Mps1 directs the assembly of Cdc20 inhibitory complexes during interphase and mitosis to control M phase timing and spindle checkpoint signaling

Maciejowski, John; George, Kelly A.; Terret, Marie-Émilie; Zhang, Chao; Shokat, Kevan M.; Jallepalli, Prasad V.

doi:10.1083/jcb.201001050

Cited by 173 publications

(279 citation statements)

References 62 publications

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“…We next determined if the Sgo intermediate for CPC recruitment was also affected by Mps1 inhibition. While Sgo2 levels were only slightly reduced, Sgo1 centromere localization was highly sensitive to Mps1 inhibition, with Sgo1 localizing over the chromosomal arms instead of to the centromere, much like we observed for Aurora B (Fig 3C; supplementary Fig S3A-C online) [14].…”

Section: Mps1 Allows Rapid Aurora B Recruitment To Centromeressupporting

confidence: 71%

“…Whereas expression of wt-INCENP did not improve alignment under these conditions, we observed a striking improvement when Aurora B localization to centromeres was restored by CB-INCENP expression (Fig 4A,B; supplementary Fig S4B online). Only mild chromosome misalignments persisted, which might reflect the Aurora B-independent role of Mps1 in chromosome biorientation [11,[13][14][15]28].…”

Section: Mps1 Recruits Aurora B To Stimulate Error Correctionmentioning

confidence: 98%

“…While Mps1 activity was dispensable for Haspin-dependent H3-T3ph (supplementary Fig S3A,D online), it was indeed required for Bub1 kinetochore localization, and H2A-T120ph (Fig 3A,B; supplementary Fig S3A online) in mitotic cells [14]. We next determined if the Sgo intermediate for CPC recruitment was also affected by Mps1 inhibition.…”

Section: Mps1 Allows Rapid Aurora B Recruitment To Centromeresmentioning

confidence: 99%

“…The error correction function of Mps1 has been attributed to the phosphorylation of the CPC subunit Borealin that is required for Aurora B activation [10]. However, Aurora B-independent mechanisms have also been proposed [11,[13][14][15]. Therefore it is unclear exactly how Mps1 promotes error correction.…”

Section: Introductionmentioning

confidence: 99%

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Mps1 promotes rapid centromere accumulation of Aurora B

et al. 2012

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Aurora B localization to mitotic centromeres, which is required for proper chromosome alignment during mitosis, relies on Haspin‐dependent histone H3 phosphorylation and on Bub1‐dependent histone H2A phosphorylation—which interacts with Borealin through a Shugoshin (Sgo) intermediate. We demonstrate that Mps1 stimulates the latter recruitment axis. Mps1 activity enhances H2A‐T120ph and is critical for Sgo1 recruitment to centromeres, thereby promoting Aurora B centromere recruitment in early mitosis. Importantly, chromosome biorientation defects caused by Mps1 inhibition are improved by restoring Aurora B centromere recruitment. As Mps1 kinetochore localization reciprocally depends on Aurora B, we propose that this Aurora B‐Mps1 recruitment circuitry cooperates with the Aurora B‐Haspin feedback loop to ensure rapid centromere accumulation of Aurora B at the onset of mitosis.

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Section: Mps1 Allows Rapid Aurora B Recruitment To Centromeressupporting

confidence: 71%

Section: Mps1 Recruits Aurora B To Stimulate Error Correctionmentioning

confidence: 98%

Section: Mps1 Allows Rapid Aurora B Recruitment To Centromeresmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Mps1 promotes rapid centromere accumulation of Aurora B

et al. 2012

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“…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.…”

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confidence: 99%

Characterization of novel MPS1 inhibitors with preclinical anticancer activity

et al. 2013

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,5,6,11,12,13 Monopolar spindle 1 (MPS1), a mitotic kinase that is overexpressed in several human cancers, contributes to the alignment of chromosomes to the metaphase plate as well as to the execution of the spindle assembly checkpoint (SAC). Here, we report the identification and functional characterization of three novel inhibitors of MPS1 of two independent structural classes, N-(4-{2- [(2-cyanophenyl) and N-cyclopropyl-4-{8-(isobutylamino)imidazo[1,2-a]pyrazin-3-yl}benzamide (Mps-BAY2b) (two imidazopyrazines). By selectively inactivating MPS1, these small inhibitors can arrest the proliferation of cancer cells, causing their polyploidization and/or their demise. Cancer cells treated with Mps-BAY1 or Mps-BAY2a manifested multiple signs of mitotic perturbation including inefficient chromosomal congression during metaphase, unscheduled SAC inactivation and severe anaphase defects. Videomicroscopic cell fate profiling of histone 2B-green fluorescent protein-expressing cells revealed the capacity of MPS1 inhibitors to subvert the correct timing of mitosis as they induce a premature anaphase entry in the context of misaligned metaphase plates. Hence, in the presence of MPS1 inhibitors, cells either divided in a bipolar (but often asymmetric) manner or entered one or more rounds of abortive mitoses, generating gross aneuploidy and polyploidy, respectively. In both cases, cells ultimately succumbed to the mitotic catastrophe-induced activation of the mitochondrial pathway of apoptosis. Of note, low doses of MPS1 inhibitors and paclitaxel (a microtubular poison) synergized at increasing the frequency of chromosome misalignments and missegregations in the context of SAC inactivation. This resulted in massive polyploidization followed by the activation of mitotic catastrophe. A synergistic interaction between paclitaxel and MPS1 inhibitors could also be demonstrated in vivo, as the combination of these agents efficiently reduced the growth of tumor xenografts and exerted superior antineoplastic effects compared with either compound employed alone. Altogether, these results suggest that MPS1 inhibitors may exert robust anticancer activity, either as standalone therapeutic interventions or combined with microtubule-targeting chemicals. Mitosis is a sophisticated process that ensures the faithful inheritance of the genetic material by the cellular progeny while preventing aneuploidy and chromosomal instability (CIN), two established hallmarks of cancer. 1-3 A set of protein kinases that are collectively known as mitotic kinases, including Aurora kinases (AURKs), mitotic cyclin-dependent kinases (CDKs), Polo-like kinases and monopolar spindle 1 (MPS1), regulates and coordinates multiple aspects of chromosome segregation during mitosis. 4 MPS1 (also known as TTK) is a dual-specificity kinase (meaning that it phosphorylates both serine/threonine and tyrosine residues) with an established role in the proper alignment and orientation of chromosomes on the metaphase plate. 5 MPS1 is a core component of the spindle assembl...

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From the Nuclear Pore to the Fibrous Corona: A MAD Journey to Preserve Genome Stability

Cunha-Silva

Conde

2020

BioEssays

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The relationship between kinetochores and nuclear pore complexes (NPCs) is intimate but poorly understood. Several NPC components and associated proteins are relocated to mitotic kinetochores to assist in different activities that ensure faithful chromosome segregation. Such is the case of the Mad1-c-Mad2 complex, the catalytic core of the spindle assembly checkpoint (SAC), a surveillance pathway that delays anaphase until all kinetochores are attached to spindle microtubules. Mad1-c-Mad2 is recruited to discrete domains of unattached kinetochores from where it promotes the rate-limiting step in the assembly of anaphase-inhibitory complexes. SAC proficiency further requires Mad1-c-Mad2 to be anchored at NPCs during interphase. However, the mechanistic relevance of this arrangement for SAC function remains ill-defined. Recent studies uncover the molecular underpinnings that coordinate the release of Mad1-c-Mad2 from NPCs with its prompt recruitment to kinetochores. Here, current knowledge on Mad1-c-Mad2 function and spatiotemporal regulation is reviewed and the critical questions that remain unanswered are highlighted.

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Mps1 directs the assembly of Cdc20 inhibitory complexes during interphase and mitosis to control M phase timing and spindle checkpoint signaling

Abstract: Cdc20 and Mad2 or Bub1 don’t come together in Mps1-null cells, resulting in a dramatic acceleration of anaphase onset (see also related papers by Hewitt et al. and Santaguida et al. in this issue).

Cited by 173 publications

References 62 publications

Mps1 promotes rapid centromere accumulation of Aurora B

Mps1 promotes rapid centromere accumulation of Aurora B

Characterization of novel MPS1 inhibitors with preclinical anticancer activity

From the Nuclear Pore to the Fibrous Corona: A MAD Journey to Preserve Genome Stability

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