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.
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
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Etienne-Manneville, S. & Hall, S. Rho GTPases in cell biology. Nature 420, 629–635 (2002)
Ohno, S. Intercellular junctions and cellular polarity: the PAR–aPKC complex, a conserved core cassette playing fundamental roles in cell polarity. Curr. Opin. Cell Biol. 13, 641–648 (2001)
Gotta, M., Abraham, M. C. & Ahringer, J. CDC-42 controls early cell polarity and spindle orientation in C. elegans. Curr. Biol. 11, 482–488 (2001)
Kay, A. J. & Hunter, C. P. CDC-42 regulates PAR protein localization and function to control cellular and embryonic polarity in C. elegans. Curr. Biol. 11, 474–481 (2001)
Etienne-Manneville, S. & Hall, A. Integrin-mediated Cdc42 activation controls cell polarity in migrating astrocytes through PKCζ. Cell 106, 489–498 (2001)
Dominguez, I., Itoh, K. & Sokol, S. Y. Role of glycogen synthase kinase 3β as a negative regulator of dorsoventral axis formation in Xenopus embryos. Proc. Natl Acad. Sci. USA 92, 8498–8502 (1995)
Emily-Fenouil, F., Ghiglione, C., Lhomond, G., Lepage, T. & Gache, C. GSK3β/shaggy mediates patterning along the animal-vegetal axis of the sea urchin embryo. Development 125, 2489–2498 (1998)
He, X., Saint-Jeannet, J.-P., Woodgett, J. R., Varmus, H. E. & Dawid, I. Glycogen synthase kinase-3 and dorsoventral patterning in Xenopus embryos. Nature 374, 617–622 (1995)
Pierce, S. B. & Kimelman, D. Regulation of Spemann organizer formation by intracellular Xgsk-3. Development 121, 755–765 (1995)
Ferkey, D. M. & Kimelman, D. GSK-3: new thoughts on an old enzyme. Dev. Biol. 225, 471–479 (2000)
Oriente, F. et al. Insulin receptor substrate-2 phosphorylation is necessary for protein kinase Cζ activation by insulin in L6hIR cells. J. Biol. Chem. 276, 37109–37119 (2001)
Harwood, J. A. Regulation of GSK-3: a cellular multiprocessor. Cell 105, 821–824 (2001)
Troussard, A. A., Tan, C., Yoganathan, T. N. & Dedhar, S. Cell–extracellular matrix interactions stimulate the AP-1 transcription factor in an integrin-linked kinase- and glycogen synthase kinase 3-dependent manner. Mol. Cell. Biol. 19, 7420–7427 (1999)
Li, L. et al. Axin and Frat1 interact with Dvl and GSK, bridging Dvl to GSK in the Wnt-mediated regulation of LEF-1. EMBO J. 18, 4233–4240 (1999)
Moon, R. T., Bowerman, B., Boutros, M. & Perrimon, N. The promise and perils of Wnt signaling through β-catenin. Science 296, 1644–1646 (2002)
Polakis, P. Wnt signaling and cancer. Genes Dev. 14, 1837–1851 (2000)
Munemitsu, S., Albert, I., Souza, B., Rubinfeld, B. & Polakis, P. Regulation of intracellular β-catenin levels by the adenomatous polyposis coli (APC) tumour-suppressor protein. Proc. Natl Acad. Sci. USA 92, 3046–3050 (1995)
Rubinfeld, B. et al. Binding of GSK3β to the APC-β-catenin complex and regulation of complex assembly. Science 272, 1023–1026 (1996)
Bienz, M. The subcellular destinations of APC proteins. Nature Rev. Mol. Cell Biol. 3, 328–338 (2002)
Mogensen, M. M., Tucker, J. B., Mackie, J. B., Prescott, A. R. & Nathke, I. S. The adenomatous polyposis coli protein unambiguously localizes to microtubule plus ends and is involved in establishing parrallel arrays of microtubule bundles in highly polarized epithelial cells. J. Cell Biol. 157, 1041–1048 (2002)
Su, L. K. et al. APC binds to the novel protein EB1. Cancer Res. 55, 2972–2977 (1995)
Barth, A. I. M., Siemers, K. A. & Nelson, W. J. Dissecting interactions between EB1, microtubules and APC in cortical clusters at the plasma membrane. J. Cell Sci. 115, 1583–1590 (2002)
Wagner, U., Utton, M., Gallo, J.-M. & Miller, C. C. J. Cellular phosphorylation of Tau by GSK-3β influences tau binding to microtubules and microtubule organisation. J. Cell Sci. 109, 1537–1543 (1996)
Lucas, F. R., Goold, R. G., Gordon-Weeks, P. R. & Salinas, P. C. Inhibition of GSK-3β leading to the loss of phosphorylated MAP-1B is an early event in axonal remodelling induced by WNT-7a or lithium. J. Cell Sci. 111, 1351–1361 (1998)
Nakamura, M., Zhou, X. Z. & Lu, K. P. Critical role for the EB1 and APC interaction in the regulation of microtubule polymerization. Curr. Biol. 11, 1062–1067 (2001)
Zumbrunn, J., Kinoshita, K., Hyman, A. A. & Nathke, I. S. Binding of the adenomatous polyposis coli protein to microtubules increases microtubule stability and is regulated by GSK3β phosphorylation. Curr. Biol. 11, 44–49 (2001)
Palazzo, A. F. et al. Cdc42, dynein, and dynactin regulate MTOC reorientation independent of Rho-regulated microtubule stabilization. Curr. Biol. 11, 1536–1541 (2001)
Berrueta, L., Tirnauer, J. S., Schuyler, S. C., Pellman, D. & Bierer, B. E. The APC-associated protein EB1 associates with components of the dynactin complex and cytoplasmic dynein intermediate chain. Curr. Biol. 9, 425–428 (1999)
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.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare that they have no competing financial interests.
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/nature01423
This article is cited by
-
Advances in Understanding the Molecular Mechanisms of Neuronal Polarity
Molecular Neurobiology (2023)
-
Direct Current Electric Field Coordinates the Migration of BV2 Microglia via ERK/GSK3β/Cofilin Signaling Pathway
Molecular Neurobiology (2022)
-
Cdc42 Facilitates Axonogenesis by Enhancing Microtubule Stabilization in Primary Hippocampal Neurons
Cellular and Molecular Neurobiology (2021)
-
Genome-wide signatures of mammalian skin covering evolution
Science China Life Sciences (2021)
-
Primary cilia control cell alignment and patterning in bone development via ceramide-PKCζ-β-catenin signaling
Communications Biology (2020)
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.