Autophosphorylation-dependent activation of human Mps1 is required for the spindle checkpoint
- *Department of Pharmacology, University of Texas Southwestern Medical Center, 6001 Forest Park Road, Dallas, TX 75390-9041; and
- †Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390-9041
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Communicated by Melanie H. Cobb, University of Texas Southwestern Medical Center, Dallas, TX, November 5, 2007 (received for review August 6, 2007)
Abstract
The spindle checkpoint ensures the accuracy of chromosome segregation during mitosis. The protein serine/threonine kinase, Mps1, is a critical component of the spindle checkpoint in human cells and regulates the kinetochore localization of key checkpoint proteins. The kinase activity of Mps1 is required for the spindle checkpoint, but how Mps1 is activated during mitosis is unclear. Here, we show that the endogenous Mps1 in mitotic HeLa cells is phosphorylated on T676, a residue in the activation loop. This phosphorylation event on Mps1 is required for its kinase activity in vitro and for spindle checkpoint signaling in vivo. T676 phosphorylation of Mps1 increases during mitosis and can occur through intermolecular/trans autophosphorylation. Induced dimerization of Mps1 is sufficient to activate its kinase activity in cells. We speculate that the kinetochore localization of Mps1 raises its local concentration, leading to its activation during mitosis through more efficient trans autophosphorylation.
Footnotes
- ‡To whom correspondence should be addressed. E-mail: hongtao.yu{at}utsouthwestern.edu
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Author contributions: J.K., Y.C., Y.Z., and H.Y. designed research; J.K., Y.C., and Y.Z. performed research; J.K., Y.C., Y.Z., and H.Y. analyzed data; and J.K. and H.Y. wrote the paper.
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The authors declare no conflict of interest.
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This article contains supporting information online at www.pnas.org/cgi/content/full/0710519105/DC1.
- © 2007 by The National Academy of Sciences of the USA
