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

• Published in: Molecular cell Vol. 52; no. 3; pp. 393 - 405
• Main Authors: Cundell, Michael J, Bastos, Ricardo Nunes, Zhang, Tongli, Holder, James, Gruneberg, Ulrike, Novak, Bela, Barr, Francis A
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.11.2013; Cell Press
• Subjects: anaphase; Animalia; CDC2 Protein Kinase - metabolism; chromosome segregation; Chromosome Segregation - genetics; Chromosomes - genetics; Cyclin B - metabolism; cyclins; cytokinesis; Cytokinesis - genetics; dephosphorylation; HeLa Cells; Humans; Microtubule-Associated Proteins - genetics; Microtubule-Associated Proteins - metabolism; Mitosis - genetics; Phosphoric Monoester Hydrolases - metabolism; Protein Phosphatase 2 - genetics; Protein Phosphatase 2 - metabolism; Protein Serine-Threonine Kinases - genetics; Protein Serine-Threonine Kinases - metabolism; Protein Tyrosine Phosphatases; separase; Separase - genetics; Separase - metabolism; Signal Transduction - genetics; yeasts
• ISSN: 1097-2765; 1097-4164; 1097-4164
• DOI: 10.1016/j.molcel.2013.09.005

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.