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Cdk5 phosphorylates and stabilizes p27kip1 contributing to actin organization and cortical neuronal migration

Nature Cell Biology volume 8, pages 17–26 (2006)Cite this article

Abstract

p27kip1, a cyclin-dependent kinase (CDK) inhibitor (CKI), generally suppresses CDK activity in proliferating cells. Although another role of p27 in cell migration has been recently suggested in vitro, the physiological importance of p27 in cell migration remains elusive, as p27-deficient mice have not shown any obvious migration-defect-related phenotypes. Here, we show that Cdk5, an unconventional neuronal CDK, phosphorylates and stabilizes p27 as an upstream regulator, maintaining the amount of p27 in post-mitotic neurons. In vivo RNA interference (RNAi) experiments showed that reduced amounts of p27 caused inhibition of cortical neuronal migration and decreased the amount of F-actin in the processes of migrating neurons. The Cdk5–p27 pathway activates an actin-binding protein, cofilin, which is also shown to be involved in cortical neuronal migration in vivo. Our findings shed light on a previously unknown new relationship between CDK and CKI in G0-arrested cells that regulates cytoskeletal reorganization and neuronal migration during corticogenesis.

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Figure 1: Cdk5 phosphorylates and stabilizes p27.
Figure 2: p27 binds to and colocalizes with Cdk5.
Figure 3: Effects of p27 shRNAs.
Figure 4: Effects of p27 shRNAs on cell cycle and differentiation.
Figure 5: Effects of p27 shRNAs on morphology of migrating neurons.
Figure 6: Cdk5 and p27 control cofilin phosphorylation.
Figure 7: CofilinS3A disturbed neuronal migration.
Figure 8: A model for the role of Cdk5 and p27 in cortical neuronal migration.

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Acknowledgements

We thank G. Bokoch, K. Kaibuchi, S. Meloche, K. Moriyama, M. Nakanishi, A. Takashima, L.H. Tsai and D.L. Turner for providing plasmids. We also thank K-i. Nakayama, K. Nakayama, R. Yu and M. Sone for helpful comments. This work was supported by the Center of Excellence (COE) grant and Grant-in-Aid for Scientific Research on Priority Areas, “Elucidation of glia-neuron network mediated information processing systems (#16047220)”, “Molecular Brain Science 16067101 (#17024030)” and “Membrane Traffic” from the Ministry of Education, Culture, Sports, and Science and Technology, Japan, and by grants from Japan Brain Foundation and Takeda Science Foundation.

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Authors and Affiliations

  1. Department of Pathology and Tumor Biology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, 606-8501, Japan

    Takeshi Kawauchi, Kaori Chihama, Yo-ichi Nabeshima & Mikio Hoshino

  2. Precursory Research for Embryonic Science and Technology (PRESTO), Japan Science and Technology Agency (JST), Kawaguchi, 332-0012, Japan

    Mikio Hoshino

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Kawauchi, T., Chihama, K., Nabeshima, Yi. et al. Cdk5 phosphorylates and stabilizes p27kip1 contributing to actin organization and cortical neuronal migration. Nat Cell Biol 8, 17–26 (2006). https://doi.org/10.1038/ncb1338

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