Abstract
The human Polo-like kinase 1 (PLK1) and its functional homologues that are present in other eukaryotes have multiple, crucial roles in meiotic and mitotic cell division1,2. By contrast, the functions of other mammalian Polo family members remain largely unknown. Plk4 is the most structurally divergent Polo family member; it is maximally expressed in actively dividing tissues and is essential for mouse embryonic development3. Here, we identify Plk4 as a key regulator of centriole duplication. Both gain- and loss-of-function experiments demonstrate that Plk4 is required — in cooperation with Cdk2, CP110 and Hs-SAS6 — for the precise reproduction of centrosomes during the cell cycle. These findings provide an attractive explanation for the crucial function of Plk4 in cell proliferation and have implications for the role of Polo kinases in tumorigenesis.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 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
Barr, F. A., Sillje, H. H. & Nigg, E. A. Polo-like kinases and the orchestration of cell division. Nature Rev. Mol. Cell Biol. 5, 429–440 (2004).
Glover, D. M. Polo kinase and progression through M phase in Drosophila: a perspective from the spindle poles. Oncogene 24, 230–237 (2005).
Swallow, C. J., Ko, M. A., Siddiqui, N. U., Hudson, J. W. & Dennis, J. W. Sak/Plk4 and mitotic fidelity. Oncogene 24, 306–312 (2005).
Elia, A. E., Cantley, L. C. & Yaffe, M. B. Proteomic screen finds pSer/pThr-binding domain localizing Plk1 to mitotic substrates. Science 299, 1228–1231 (2003).
Leung, G. C. et al. The Sak polo-box comprises a structural domain sufficient for mitotic subcellular localization. Nature Struct. Biol. 9, 719–724 (2002).
Lowery, D. M., Lim, D. & Yaffe, M. B. Structure and function of Polo-like kinases. Oncogene 24, 248–259 (2005).
Fode, C., Motro, B., Yousefi, S., Heffernan, M. & Dennis, J. W. Sak, a murine protein-serine/threonine kinase that is related to the Drosophila polo kinase and involved in cell proliferation. Proc. Natl Acad. Sci. USA 91, 6388–6392 (1994).
Karn, T. et al. Human Sak related to the Plk/polo family of cell cycle kinases shows high mRNA expression in testis. Oncol. Rep. 4, 505–510 (1997).
Hudson, J. W. et al. Late mitotic failure in mice lacking Sak, a polo-like kinase. Curr. Biol. 11, 441–446 (2001).
Ko, M. A. et al. Plk4 haploinsufficiency causes mitotic infidelity and carcinogenesis. Nature Genet. 37, 883–888 (2005).
Fode, C., Binkert, C. & Dennis, J. W. Constitutive expression of murine Sak-a suppresses cell growth and induces multinucleation. Mol. Cell Biol. 16, 4665–4672 (1996).
Meraldi, P., Honda, R. & Nigg, E. A. Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p53−/− cells. EMBO J. 21, 483–492 (2002).
Nigg, E. A. Centrosome aberrations: cause or consequence of cancer progression? Nature Rev. Cancer 2, 815–825 (2002).
Sluder, G. in Centrosomes in Development and Disease (ed. Erich A. Nigg) 167–189 (Wiley-VCH, Weinheim, 2004).
Balczon, R. et al. Dissociation of centrosome replication events from cycles of DNA synthesis and mitotic division in hydroxyurea-arrested Chinese hamster ovary cells. J. Cell Biol. 130, 105–115 (1995).
Meraldi, P., Lukas, J., Fry, A. M., Bartek, J. & Nigg, E. A. Centrosome duplication in mammalian somatic cells requires E2F and Cdk2- cyclin A. Nature Cell Biol. 1, 88–93 (1999).
Khodjakov, A. & Rieder, C. L. Centrosomes enhance the fidelity of cytokinesis in vertebrates and are required for cell cycle progression. J. Cell Biol. 153, 237–242 (2001).
Salisbury, J. L., Suino, K. M., Busby, R. & Springett, M. Centrin-2 is required for centriole duplication in mammalian cells. Curr. Biol. 12, 1287–1292 (2002).
Lacey, K. R., Jackson, P. K. & Stearns, T. Cyclin-dependent kinase control of centrosome duplication. Proc. Natl Acad. Sci. USA 96, 2817–2822 (1999).
Matsumoto, Y., Hayashi, K. & Nishida, E. Cyclin-dependent kinase 2 (Cdk2) is required for centrosome duplication in mammalian cells. Curr. Biol. 9, 429–432 (1999).
Meraldi, P., Lukas, J., Fry, A. M., Bartek, J. & Nigg, E. A. Centrosome duplication in mammalian somatic cells requires E2F and Cdk2-cyclin A. Nature Cell Biol. 1, 88–93 (1999).
Hinchcliffe, E. H., Li, C., Thompson, E. A., Maller, J. L. & Sluder, G. Requirement of Cdk2-cyclin E activity for repeated centrosome reproduction in Xenopus egg extracts [see comments]. Science 283, 851–854 (1999).
Warnke, S. et al. Polo-like kinase-2 is required for centriole duplication in mammalian cells. Curr. Biol. 14, 1200–1207 (2004).
Matsumoto, Y. & Maller, J. L. Calcium, calmodulin, and CaMKII requirement for initiation of centrosome duplication in Xenopus egg extracts. Science 295, 499–502 (2002).
van Kreeveld, S. & Winey, M. in Centrosomes in Development and Disease (ed. Erich A. Nigg) 43–70 (Wiley-VCH, Weinheim, 2004).
O'Connell, K. F. et al. The C. elegans zyg-1 gene encodes a regulator of centrosome duplication with distinct maternal and paternal roles in the embryo. Cell 105, 547–558 (2001).
Ma, S., Charron, J. & Erikson, R. L. Role of Plk2 (Snk) in mouse development and cell proliferation. Mol. Cell Biol. 23, 6936–6943 (2003).
Bettencourt-Dias, M. et al. Genome-wide survey of protein kinases required for cell cycle progression. Nature 432, 980–987 (2004).
Chen, Z., Indjeian, V. B., McManus, M., Wang, L. & Dynlacht, B. D. CP110, a cell cycle-dependent CDK substrate, regulates centrosome duplication in human cells. Dev. Cell 3, 339–350 (2002).
Dammermann, A. et al. Centriole assembly requires both centriolar and pericentriolar material proteins. Dev. Cell 7, 815–829 (2004).
Leidel, S., Delattre, M., Cerutti, L., Baumer, K. & Gonczy, P. SAS-6 defines a protein family required for centrosome duplication in C. elegans and in human cells. Nature Cell Biol. 7, 115–125 (2005).
Blangy, A. et al. Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell 83, 1159–1169 (1995).
Elbashir, S. M. et al. Duplexes of 21-nucleotide RNAs mediate RNA interference in cultured mammalian cells. Nature 411, 494–498 (2001).
Acknowledgements
We thank M. Bornens (Curie Institute, Paris) for the kind gift of HeLa cells expressing eGFP–centrin; and X. Yan and M. Casenghi for helpful advice and comments. We also thank J. Dennis, M. Ko and C. Swallow (Samuel Lunenfeld Institute, University of Toronto) for open discussions and for sharing results prior to publication. This work was supported by the Max-Planck Society, the Fonds der Chemischen Industrie and the Deutsche Forschungsgemeinschaft (SFB413).
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Information
Supplementary figures S1 and S2 (PDF 388 kb)
Rights and permissions
About this article
Cite this article
Habedanck, R., Stierhof, YD., Wilkinson, C. et al. The Polo kinase Plk4 functions in centriole duplication. Nat Cell Biol 7, 1140–1146 (2005). https://doi.org/10.1038/ncb1320
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ncb1320
This article is cited by
-
Ana1/CEP295 is an essential player in the centrosome maintenance program regulated by Polo kinase and the PCM
EMBO Reports (2024)
-
Prolonged overexpression of PLK4 leads to formation of centriole rosette clusters that are connected via canonical centrosome linker proteins
Scientific Reports (2024)
-
Polo-like kinase 4 inhibitor CFI-400945 inhibits carotid arterial neointima formation but increases atherosclerosis
Cell Death Discovery (2023)
-
Polo-like kinase 4 (Plk4) potentiates anoikis-resistance of p53KO mammary epithelial cells by inducing a hybrid EMT phenotype
Cell Death & Disease (2023)
-
Architectural basis for cylindrical self-assembly governing Plk4-mediated centriole duplication in human cells
Communications Biology (2023)