Cdc42 regulates GSK-3β and adenomatous polyposis coli to control cell polarity

Abstract

Cell polarity is a fundamental property of all cells. In higher eukaryotes, the small GTPase Cdc42, acting through a Par6–atypical protein kinase C (aPKC) complex, is required to establish cellular asymmetry during epithelial morphogenesis, asymmetric cell division and directed cell migration1,2,3,4,5. However, little is known about what lies downstream of this complex. Here we show, through the use of primary rat astrocytes in a cell migration assay, that Par6–PKCζ interacts directly with and regulates glycogen synthase kinase-3β (GSK-3β) to promote polarization of the centrosome and to control the direction of cell protrusion. Cdc42-dependent phosphorylation of GSK-3β occurs specifically at the leading edge of migrating cells, and induces the interaction of adenomatous polyposis coli (Apc) protein with the plus ends of microtubules. The association of Apc with microtubules is essential for cell polarization. We conclude that Cdc42 regulates cell polarity through the spatial regulation of GSK-3β and Apc. This role for Apc may contribute to its tumour-suppressor activity.

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Figure 1: Glycogen synthase kinase-3β (GSK-3β) is phosphorylated downstream of Cdc42 and protein kinase Cζ (PKCζ) during astrocyte migration.
Figure 2: Spatially localized inhibition of GSK-3 is required to establish cell polarity.
Figure 3: β-Catenin is stabilized and localized at the leading edge of migrating cells.
Figure 4: The association of Apc with microtubules is regulated by the Cdc42–PKCζ–GSK-3 pathway.

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Acknowledgements

This work was supported by a Cancer Research UK programme grant, the Medical Research Council and by an EMBO Long-Term Fellowship (S.E.-M.). We thank S. Martin, V. M. Lee, R. Kypta, B. M. Gumbiner, P. Aspenström, I. Näthke and C. von Eichel-Streiber for plasmids and reagents.

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Correspondence to Alan Hall.

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Etienne-Manneville, S., Hall, A. Cdc42 regulates GSK-3β and adenomatous polyposis coli to control cell polarity. Nature 421, 753–756 (2003). https://doi.org/10.1038/nature01423

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