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

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• Faithful cell division requires correct kinetochore-microtubule attachments for chromosome biorientation.
• Aurora B kinase (ABK) and Aurora A kinase (AAK) destabilize erroneous attachments via phosphorylation.
• The role of MPS1 in directly targeting NDC80 or activating Aurora kinases in metazoans is unclear.

Purpose of the Study:

• To elucidate the novel mechanism of MPS1 acting upstream of AAK in mitotic error correction.
• To investigate the crosstalk between kinetochores and centrosomes involving MPS1 and AAK.
• To determine if MPS1 modulates centrosome activity to ensure proper chromosome segregation.

Main Methods:

• Studied MPS1's role in activating AAK at centrosomes in *Drosophila* and human cells.
• Investigated MPS1-mediated phosphorylation of AAK's C-lobe.
• Assessed chromosome alignment and kinetochore-microtubule attachments upon MPS1 depletion or tethering of MPS1/AAK mutants.

Main Results:

• MPS1 on pole-proximal kinetochores phosphorylates and activates AAK at centrosomes, creating an activity gradient.
• This gradient destabilizes mal-oriented kinetochores near spindle poles, promoting error correction.
• MPS1 depletion in *Drosophila* causes chromosome misalignment; rescue observed with MPS1 or active AAK at centrosomes. Similar MPS1-AAK crosstalk occurs in human cells, phosphorylating NDC80.

Conclusions:

• Uncovered a novel MPS1-AAK signaling pathway essential for efficient mitotic error correction.
• Demonstrated that kinetochores can modulate centrosome outputs to ensure accurate chromosome segregation.
• This crosstalk mechanism is conserved in both *Drosophila* and human cells.