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

Area of Science:

• Cell Biology
• Molecular Biology
• Genetics

Background:

• Faithful cell division requires accurate chromosome biorientation, where sister kinetochores attach to microtubules from opposite poles.
• Errors in kinetochore-microtubule attachments are corrected by kinases like AURORA B (ABK) and AURORA A (AAK).
• The role of MPS1 in error correction and its interaction with AURORA kinases in metazoans remained unclear.

Purpose of the Study:

• To elucidate the novel mechanism of MPS1-mediated error correction in kinetochore-microtubule attachments.
• To investigate the crosstalk between MPS1 and AURORA A kinase (AAK) in metazoans.
• To understand how kinetochores communicate with centrosomes to ensure proper chromosome segregation.

Main Methods:

• Investigated MPS1's role in kinetochore-microtubule attachment error correction in Drosophila and human cells.
• Utilized proximity-based activation assays and genetic manipulations (MPS1 depletion, AAK mutants).
• Analyzed chromosome misalignment and kinetochore-microtubule attachment errors.

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 caused chromosome misalignment, rescuable by tethering MPS1 or active AAK to centrosomes.
• MPS1-dependent AAK activation and NDC80 phosphorylation by AAK were observed in human cells.

Conclusions:

• Discovered a novel MPS1-AAK crosstalk mechanism essential for efficient error correction during mitosis.
• Kinetochores can modulate centrosome activity to ensure accurate chromosome segregation.
• This proximity-based activation of AAK by MPS1 is conserved in human cells and crucial for proper cell division.