The BEG (PP2A-B55/ENSA/Greatwall) Pathway Ensures Cytokinesis follows Chromosome Separation

Summary

Cytokinesis follows separase activation and chromosome segregation. This order is ensured in budding yeast by the mitotic exit network (MEN), where Cdc14p dephosphorylates key conserved Cdk1-substrates exemplified by the anaphase spindle-elongation protein Ase1p. However, in metazoans, MEN and Cdc14 function is not conserved. Instead, the PP2A-B55α/ENSA/Greatwall (BEG) pathway controls the human Ase1p ortholog PRC1. In this pathway, PP2A-B55 inhibition is coupled to Cdk1-cyclin B activity, whereas separase inhibition is maintained by cyclin B concentration. This creates two cyclin B thresholds during mitotic exit. Simulation and experiments using PRC1 as a model substrate show that the first threshold permits separase activation and chromosome segregation, and the second permits PP2A-B55 activation and initiation of cytokinesis. Removal of the ENSA/Greatwall (EG) timer module eliminates this second threshold, as well as associated delay in PRC1 dephosphorylation and initiation of cytokinesis, by uncoupling PP2A-B55 from Cdk1-cyclin B activity. Therefore, temporal order during mitotic exit is promoted by the metazoan BEG pathway.

Graphical Abstract

Highlights

• •

  ENSA/Greatwall (EG) timer module delays cytokinesis until after chromosome separation

• •

  PP2A-B55 and separase activation occur at discrete cyclin B thresholds

• •

  The BEG pathway promotes timely recruitment of PRC1 and Plk1 to anaphase spindles

• •

  PP2A-B55 is functionally equivalent to yeast Cdc14 for Ase1/PRC1 regulation