title: A PP1-PP2A phosphatase relay controls mitotic progression.
abstract: The widespread reorganization of cellular architecture in mitosis is achieved through extensive protein phosphorylation, driven by the coordinated activation of a mitotic kinase network and repression of counteracting phosphatases. Phosphatase activity must subsequently be restored to promote mitotic exit. Although Cdc14 phosphatase drives this reversal in budding yeast, protein phosphatase 1 (PP1) and protein phosphatase 2A (PP2A) activities have each been independently linked to mitotic exit control in other eukaryotes. Here we describe a mitotic phosphatase relay in which PP1 reactivation is required for the reactivation of both PP2A-B55 and PP2A-B56 to coordinate mitotic progression and exit in fission yeast. The staged recruitment of PP1 (the Dis2 isoform) to the regulatory subunits of the PP2A-B55 and PP2A-B56 (B55 also known as Pab1; B56 also known as Par1) holoenzymes sequentially activates each phosphatase. The pathway is blocked in early mitosis because the Cdk1-cyclin B kinase (Cdk1 also known as Cdc2) inhibits PP1 activity, but declining cyclin B levels later in mitosis permit PP1 to auto-reactivate. PP1 first reactivates PP2A-B55; this enables PP2A-B55 in turn to promote the reactivation of PP2A-B56 by dephosphorylating a PP1-docking site in PP2A-B56, thereby promoting the recruitment of PP1. PP1 recruitment to human, mitotic PP2A-B56 holoenzymes and the sequences of these conserved PP1-docking motifs suggest that PP1 regulates PP2A-B55 and PP2A-B56 activities in a variety of signalling contexts throughout eukaryotes.
authors.affiliation: Cell Division Group, CRUK Manchester Institute, University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.
authors.forename: Agnes
authors.initials: A
authors.lastname: Grallert
authors.affiliation: Cell Division Group, CRUK Manchester Institute, University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.
authors.forename: Elvan
authors.initials: E
authors.lastname: Boke
authors.affiliation: The Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.
authors.forename: Anja
authors.initials: A
authors.lastname: Hagting
authors.affiliation: Cell Division Group, CRUK Manchester Institute, University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.
authors.forename: Ben
authors.initials: B
authors.lastname: Hodgson
authors.affiliation: Biological Mass Spectrometry, CRUK Manchester Institute, University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Connolly
authors.affiliation: Biological Mass Spectrometry, CRUK Manchester Institute, University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.
authors.forename: John R
authors.initials: JR
authors.lastname: Griffiths
authors.affiliation: Biological Mass Spectrometry, CRUK Manchester Institute, University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.
authors.forename: Duncan L
authors.initials: DL
authors.lastname: Smith
authors.affiliation: The Gurdon Institute, University of Cambridge, Cambridge CB2 1QN, UK.
authors.forename: Jonathon
authors.initials: J
authors.lastname: Pines
authors.affiliation: Cell Division Group, CRUK Manchester Institute, University of Manchester, Wilmslow Road, Manchester, M20 4BX, UK.
authors.forename: Iain M
authors.initials: IM
authors.lastname: Hagan
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001665:Binding Sites; D016203:CDC2 Protein Kinase / Q000378:metabolism; D020090:Chromosome Segregation; D017124:Conserved Sequence; D019926:Cyclin B / Q000378:metabolism; D004789:Enzyme Activation; D006367:HeLa Cells; D020035:Holoenzymes / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008938:Mitosis; D008969:Molecular Sequence Data; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000737:chemistry / Q000378:metabolism*; D021122:Protein Subunits / Q000737:chemistry / Q000378:metabolism; D012568:Schizosaccharomyces / Q000166:cytology* / Q000201:enzymology*; D029702:Schizosaccharomyces pombe Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D019926:Cyclin B; D020035:Holoenzymes; D007527:Isoenzymes; D021122:Protein Subunits; D029702:Schizosaccharomyces pombe Proteins; D016203:CDC2 Protein Kinase; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2