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A more recent version of this article appeared on April 1, 2003
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Submitted on May 10, 2002
Revised on October 22, 2002
Accepted on December 9, 2002
1 Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111
2 Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111 (present address: Department of Oncology, University of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, T6G 1Z2)
3 Department of Oncology, DNAX Research Institute, Palo Alto, California 94304-1104
* Corresponding author. E-mail address: tj_yen{at}fccc.edu.
We have determined that the previously identified dual-specificity protein kinase, TTK, is the human ortholog of the yeast MPS1 kinase. Yeast MPS1 (monopolar spindle) is required for spindle pole duplication and the spindle checkpoint. Consistent with the recently identified vertebrate MPS1 homologs, we found that hMPS1 is localized to centrosomes and kinetochores. In addition, hMPS1 is part of a growing list of kinetochore proteins that are localized to nuclear pores. hMPS1 is required by cells to arrest in mitosis in response to spindle defects and kinetochore defects resulting from the loss of the kinesin-like protein, CENP-E. The pattern of kinetochore localization of hMPS1 in CENP-E defective cells suggests that the interaction with the kinetochore is sensitive to microtubule occupancy rather than kinetochore tension. hMPS1 is required for MAD1, MAD2 but not hBUB1, hBUBR1 and hROD to bind to kinetochores. We localized the kinetochore targeting domain in hMPS1 and found that it can abrogate the mitotic checkpoint in a dominant negative fashion. Lastly, hMPS1 was found to associate with the Anaphase Promoting Complex (APC) thus raising the possibility that its checkpoint functions extend beyond the kinetochore.
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