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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 (refs 14) 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.

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Figure 1: The p35/Cdk5 kinase associates with Rac in a GTP-dependent manner.
Figure 2: In neurons, p35 co-localizes and associates with Rac and Pak1 at the cell periphery.
Figure 3: The p35/Cdk5 kinase associates with and phosphorylates Pak1 in a Rac-dependent manner.
Figure 4: The p35/Cdk5 kinase inhibits Pak1 activity but not its affinity for Rac.

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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.

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Correspondence to Li-Huei Tsai.

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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

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