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MBC in Press, published online ahead of print September 5, 2007
Mol. Biol. Cell 10.1091/mbc.E07-03-0283

A more recent version of this article appeared on November 1, 2007
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Submitted on March 27, 2007
Revised on July 13, 2007
Accepted on August 24, 2007

Preventing the Degradation of Mps1 at Centrosomes Is Sufficient to Cause Centrosome Reduplication in Human Cells

Christopher Kasbek,*{dagger} Ching-Hui Yang,*{dagger} Adlina Mohd Yusof,* Heather M. Chapman,* Mark Winey,{ddagger} and Harold A. Fisk*

*Department of Molecular Genetics, The Ohio State University, Columbus, OH 43210-1292; {ddagger}Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder, CO 80309

Monitoring Editor: Stephen Doxsey

Supernumerary centrosomes promote the assembly of abnormal mitotic spindles in many human tumors. In human cells overexpression of the Cdk2 partner cyclin A during a prolonged S-phase produces extra centrosomes, called centrosome reduplication. Cdk2 activity protects the Mps1 protein kinase from proteasome-mediated degradation, and we demonstrate here that Mps1 mediates cyclin A-dependent centrosome reduplication. Overexpression of cyclin A or a brief proteasome inhibition increases the centrosomal levels of Mps1, while depletion of Cdk2 leads to the proteasome-dependent loss of Mps1 from centrosomes only. When a Cdk2 phosphorylation site within Mps1 (T468) is mutated to alanine Mps1 cannot accumulate at centrosomes or participate in centrosome duplication. In contrast, phosphomimetic mutations at T468 or deletion of the region surrounding T468 prevent the proteasome-dependent removal of Mps1 from centrosomes in the absence of Cdk2 activity. Moreover, cyclin A-dependent centrosome reduplication requires Mps1, and these stabilizing Mps1 mutations cause centrosome reduplication, bypassing cyclin A. Together, our data demonstrate that the region surrounding T468 contains a motif that regulates the accumulation of Mps1 at centrosomes. We suggest that phosphorylation of T468 attenuates the degradation of Mps1 at centrosomes, and that preventing this degradation is necessary and sufficient to cause centrosome reduplication in human cells.

{dagger}These authors contributed equally to this work.

Address correspondence to: Harold A. Fisk (fisk.13{at}osu.edu)




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