Sustained Mps1 activity is required in mitosis to recruit O-Mad2 to the Mad1–C-Mad2 core complex

Abstract

To satisfy the mitotic checkpoint and drive chromosome congression, the Mps1 kinase lets go of kinetochores by phosphorylating itself in trans (see also related papers by Maciejowski et al. and Santaguida et al. in this issue).

Characterization of novel MPS1 inhibitors with preclinical anticancer activity

“…Even in the absence of SAC activators, both classes of MPS1 inhibitors markedly increased the rate of chromosome misalignments resulting from erroneous MT-KT attachments and promoted a premature anaphase entry (i.e., before the formation of a correct equatorial metaphase plate). These results are in line with previous findings obtained with other MPS1-specific inhibitors, [8][9][10]12,15,47 upon MPS1 depletion 16,24 or following the conditional knockout of TTK, 11 confirming the central implication of this mitotic kinase in SAC function and chromosome congression. Upon exposure to MPS1 inhibitors, colorectal carcinoma cells displayed severely abnormal anaphases, and, as they progressed in mitosis, they underwent two alternative catastrophic fates: (i) they divided in a bipolar (often asymmetrical) manner, generating two aneuploid cells that most often died in the following interphase, or (ii) they failed to complete cytokinesis and hence became hyperploid.…”

“…10,15,47 Conversely, it has been reported that the absence of MPS1 favors cytokinesis failure and polyploidy. 8,16,48 This discrepancy may reflect differences in the experimental models or the strategy used for MPS1 inhibition. 7,11 Indeed, as the inactivation of 490% of MPS1 is required for the induction of mitotic abnormalities, 7,11 in some studies MPS1 inhibition may have been partial, yielding suboptimal effects on mitosis.…”

“…6 Although the precise contribution of MPS1 to SAC functions remains elusive, 7 accumulating evidence suggests that MPS1 facilitates SAC activation by promoting the recruitment of SAC components to unoccupied KTs. [8][9][10][11][12][13][14][15] MPS1 has also been implicated in the so-called 'error correction mechanism', 16 a poorly characterized process that resolves the erroneous KT-MT attachments that frequently form in the early steps of mitosis. 17,18 According to current models, AURKB, one component of the chromosomal passenger complex (reviewed by Ruchaud et al 19 ), catalyzes this process by destabilizing incorrect attachments, hence generating free KTs that activate the SAC.…”

Dynamic localization of Mps1 kinase to kinetochores is essential for accurate spindle microtubule attachment

“…In budding yeast mitosis, Mps1 regulates mitotic chromosome alignment by promoting kinetochore biorientation independently of Ipl1 (aurora B in humans) (31), but in budding yeast meiosis Mps1 must collaborate with Ipl1 to mediate meiotic kinetochore biorientation (32). In humans, Mps1 regulates chromosomal alignment by modulating aurora B kinase activity (33), but recent chemical biology studies show that Mps1 kinase activity is important for proper chromosome alignment and segregation, independently of aurora B (22,(34)(35)(36). Therefore whether Mps1 regulates chromosome alignment through modulation of aurora B kinase activity is still under debate (37).…”

The Renaissance or the cuckoo clock

“…It is thought that the closed conformation can catalyse the binding of the open form to Cdc20, and once bound the open form is converted to the closed form. Thus, a population of closed Mad2 stably bound to unattached kinetochores through the Mad1 protein continually promotes the binding of open Mad2 to Cdc20 by a mechanism that requires the Mps1 kinase [82]. The Mad2 -Cdc20 complex subsequently binds to the Mad3/BubR1-Bub3 complex [83,84], which prevents Cdc20 forming the substrate receptor on the APC/C.…”