Microtubule end-on attachment maturation regulates Mps1 association with its kinetochore receptor

Pleuger, Richard; Cozma, Christian; Hohoff, Simone; Denkhaus, Christian; Dudziak, Alexander; Kaschani, Farnusch; Kaiser, Markus; Musacchio, Andrea; Vetter, Ingrid R.; Westermann, Stefan

doi:10.1016/j.cub.2024.03.062

Cited by 6 publications

(2 citation statements)

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“…However, a pool of MPS1 still localizes to microtubule-attached kinetochores either through association with the NDC80 complex or other kinetochore receptors [7,12]. Three recent studies in budding yeast showed that MPS1 binds to regions in the CH-domains of the NDC80 complex that are on the opposite side of the microtubule binding region [16][17][18] and, accordingly, purified budding yeast NDC80 complex was shown to simultaneously bind microtubules and MPS1 in vitro [17]. It has been suggested that this interaction interface is conserved [18]; if so then this mechanism could explain how a population of MPS1 remains at microtubule-attached metazoan kinetochores.…”

Section: Discussionmentioning

confidence: 99%

“…The effect of MPS1 depletion on AAK activation was next examined following depolymerization of microtubules with colchicine since MPS1 becomes enriched at unattached kinetochores via direct interaction with the NDC80 complex [13][14][15][16][17][18]. High levels of AAK T311Ph were observed in control cells, but AAK activation was significantly compromised following depletion of either MPS1 or NDC80, which mis-localized MPS1 from kinetochores (Figures 1C, 1D and S1C).…”

Section: Polar Chromosomes Promote Aak Activation At Centrosomes In A...mentioning

confidence: 99%

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Proximity-based activation of AURORA A by MPS1 potentiates error correction

Leça,

Barbosa,

Rodriguez-Calado

et al. 2024

Preprint

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SUMMARYFaithfull cell division relies on mitotic chromosomes becoming bioriented with each pair of sister kinetochores bound to microtubules oriented toward opposing spindle poles. Erroneous kinetochore-microtubule attachments often form during early mitosis, but are destabilized through the phosphorylation of outer kinetochore proteins by centromeric AURORA B kinase (ABK) and centrosomal AURORA A kinase (AAK), thus allowing for re-establishment of attachments until biorientation is achieved. MPS1-mediated phosphorylation of NDC80 has also been shown to directly weaken the kinetochore-microtubule interface in yeast. In human cells, MPS1 has been proposed to transiently accumulate at end-on attached kinetochores and phosphorylate SKA3 to promote microtubule release. Whether MPS1 directly targets NDC80 and/or promotes the activity of AURORA kinases in metazoans remains unclear. Here, we report a novel mechanism involving communication between kinetochores and centrosomes, wherein MPS1 acts upstream of AAK to promote error correction. MPS1 on pole-proximal kinetochores phosphorylates the C-lobe of AAK thereby increasing its activation at centrosomes. This proximity-based activation ensures the establishment of a robust AAK activity gradient that locally destabilizes mal-oriented kinetochores near spindle poles. Accordingly, MPS1 depletion fromDrosophilacells causes severe chromosome misalignment and erroneous kinetochore-microtubule attachments, which can be rescued by tethering either MPS1 or constitutively active AAK mutants to centrosomes. Proximity-based activation of AAK by MPS1 also occurs in human cells to promote AAK-mediated phosphorylation of the NDC80 N-terminal tail. These findings uncover an MPS1-AAK cross-talk that is required for efficient error correction, showcasing the ability of kinetochores to modulate centrosome outputs to ensure proper chromosome segregation.

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