title: PP1 initiates the dephosphorylation of MASTL, triggering mitotic exit and bistability in human cells.
abstract: Entry into mitosis is driven by the phosphorylation of thousands of substrates, under the master control of Cdk1. During entry into mitosis, Cdk1, in collaboration with MASTL kinase, represses the activity of the major mitotic protein phosphatases, PP1 and PP2A, thereby ensuring mitotic substrates remain phosphorylated. For cells to complete and exit mitosis, these phosphorylation events must be removed, and hence, phosphatase activity must be reactivated. This reactivation of phosphatase activity presumably requires the inhibition of MASTL; however, it is not currently understood what deactivates MASTL and how this is achieved. In this study, we identified that PP1 is associated with, and capable of partially dephosphorylating and deactivating, MASTL during mitotic exit. Using mathematical modelling, we were able to confirm that deactivation of MASTL is essential for mitotic exit. Furthermore, small decreases in Cdk1 activity during metaphase are sufficient to initiate the reactivation of PP1, which in turn partially deactivates MASTL to release inhibition of PP2A and, hence, create a feedback loop. This feedback loop drives complete deactivation of MASTL, ensuring a strong switch-like activation of phosphatase activity during mitotic exit.
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
authors.forename: Samuel
authors.initials: S
authors.lastname: Rogers
authors.affiliation: Systems Biology Ireland, University College Dublin, Dublin 4, Ireland.
authors.forename: Dirk
authors.initials: D
authors.lastname: Fey
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia.
authors.forename: Rachael A
authors.initials: RA
authors.lastname: McCloy
authors.affiliation: The Charles Perkins Centre, School of Molecular Bioscience and Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Benjamin L
authors.initials: BL
authors.lastname: Parker
authors.affiliation: School of Chemistry, The University of Sydney, Sydney 2006, New South Wales, Australia.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Mitchell
authors.affiliation: School of Chemistry, The University of Sydney, Sydney 2006, New South Wales, Australia.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Payne
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Biomedical Sciences Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Daly
authors.affiliation: The Charles Perkins Centre, School of Molecular Bioscience and Sydney Medical School, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: David E
authors.initials: DE
authors.lastname: James
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia St. Vincent's Clinical School, Faculty of Medicine, UNSW, Darlinghurst 2010, New South Wales, Australia.
authors.forename: C Elizabeth
authors.initials: CE
authors.lastname: Caldon
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia St. Vincent's Clinical School, Faculty of Medicine, UNSW, Darlinghurst 2010, New South Wales, Australia Department of Thoracic Medicine, St Vincent's Hospital, Darlinghurst, New South Wales 2010, Australia.
authors.forename: D Neil
authors.initials: DN
authors.lastname: Watkins
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia St. Vincent's Clinical School, Faculty of Medicine, UNSW, Darlinghurst 2010, New South Wales, Australia.
authors.forename: David R
authors.initials: DR
authors.lastname: Croucher
authors.affiliation: The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Darlinghurst, New South Wales 2010, Australia St. Vincent's Clinical School, Faculty of Medicine, UNSW, Darlinghurst 2010, New South Wales, Australia a.burgess@garvan.org.au.
authors.forename: Andrew
authors.initials: A
authors.lastname: Burgess
mesh_terms: D016203:CDC2 Protein Kinase; D045744:Cell Line, Tumor; D018844:Cyclin-Dependent Kinases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008938:Mitosis / Q000502:physiology*; D008962:Models, Theoretical; D010766:Phosphorylation; D054645:Protein Phosphatase 1 / Q000378:metabolism*; D054648:Protein Phosphatase 2 / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D008869:Microtubule-Associated Proteins; D034741:RNA, Small Interfering; C555237:MASTL protein, human; D017346:Protein Serine-Threonine Kinases; D016203:CDC2 Protein Kinase; C528899:CDK1 protein, human; D018844:Cyclin-Dependent Kinases; D054645:Protein Phosphatase 1; D054648:Protein Phosphatase 2
keywords: Bistable switch; Cdk1; Greatwall; Kinase; MASTL; Mitotic exit; PP1; PP2A; Phosphatase