Leça, N., Barbosa, F., Rodriguez-Calado, S., Esposito Verza, A., Moura, M., Pedroso, P.D., Pinto, I., Artes, E., Bange, T., Sunkel, C.E., Barisic, M., Maresca, T.J., Conde, C. (2025). Proximity-based activation of AURORA A by MPS1 potentiates error correction.  Curr. Biol. 35(8): 1935--1947.e8.

FBrf0262135

Research paper

Faithful 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.[1][,][2][,][3][,][4][,][5][,][6][,][7][,][8][,][9] MPS1-mediated phosphorylation of NDC80 has also been shown to directly weaken the kinetochore-microtubule interface in yeast.[10] In human cells, MPS1 has been proposed to transiently accumulate at end-on attached kinetochores[11] and phosphorylate SKA3 to promote microtubule release.[12] 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 crosstalk that is required for efficient error correction, showcasing the ability of kinetochores to modulate centrosome outputs to ensure proper chromosome segregation.

PMC12014372 (PMC) (EuropePMC)