Proteomics

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


ABSTRACT: Faithfull cell division relies on mitotic chromosomes becoming bioriented with each pair of sister kinetochores bound to microtubules from 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 from Drosophila cells 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.

INSTRUMENT(S): Orbitrap Exploris 480

ORGANISM(S): Drosophila Melanogaster (fruit Fly)

SUBMITTER: Tanja Bange  

LAB HEAD: Tanja Bange

PROVIDER: PXD056173 | Pride | 2025-04-03

REPOSITORIES: Pride

Dataset's files

Source:
Action DRS
20210719_TB_SA_N10.raw Raw
20210719_TB_SA_N10_20210802091907.raw Raw
20210719_TB_SA_N11.raw Raw
20210719_TB_SA_N11_20210802103912.raw Raw
20210719_TB_SA_N12.raw Raw
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