hide
Free keywords:
-
Abstract:
Mps1 is an essential component of the spindle assembly checkpoint. In
this study, we describe a novel Mps1 inhibitor, AZ3146, and use it to
probe the role of Mps1's catalytic activity during mitosis. When Mps1 is
inhibited before mitotic entry, subsequent recruitment of Mad1 and Mad2
to kinetochores is abolished. However, if Mps1 is inhibited after
mitotic entry, the Mad1-C-Mad2 core complex remains kinetochore bound,
but O-Mad2 is not recruited to the core. Although inhibiting Mps1 also
interferes with chromosome alignment, we see no obvious effect on aurora
B activity. In contrast, kinetochore recruitment of centromere protein E
(CENP-E), a kinesin-related motor protein, is severely impaired.
Strikingly, inhibition of Mps1 significantly increases its own abundance
at kinetochores. Furthermore, we show that Mps1 can dimerize and
transphosphorylate in cells. We propose a model whereby Mps1
transphosphorylation results in its release from kinetochores, thus
facilitating recruitment of O-Mad2 and CENP-E and thereby simultaneously
promoting checkpoint signaling and chromosome congression.
