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Vol. 14, Issue 4, 1638-1651, April 2003
§
and
*Fox Chase Cancer Center, Philadelphia, Pennsylvania
19111; and We have determined that the previously identified
dual-specificity protein kinase TTK is the human orthologue 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 homologues, 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 their
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 manner. Last, hMPS1 was found to
associate with the anaphase promoting complex, thus raising the
possibility that its checkpoint functions extend beyond the kinetochore.
Department of Oncology, DNAX Research
Institute, Palo Alto, California 94304-1104
Online
version of this article contains supplemental figures. The online
version is available at www.molbiolcell.org.
Corresponding author. E-mail address:
tj_yen{at}fccc.edu.
The first two authors contributed equally to this work.
§
Present address: Department of Oncology, University
of Alberta, Cross Cancer Institute, 11560 University Avenue, Edmonton, Alberta, Canada T6G 1Z2.
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