A role for IκB kinase 2 in bipolar spindle assembly

doi:10.1073/pnas.0706493104

A role for IκB kinase 2 in bipolar spindle assembly

*Genomics Institute of the Novartis Research Foundation, 10675 John J. Hopkins Drive, San Diego, CA 92121;
^†Institute for Molecular and Cell Biology, 61 Biopolis Drive, Proteos, 3-02B, Singapore Singapore 138673;
^‡Department of Physiology and Biophysics, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, NY 10461; and
^§The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037

Edited by Peter K. Vogt, The Scripps Research Institute, La Jolla, CA, and approved September 4, 2007 (received for review July 11, 2007)

Abstract

IκB kinase 2 (IKK2 or IKKβ) is a component of the IKK complex that coordinates the cellular response to a diverse set of extracellular stimuli, including cytokines, microbial infection, and stress. In response to an external stimulus, the complex is activated, resulting in the phosphorylation and subsequent proteasome-mediated degradation of IκB proteins. This event triggers the nuclear import of the NF-κB transcription factor, which activates the transcription of genes that regulate a variety of fundamental biological processes, including immune response, cell survival, and development. Here, we define an essential role for IKK2 in normal mitotic progression and the maintenance of spindle bipolarity. Chemical and genetic perturbation of IKK2 promotes the formation of multipolar spindles and chromosome missegregation. Depletion of IKK2 results in the deregulation of Aurora A protein stability and coincident hyperactivation of a putative Aurora A substrate, the mitotic motor KIF11. These data support a function for IKK2 as an antagonist of Aurora A signaling during mitosis. Additionally, our results indicate a direct role for IKK2 in the maintenance of genome stability and underscore the potential for oncogenic consequences in targeting this kinase for therapeutic intervention.

Footnotes

^¶To whom correspondence should be sent at the present address:
Infectious and Inflammatory Disease Center, Burnham Institute for Medical Research, 10901 North Torrey Pines Road, La Jolla, CA 92037.
E-mail: schanda{at}burnham.org
Author contributions: J.T.I., T.J.M., M.A.G.-F., D.J.S., V.T., and S.K.C. designed research; J.T.I., T.J.M., P.D.D., H.T., D.X., M.A.G.-F., and V.T. performed research; L.J.M. and I.M.V. contributed new reagents/analytic tools; J.T.I., T.J.M., Y.Z., D.R.R., V.T., and S.K.C. analyzed data; and J.T.I. and S.K.C. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0706493104/DC1.
Abbreviations:

IKK,

IκB kinase;

βTRCP,

β-transducin repeat-containing protein;

MEF,

mouse embryonic fibroblast.