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A functional genomic screen identifies a role for TAO1 kinase in spindle-checkpoint signalling

Nature Cell Biology volume 9, pages 556–564 (2007)Cite this article

Abstract

Defects in chromosome–microtubule attachment trigger spindle-checkpoint activation and delay mitotic progression1,2. How microtubule attachment is sensed and integrated into the steps of checkpoint-signal amplification is poorly understood. In a functional genomic screen targeting human kinases and phosphatases, we identified a microtubule affinity-regulating kinase kinase, TAO1 (also known as MARKK) as an important regulator of mitotic progression, required for both chromosome congression and checkpoint-induced anaphase delay. TAO1 interacts with the checkpoint kinase BubR1 and promotes enrichment of the checkpoint protein Mad2 at sites of defective attachment, providing evidence for a regulatory step that precedes the proposed Mad2–Mad1 dependent checkpoint-signal amplification step3. We propose that the dual functions of TAO1 in regulating microtubule dynamics and checkpoint signalling may help to coordinate the establishment and monitoring of correct congression of chromosomes, thereby protecting genomic stability in human cells.

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Figure 1: shRNA screen identifies new candidate spindle-checkpoint kinases.
Figure 2: TAO1 kinase activity is elevated in mitosis and required for its checkpoint function.
Figure 3: TAO1-depleted cells display precocious anaphase onset and chromosome missegregation.
Figure 4: TAO1 kinase regulates chromosome congression in an Aurora-B independent manner.
Figure 5: TAO1 recruits Mad2 to unattached kinetochores and interacts with BubR1.

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Acknowledgements

We thank H. Yu, S. Taylor, W. Earnshaw, H. Kung, N. Gray, D.Allis and J. Jin for gifts of reagents, M. Vidal for providing access to their BioRobot platform, S. Lyman and R. King for communicating unpublished results and assistance with the development of the taxol screening assay, C. Shamu for access to the ICCB-Longwood screening facilities, and members of the Elledge lab for their critical reading of the manuscript. F.S. is a fellow of the Helen Hay Whitney Foundation. M.S. is supported by a post-doctoral fellowship from the American Cancer Society. The siRNA and ICCB-Longwood resources used were funded in part by a National Cancer Institute grant CA78048 (Tim Mitchison). This work was supported by grants from the National Institutes of Health (NIH) and Department of Defense to S.J.E., by grants from the NIH to J.W.H and to P.K.S. S.J.E. and G.J.H. are investigators with the Howard Hughes Medical Institute.

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Author notes

  1. Viji M. Draviam and Frank Stegmeier: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biology, Massachusetts Institute of Technology, Cambridge, 02139, MA, USA

    Viji M. Draviam & Peter K. Sorger

  2. Department of Systems Biology, Harvard Medical School, Boston, 02115, MA, USA

    Viji M. Draviam & Peter K. Sorger

  3. Department of Genetics, Howard Hughes Medical Institute, Harvard Partners Center for Genetics and Genomics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, 02115, MA, USA

    Frank Stegmeier, Anthony Liang & Stephen J. Elledge

  4. Department of Pathology, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, 02115, MA, USA

    Grzegorz Nalepa, Mathew E. Sowa, Jing Chen & J. Wade Harper

  5. Cold Spring Harbor Laboratory, Watson School of Biological Sciences, 1 Bungtown Road, Cold Spring Harbor, 11724, NY, USA

    Gregory J. Hannon

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Draviam, V., Stegmeier, F., Nalepa, G. et al. A functional genomic screen identifies a role for TAO1 kinase in spindle-checkpoint signalling. Nat Cell Biol 9, 556–564 (2007). https://doi.org/10.1038/ncb1569

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