Many Hats for Cdk Inhibitor

Abstract

Analysis of control of cell migration during development of the mammalian brain has revealed a striking example of the efficiency with which biological systems are organized and how multifunctional proteins may coordinate biological processes during development. The cyclin-dependent kinases (CDKs) are best known as regulators of the cell division cycle, but postmitotic neurons express a related protein, Cdk5, which has been implicated in control of neuronal migration. The activity of Cdks is regulated by CDK inhibitors like the protein p27kip1, which inhibits mitotic Cdks to allow cells to exit from the cell cycle. Because p27 has also been implicated in control of cell migration and contains a potential site of phosphorylation by Cdk5, Kawauchi et al . explored the interaction of these proteins in control of development of neurons of the cerebral cortex. Although mitotic cyclins oppose the actions of p27 by promoting its degradation, Kawauchi et al . provide evidence that phosphorylation of p27 by Cdk5 promotes stabilization of the protein. Treatment of cultured cortical neurons with short hairpin RNAs (shRNAs) to decrease the abundance of Cdk5 decreased both phosphorylation and abundance of p27. The p27 protein appears to have a critical role in control of migration because electroporation of shRNA to block p27 expression in embryos in utero prevented proper migration of cortical neurons. This effect of p27 appears to be mediated in part by control of the actin cytoskeleton. Depletion of p27 disrupted formation of F (filamentous) actin in the developing brain cells, and phosphorylation of the actin-binding protein cofilin was altered after depletion of p27 or pharmacological inhibition of Cdk5. The authors propose that p27 functions first to inhibit mitotic Cdks and cause proliferating neurons to withdraw from the cell cycle. Having accomplished that, it then associates with Cdk5 to promote cytoskeletal reorganization and migration of cortical neurons. T. Kawauchi, K. Chihama, Y.-i. Nabeshima, M. Hoshino, Cdk5 phosphorylates and stabilizes p27 kip1 contributing to actin organization and cortical neuronal migration. Nat. Cell Biol. 8 , 17-26 (2006). [PubMed]