily and its role in phosphorylation signaling pathways. Eur. J. Biochem. 242, 171–185 (1996).
Sells, M. A. & Chernoff, J. Emerging from the Pak: the p21-activated protein kinase family. Trends Cell Biol. 7, 162–166 (1997).
Sells, M. A., Knaus, U. G., Bagrodia, S., Ambrose, D. M., Bokoch, G. M. & Chernoff, J. Human p21-activated kinase (Pak1) regulates actin organization in mammalian cells. Curr. Biol. 7, 202–210 (1997).
Hall, A. Rho GTPases and the actin cytoskeleton. Science 279, 509–514 (1998).
Manser, E.et al. Expression and constitutively active α-Pak reveals effects of the kinase on actin and focal complexes. Mol. Cell. Biol. 17, 1129–1143 (1997).
van den Heuvel, S. & Harlow, E. Distinct roles for cyclin-dependent kinases in cell cycle control. Science 262, 2050–2054 (1993).
Lamarche, N.et al. Rac and Cdc42 induce actin polymerization and G1 cell cycle progression independently of p65PAK and the JNK/SAPK MAP kinase cascade. Cell 87, 519–529 (1996).
Westwick, J. K.et al. Rac regulation of transformation, gene expression, and actin organization by multiple, PAK-independent pathways. Mol. Cell. Biol. 17, 1324–1335 (1997).
Kinsella, B. T., Erdman, R. A. & Maltese, W. A. Carboxyl-terminal isoprenilation of ras-related GTP-binding proteins encoded by rac1, rac2 and ra1A. J. Biol. Chem. 266, 9786–9794 (1991).
Manser, E.et al. Molecular cloning of a new member of the p21-Cdc42/Rac-activated kinase (PAK) family. J. Biol. Chem. 270, 25070–25078 (1995).
Manser, E., Leung, T., Salihuddin, H., Zhao, Z. & Lim, L. Abrain serine/threonine protein kinase activated by cdc42 and rac1. Nature 367, 40–46 (1994).
Lu, W., Katz, S., Gupta, R. & Mayer, B. J. Activation of Pak by membrane localization mediated by an SH3 domain from the adaptor protein Nck. Curr. Biol. 7, 85–94 (1996).
Meijer, L.et al. Biochemical and cellular effects of roscovitine, a potent and selective inhibitor of the cyclin-dependent kinases cdc2, cdk2 and cdk5. Eur. J. Biochem. 243, 527–536 (1997).
Dharmawardhane, S., Sanders, L. C., Martin, S. S., Daniels, R. H. & Bokoch, G. M. Localization of p21-activated kinase 1 (PAK1) to pinocytic vesicles and cortical actin structures in stimulated cells. J.Cell Biol. 138, 1265–1278 (1997).
Daniels, R. H., Hall, P. S. & Bokoch, G. M. Membrane targeting of p21-activated kinase 1 (PAK1) induces neurite outgrowth from PC12 cells. EMBO J. 17, 754–764 (1998).
Patrick, G. N., Zhou, P., Kwon, Y. T., Howley, P. M. & Tsai, L.-H. p35, the neuronal specific activator of cdk5, is degraded by the ubiquitin-proteasome pathway. J. Biol. Chem.(in the press).
Dynlacht, B. D., Moberg, K., Lees, J. A., Harlow, E. & Zhu, L. Specific regulation of E2F family members by cyclin-dependent kinases. Mol. Cell. Biol. 17, 3867–3875 (1997).
Acknowledgements
We thank K. Moberg and J. Lees for advice and technical help with the two-dimensional gel phosphopeptide analysis; A. Hall and J. Blenis for reagents and discussions; K. Buckley for anti-SV2 antibodies; J. Settleman for Ras expression constructs and advice; L. B. Chen and N. Perrimon for the use of confocal microscopes; and Y. T. Kwon, S. Humbert, G. Patrick, L. Zukeberg and V. Tannoch for help with the manuscript. This work was partly supported by NSF and NIH grants to L.-H.T. M.N. is supported by the Medical Foundation Charles King Trust. L.-H.T. is an assistant investigator of the Howard Hughes Medical Institute, a Rita Allen Foundation scholar and a recipient of an Esther A. and Joseph Klingenstein fund.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Nikolic, M., Chou, M., Lu, W. et al. The p35/Cdk5 kinase is a neuron-specific Rac effector that inhibits Pak1 activity. Nature 395, 194–198 (1998). https://doi.org/10.1038/26034
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/26034
This article is cited by
-
PFTK1 kinase regulates axogenesis during development via RhoA activation
BMC Biology (2023)
-
NPC1-dependent alterations in KV2.1–CaV1.2 nanodomains drive neuronal death in models of Niemann-Pick Type C disease
Nature Communications (2023)
-
The p21-activated kinases in neural cytoskeletal remodeling and related neurological disorders
Protein & Cell (2022)
-
CB1R regulates CDK5 signaling and epigenetically controls Rac1 expression contributing to neurobehavioral abnormalities in mice postnatally exposed to ethanol
Neuropsychopharmacology (2019)
-
Tale of the Good and the Bad Cdk5: Remodeling of the Actin Cytoskeleton in the Brain
Molecular Neurobiology (2018)
Comments
By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.