Controlling mitotic entry and progression

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For several years, our laboratory has been interested in the mechanisms that control mitotic entry, progression and exit. The main aim of mitosis, a crucial phase of the cell cycle, is to assure equal chromosome segregation in divided cells. For that, an extensive number of mitotic regulators are activated, re-localized, modified, degraded… These modifications are under the control of several signalling pathways that modulate the different phases of mitosis. We focus our interest on the molecular mechanisms that control cell division. Notably, we are interested in the coordinated activation/inactivation of multiple kinases and phosphatases and their substrates that, together, ensure the correct implementation of mitosis and meiosis. Our recent results show that these mitotic regulators could also play a role in the control of other cell cycle phases or of other cell features, such as DNA replication or cell transformation.

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Anna Castro

Thierry Lorca

Members of the team

  • Priya AMIN
    (Post-Doc) +33 (0)4 34 35 9
  • Sushil AWAL
    (Staff Scientist) +33 (0)4 34 35 9
  • Anna CASTRO Group Leader
    (Staff Scientist) +33 (0)4 34 35 95 56
  • Sophie CHARRASSE
    (Staff Scientist) +33 (0)4 34 35 95 57
    (Trainee) +33 (0)4 34 35 95 57
  • Perrine GOGUET
    (Post-Doc) +33 (0)4 34 35 95 57
  • Jean claude LABBE
    (Staff Scientist) +33 (0)4 34 35 95 53
  • Thierry LORCA Group Leader
    (Staff Scientist) +33 (0)4 34 35 95 56
  • Francisca MECHALI
    (Research Assistant) +33 (0)4 34 35 95 43
  • Suzanne VIGNERON
    (Research Assistant) +33 (0)4 34 35 95 56
    • 2019

      Arpp19 and ENSA, two PP2A-B55 phosphatase inhibitors that differentially control the cell cycle

      Hached K, Goguet-Rubio P, Charrasse S, Lorca T, Castro A.

      Med Sci (Paris). 35(6-7):504-506 Pubmed

    • 2019

      ENSA and ARPP19 differentially control cell cycle progression and development.

      Hached K, Goguet P, Charrasse S, Vigneron S, Sacristan MP, Lorca T, Castro A.

      J Cell Biol. pii: jcb.201708105. Pubmed

    • 2018

      Greatwall kinase at a glance.

      Castro A, Lorca T.

      J Cell Sci. 131(20). Pubmed

    • 2018

      Cyclin A-cdk1-Dependent Phosphorylation of Bora Is the Triggering Factor Promoting Mitotic Entry.

      Vigneron S, Sundermann L, Labbé JC, Pintard L, Radulescu O, Castro A, Lorca T.

      Dev Cell. 45(5):637-650. Pubmed

    • 2017

      Ensa controls S-phase length by modulating Treslin levels.

      Charrasse S, Gharbi-Ayachi A, Burgess A, Vera J, Hached K, Raynaud P, Schwob E, Lorca T, Castro A.

      Nat Commun. 8(1):206 Pubmed

    • 2017

      Loss of Centromere Cohesion in Aneuploid Human Oocytes Correlates with Decreased Kinetochore Localization of the Sac Proteins Bub1 and Bubr1.

      Lagirand-Cantaloube J, Ciabrini C, Charrasse S, Ferrieres A, Castro A, Anahory T, Lorca T.

      Sci Rep. 7:44001. Pubmed

    • 2016

      CDK1 Prevents Unscheduled PLK4-STIL Complex Assembly in Centriole Biogenesis.

      Zitouni S, Francia ME, Leal F, Montenegro Gouveia S, Nabais C, Duarte P, Gilberto S, Brito D, Moyer T, Kandels-Lewis[...]

      Curr Biol. 26:1127-37. Pubmed

    • 2016

      The master Greatwall kinase, a critical regulator of mitosis and meiosis.

      Vigneron S, Robert P, Hached K, Sundermann L, Charrasse S, Labbé JC, Castro A, Lorca T.

      Int J Dev Biol. 60:245-254. Pubmed

    • 2016

      Greatwall dephosphorylation and inactivation upon mitotic exit is triggered by PP1.

      Ma S, Vigneron S, Robert P, Strub JM, Cianferani S, Castro A, Lorca T.

      J Cell Sci. 129:1329-39. Pubmed

    • 2015

      Greatwall promotes cell transformation by hyperactivating AKT in human malignancies.

      Vera J, Lartigue L, Vigneron S, Gadea G, Gire V, Del Rio M, Soubeyran I, Chibon F, Lorca T, Castro[...]

      Elife. 4:e10115. Pubmed

    • 2015

      Global Phosphoproteomic Mapping of Early Mitotic Exit in Human Cells Identifies Novel Substrate Dephosphorylation Motifs.

      McCloy RA, Parker BL, Rogers S, Chaudhuri R, Gayevskiy V, Hoffman NJ, Ali N, Watkins DN, Daly RJ, James DE,[...]

      Mol Cell Proteomics. 14:2194-212. Pubmed

    • 2014

      Partial inhibition of Cdk1 in G 2 phase overrides the SAC and decouples mitotic events.

      McCloy RA, Rogers S, Caldon CE, Lorca T, Castro A, Burgess A.

      Cell Cycle. 13:1400-12. Pubmed

    • 2013

      Greatwall is essential to prevent mitotic collapse after nuclear envelope breakdown in mammals.

      Álvarez-Fernández M, Sánchez-Martínez R, Sanz-Castillo B, Gan PP, Sanz-Flores M, Trakala M, Ruiz-Torres M, Lorca T, Castro A, Malumbres M.

      Proc Natl Acad Sci U S A. 110(43):17374-9. Pubmed

    • 2013

      Budding yeast greatwall and endosulfines control activity and spatial regulation of PP2A(Cdc55) for timely mitotic progression.

      Juanes MA, Khoueiry R, Kupka T, Castro A, Mudrak I, Ogris E, Lorca T, Piatti S.

      PLoS Genet. 9(7):e1003575. Pubmed

    • 2012

      Quantitative live imaging of endogenous DNA replication in mammalian cells.

      Burgess A, Lorca T, Castro A.

      PLoS One. 7(9):e45726. Pubmed

    • 2012

      Deciphering the New Role of the Greatwall/PP2A Pathway in Cell Cycle Control.

      Lorca T, Castro A.

      Genes Cancer. 3(11-12):712-20. Pubmed

    • 2012

      CDK-dependent potentiation of MPS1 kinase activity is essential to the mitotic checkpoint.

      Morin V, Prieto S, Melines S, Hem S, Rossignol M, Lorca T, Espeut J, Morin N, Abrieu A.

      Curr Biol. 22(4):289-95. Pubmed

    • 2011

      Characterization of the mechanisms controlling Greatwall activity.

      Vigneron S, Gharbi-Ayachi A, Raymond AA, Burgess A, Labbé JC, Labesse G, Monsarrat B, Lorca T, Castro A.

      Mol Cell Biol. 31(11):2262-75. Pubmed

    • 2011

      [Greatwall, a new guardian of mitosis].[Article in French]

      Gharbi-Ayachi A, Burgess A, Vigneron S, Labbé JC, Castro A, Lorca T.

      Med Sci (Paris). 27(4):352-4. Pubmed

    • 2010

      Loss of human Greatwall results in G2 arrest and multiple mitotic defects due to deregulation of the cyclin B-Cdc2/PP2A balance.

      Burgess A, Vigneron S, Brioudes E, Labbé JC, Lorca T, Castro A.

      Proc Natl Acad Sci U S A. 107(28):12564-9. Pubmed

    • 2010

      Constant regulation of both the MPF amplification loop and the Greatwall-PP2A pathway is required for metaphase II arrest and correct entry into the first embryonic cell cycle.

      Lorca T, Bernis C, Vigneron S, Burgess A, Brioudes E, Labbé JC, Castro A.

      J Cell Sci. 123(Pt 13):2281-91. Pubmed

    • 2010

      The substrate of Greatwall kinase, Arpp19, controls mitosis by inhibiting protein phosphatase 2A.

      Gharbi-Ayachi A, Labbé JC, Burgess A, Vigneron S, Strub JM, Brioudes E, Van-Dorsselaer A, Castro A, Lorca T.

      Science. 330(6011):1673-7. Pubmed

    • 2009

      Greatwall maintains mitosis through regulation of PP2A.

      Vigneron S, Brioudes E, Burgess A, Labbé JC, Lorca T, Castro A.

      EMBO J. 28(18):2786-93. Pubmed

    The Greatwall/ARPP19-ENSA/PP2A-B55 pathway and the cell cycle.

    Our laboratory studies the role of kinases and phosphatases in the regulation of mitotic entry and progression. Mitosis requires massive protein phosphorylation that is mostly promoted by the master kinase cyclin B-CDK1. Historically, it was assumed that protein phosphorylation in mitosis was under the control of cyclin B-CDK1 and that the phosphatase activity responsible of protein dephosphorylation was constant. For the first time, we demonstrated that like for the kinase activity, phosphatase activity is also modulated for correct mitosis. Our studies in Xenopus laevis egg extracts identified a new pathway that controls mitotic phosphatase activity and that includes the kinase Greatwall (GWL) and its substrates ARPP19 and ENSA. We showed that at mitotic entry, GWL is activated and phosphorylates ARPP19 and ENSA, thus promoting their binding to PP2A-B55 and the inhibition of this phosphatase. This leads to stable protein phosphorylation and mitotic entry. We then demonstrated that this pathway is conserved in human cells in culture. We are currently investigating the role of GWL/ARPP19-ENSA/PP2A-B55 in tissue homeostasis by using inducible knock out mouse models. Interestingly, besides the role in mitotic division, we demonstrated that this signalling pathway is also involved in other cell cycle phases. Specifically, our recent data show that this cascade contributes to the control of S phase, by regulating DNA replication dynamics. Finally, we identified GWL as a potent oncogene that promotes cell transformation by controlling AKT activity. Next, we will try to identify the mechanisms beneath the phenotypes observed in adult knock out mice and the pathway(s) responsible of GWL-dependent AKT regulation. Moreover, we will investigate the pathway by which GWL/ENSA/PP2A-B55 controls S phase and try to identify new GWL substrates.