Chromosome segregation errors: a double-edged sword - TI Pharma

Non-MCC members, but important mitotic checkpoint proteins, are the kinases Bub1 and Mps1 (Mps1
will be discussed in more detail in section 2.4). Although conflicting data have been published on the
role of Bub1 kinase activity in checkpoint activation 112-114 , the presence of Bub1 protein is required to
delay anaphase onset in the presence of unattached kinetochores 74,115 . In contrast to this, Mps1 kinase
activity is absolutely essential for mitotic checkpoint function 116-119 . It was recently shown that Mps1
in both yeast and human cells phosphorylates Knl1 and thereby promotes Bub3 and Bub1 binding to
kinetochores 120-122 . Moreover, it has been found to be required for localization of Mad1 and Mad2
to unattached kinetochores and is therefore thought to be upstream of MCC formation 118,119,123-125 .
When all kinetochores are attached, the mitotic checkpoint is silenced and the cell exits mitosis 70 .
Several mechanisms for mitotic checkpoint silencing have been described, one of which is dyneindependent
kinetochore-stripping of checkpoint proteins 48,126 . By walking to the minus-end of the
kinetochore-MTs and simultaneously binding checkpoint proteins, dynein can reduce MCC formation.
Secondly, phosphatases could help in silencing the checkpoint by counteracting phosphorylation
events 127 . Thirdly, p31 comet -dependent inactivation of the checkpoint by structural mimicry and direct
binding to C-MAD2 has been shown to be important as well 128-130 . p31 comet is thought to silence the
checkpoint both dependently 131 and independently 132-134 of its kinetochore localization. Finally, Cdc20
ubiquitination could also contribute to MCC disassembly 132,135 , although this remains controversial
since Cdc20 ubiquitination has also been described to aid in keeping APC/C activity low 136 .
2.4 Mps1 (Monopolar spindle 1)
Originally identified as a kinase essential for spindle pole body duplication in budding yeast 137-139 , Mps1
kinase was soon after found to be important for mitotic checkpoint signaling as well 140,141 . Although its
role in mitotic checkpoint functioning has been found to be conserved in higher eukaryotes 124,142,143 , the
effect of Mps1 on spindle pole duplication remains controversial. In budding yeast, Mps1 temperaturesensitive
mutants clearly result in monopolar spindle formation 137,144 . In line with this, Mps1 has
been shown to localize to centrosomes 145,146 and overexpression of Mps1 in human and mouse
cells resulted in overduplication of centrosomes 145-147 . However, other studies could not reproduce
these effects of Mps1 on centrosome duplication as well as its centrosome localization 119,143,148 .
Mps1 localizes to outer kinetochores via its N-terminus 124,148 and its protein levels are specifically
increased during G2 and mitosis 142,143,149-151 . In both budding yeast and human cells, Mps1 was found
to be targeted for proteasomal degradation by the APC/C 152,153 . These data all correlate with a function
for Mps1 specifically during mitosis. Indeed, on top of a role in the mitotic checkpoint 117,118,123 ,
Mps1 kinase activity has been implicated in chromosome alignment as well 116 . By phosphorylating
Borealin, Mps1 indirectly stimulates Aurora B kinase activity at the kinetochore, resulting in correction
of erroneous kinetochore-MT attachments 116 . Interestingly, Aurora B has also been implicated in
targeting Mps1 to the kinetochore in prophase 154 , which suggests that these two kinases together
influence error-correction and possibly also mitotic checkpoint activity 154,155 . Depletion of the outer
kinetochore proteins Prp4 156 or the Ndc80 complex member Hec1 125,148,154 affects Mps1 localization
to the kinetochores, which indicates that these proteins might function as its kinetochore receptors.
Mps1 exchanges very rapidly at the kinetochores 157 and has been shown to promote MCC formation
already in interphase, when kinetochores are not fully matured 119 . This indicates that Mps1
kinetochore localization might not be required for full checkpoint activity. However, stable targeting of
Mps1 to the kinetochore has been shown to result in sustained mitotic checkpoint activity 158 , which
shows that Mps1 at kinetochores most likely does play a role in acquiring checkpoint activity and that
release from kinetochores is necessary to exit mitosis 158 .
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General Introduction 1