title: The BEG (PP2A-B55/ENSA/Greatwall) pathway ensures cytokinesis follows chromosome separation.
abstract: 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.
authors.affiliation: University of Oxford, Department of Biochemistry, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cundell
authors.forename: Ricardo Nunes
authors.initials: RN
authors.lastname: Bastos
authors.forename: Tongli
authors.initials: T
authors.lastname: Zhang
authors.forename: James
authors.initials: J
authors.lastname: Holder
authors.forename: Ulrike
authors.initials: U
authors.lastname: Gruneberg
authors.forename: Bela
authors.initials: B
authors.lastname: Novak
authors.forename: Francis A
authors.initials: FA
authors.lastname: Barr
mesh_terms: D016203:CDC2 Protein Kinase / Q000378:metabolism; D020090:Chromosome Segregation / Q000235:genetics*; D002875:Chromosomes / Q000235:genetics; D019926:Cyclin B / Q000378:metabolism; D048749:Cytokinesis / Q000235:genetics*; D006367:HeLa Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008938:Mitosis / Q000235:genetics; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases; D064247:Separase / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D019926:Cyclin B; D008869:Microtubule-Associated Proteins; C512974:PPP2R2A protein, human; C555237:MASTL protein, human; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; C517189:PPP2CA protein, human; D054648:Protein Phosphatase 2; D010744:Phosphoric Monoester Hydrolases; C120902:CDC14A protein, human; D017027:Protein Tyrosine Phosphatases; D064247:Separase