The Greatwall–PP2A Axis in Cell Cycle Control
- 5.5k Downloads
Cell cycle progression is largely controlled by reversible protein phosphorylation mediated by cyclically activated kinases and phosphatases. It has long been known that cyclin B–Cdk1 activation triggers mitotic entry, and the enzymatic network controlling its activation and inactivation has been well characterized. Much more recently protein phosphatase 2A (PP2A) together with its B55 regulatory subunit has been recognized as the major activity dephosphorylating Cdk1 targets. Moreover, PP2A-B55 activity is high in late M phase and interphase, but low at mitotic entry. A series of discoveries in the fly and frog model systems have uncovered the molecular mechanism mediating this regulation. The Greatwall (Gwl) kinase activates endosulfines, which become specific inhibitors of PP2A-B55. Cdk1-dependent activation of Gwl at mitotic entry leads to PP2A-B55 downregulation, which synergizes with Cdk1 activation to promote the phosphorylated states of several mitotic substrates. Much less is known on the mechanisms inactivating Gwl and endosulfines at mitotic exit. Recent reports show the importance of spatiotemporal regulation of Gwl, endosulfines, and PP2A-B55 for cell cycle progression. The various systems and cell types differ in their dependence on the Gwl–PP2A axis for cell cycle progression. Moreover, this pathway also regulates gene expression in yeast, and this function could be conserved in metazoans.
Key wordsCell cycle Mitosis Mitotic exit Greatwall PP2A B55 Endosulfine Cdk1
Work on the Gwl–PP2A axis in V.A.’s lab is supported by the Canadian Institutes of Health Research (CIHR). V.A. also holds a New Investigator Award from the CIHR. P.W. holds a studentship from the Fonds de recherche du Québec—Santé (FRQ-S). IRIC is supported in part by the Canadian Center of Excellence in Commercialization and Research, the Canada Foundation for Innovation, and the FRQ-S. Work in M.M.’s laboratory was funded by grants from Bayer Pharma AG, Fundación Ramón Areces, MINECO (SAF2012-38215), the OncoCycle Programme (S2010/BMD-2470) from the Comunidad de Madrid, and the European Union Seventh Framework Programme (MitoSys project; HEALTH-F5-2010-241548).
- 1.Morgan DO (2007) The cell cycle: principles of control, Primers in Biology. New Science, LondonGoogle Scholar
- 11.Mocciaro A, Schiebel E (2010) Cdc14: a highly conserved family of phosphatases with non-conserved functions? J Cell Sci 123 (Pt 17):2867–2876Google Scholar
- 13.Mayer-Jaekel RE, Ohkura H, Ferrigno P, Andjelkovic N, Shiomi K, Uemura T, Glover DM, Hemmings BA (1994) Drosophila mutants in the 55 kDa regulatory subunit of protein phosphatase 2A show strongly reduced ability to dephosphorylate substrates of p34cdc2. J Cell Sci 107(Pt 9):2609–2616PubMedGoogle Scholar
- 20.Schmitz MH, Held M, Janssens V, Hutchins JR, Hudecz O, Ivanova E, Goris J, Trinkle-Mulcahy L, Lamond AI, Poser I, Hyman AA, Mechtler K, Peters JM, Gerlich DW (2010) Live-cell imaging RNAi screen identifies PP2A-B55alpha and importin-beta1 as key mitotic exit regulators in human cells. Nat Cell Biol 12(9):886–893PubMedCrossRefGoogle Scholar
- 21.Manchado E, Guillamot M, de Carcer G, Eguren M, Trickey M, Garcia-Higuera I, Moreno S, Yamano H, Canamero M, Malumbres M (2010) Targeting mitotic exit leads to tumor regression in vivo: modulation by Cdk1, Mastl, and the PP2A/B55alpha, delta phosphatase. Cancer Cell 18(6):641–654PubMedCrossRefGoogle Scholar
- 37.Rangone H, Wegel E, Gatt MK, Yeung E, Flowers A, Debski J, Dadlez M, Janssens V, Carpenter AT, Glover DM (2011) Suppression of scant identifies Endos as a substrate of greatwall kinase and a negative regulator of protein phosphatase 2A in mitosis. PLoS Genet 7(8):e1002225PubMedCentralPubMedCrossRefGoogle Scholar
- 41.Alvarez-Fernandez M, Sanchez-Martinez R, Sanz-Castillo B, Gan PP, Sanz-Flores M, Trakala M, Ruiz-Torres M, Lorca T, Castro A, Malumbres M (2013) Greatwall is essential to prevent mitotic collapse after nuclear envelope breakdown in mammals. Proc Natl Acad Sci U S A 110(43):17374–17379PubMedCentralPubMedCrossRefGoogle Scholar
- 47.Kim MY, Bucciarelli E, Morton DG, Williams BC, Blake-Hodek K, Pellacani C, Von Stetina JR, Hu X, Somma MP, Drummond-Barbosa D, Goldberg ML (2012) Bypassing the Greatwall-endosulfine pathway: plasticity of a pivotal cell-cycle regulatory module in Drosophila melanogaster and Caenorhabditis elegans. Genetics 191(4):1181–1197PubMedCentralPubMedCrossRefGoogle Scholar
- 59.Talarek N, Cameroni E, Jaquenoud M, Luo X, Bontron S, Lippman S, Devgan G, Snyder M, Broach JR, De Virgilio C (2010) Initiation of the TORC1-regulated G0 program requires Igo1/2, which license specific mRNAs to evade degradation via the 5'-3' mRNA decay pathway. Mol Cell 38(3):345–355PubMedCentralPubMedCrossRefGoogle Scholar