title: Protein phosphatase 1 is essential for Greatwall inactivation at mitotic exit.
abstract: Entry into mitosis is mediated by the phosphorylation of key cell cycle regulators by cyclin-dependent kinase 1 (Cdk1). In Xenopus embryos, the M-phase-promoting activity of Cdk1 is antagonized by protein phosphatase PP2A-B55. Hence, to ensure robust cell cycle transitions, Cdk1 and PP2A-B55 must be regulated so that their activities are mutually exclusive. The mechanism underlying PP2A-B55 inactivation at mitotic entry is well understood: Cdk1-activated Greatwall (Gwl) kinase phosphorylates Ensa/Arpp19, thereby enabling them to bind to and inhibit PP2A-B55. However, the re-activation of PP2A-B55 during mitotic exit, which is essential for cell cycle progression, is less well understood. Here, we identify protein phosphatase PP1 as an essential component of the PP2A-B55 re-activation pathway in Xenopus embryo extracts. PP1 initiates the re-activation of PP2A-B55 by dephosphorylating Gwl. We provide evidence that PP1 targets the auto-phosphorylation site of Gwl, resulting in efficient Gwl inactivation. This step is necessary to facilitate subsequent complete dephosphorylation of Gwl by PP2A-B55. Thus, by identifying PP1 as the phosphatase initiating Gwl inactivation, our study provides the molecular explanation for how Cdk1 inactivation is coupled to PP2A-B55 re-activation at mitotic exit.
authors.affiliation: Department of Molecular Genetics, University of Konstanz, Konstanz, Germany Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Heim
authors.affiliation: Department of Molecular Genetics, University of Konstanz, Konstanz, Germany.
authors.forename: Anja
authors.initials: A
authors.lastname: Konietzny
authors.affiliation: Department of Molecular Genetics, University of Konstanz, Konstanz, Germany Konstanz Research School Chemical Biology, University of Konstanz, Konstanz, Germany Thomas.U.Mayer@uni-konstanz.de.
authors.forename: Thomas U
authors.initials: TU
authors.lastname: Mayer
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D008938:Mitosis / Q000235:genetics; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D014981:Xenopus; D029867:Xenopus Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D029867:Xenopus Proteins; C544010:MASTL protein, Xenopus; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2; C584831:ppp2r2a protein, Xenopus laevis
keywords: Greatwall; PP1; PP2A‐B55; Xenopus embryos; mitosis