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Abstract:
The catalytic activity of the MPS1 kinase is crucial for the spindle
assembly checkpoint and for chromosome biorientation on the mitotic
spindle. We report that the small molecule reversine is a potent mitotic
inhibitor of MPS1. Reversine inhibits the spindle assembly checkpoint in
a dose-dependent manner. Its addition to mitotic HeLa cells causes the
ejection of Mad1 and the ROD-ZWILCH-ZW10 complex, both of which are
important for the spindle checkpoint, from unattached kinetochores. By
using reversine, we also demonstrate that MPS1 is required for the
correction of improper chromosome-microtubule attachments. We provide
evidence that MPS1 acts downstream from the AURORA B kinase, another
crucial component of the error correction pathway. Our experiments
describe a very useful tool to interfere with MPS1 activity in human
cells. They also shed light on the relationship between the error
correction pathway and the spindle checkpoint and suggest that these
processes are coregulated and are likely to share at least a subset of
their catalytic machinery.
