Dual Regulation of the Mitotic Exit Network (MEN) by PP2A-Cdc55 Phosphatase

English version České info

Exit from mitosis in budding yeast is triggered by activation of the key mitotic phosphatase Cdc14. At anaphase onset, the protease separase and Zds1 promote the downregulation of PP2A^Cdc55 phosphatase, which facilitates Cdk1-dependent phosphorylation of Net1 and provides the first wave of Cdc14 activity. Once Cdk1 activity starts to decline, the mitotic exit network (MEN) is activated to achieve full Cdc14 activation. Here we describe how the PP2A^Cdc55 phosphatase could act as a functional link between FEAR and MEN due to its action on Bfa1 and Mob1. We demonstrate that PP2A^Cdc55 regulates MEN activation by facilitating Cdc5 -⁠ and Cdk1-dependent phosphorylation of Bfa1 and Mob1, respectively. Downregulation of PP2A^Cdc55 initiates MEN activity up to Cdc15 by Bfa1 inactivation. Surprisingly, the premature Bfa1 inactivation observed does not entail premature MEN activation, since an additional Cdk1-Clb2 inhibitory signal acting towards Dbf2-Mob1 activity restrains MEN activity until anaphase. In conclusion, we propose a clear picture of how PP2A^Cdc55 functions affect the regulation of various MEN components, contributing to mitotic exit.

Vyšlo v časopise: Dual Regulation of the Mitotic Exit Network (MEN) by PP2A-Cdc55 Phosphatase. PLoS Genet 9(12): e32767. doi:10.1371/journal.pgen.1003966
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.pgen.1003966

Souhrn

Zdroje

1. ShouW, SeolJH, ShevchenkoA, BaskervilleC, MoazedD, et al. (1999) Exit from Mitosis Is Triggered by Tem1-Dependent Release of the Protein Phosphatase Cdc14 from Nucleolar RENT Complex. Cell 97 : 233–244.

2. VisintinR, HwangES, AmonA (1999) Cfi1 prevents premature exit from mitosis by anchoring Cdc14 phosphatase in the nucleolus. Nature 398 : 818–823.

3. ShouW, DeshaiesR (2002) Multiple telophase arrest bypassed (tab) mutants alleviate the essential requirement for Cdc15 in exit from mitosis in S. cerevisiae. BMC Genetics 3 : 4.

4. YoshidaS, Toh-eA (2002) Budding yeast Cdc5 phosphorylates Net1 and assists Cdc14 release from the nucleolus. Biochem Biophys Res Commun 294 : 687–691.

5. AzzamR, ChenSL, ShouW, MahAS, AlexandruG, et al. (2004) Phosphorylation by cyclin B-Cdk underlies release of mitotic exit activator Cdc14 from the nucleolus. Science 305 : 516–519.

6. QueraltE, UhlmannF (2008) Cdk-counteracting phosphatases unlock mitotic exit. Curr Opin Cell Biol 20 : 661–668.

7. RockJM, AmonA (2009) The FEAR network. Curr Biol 19: R1063–1068.

8. MocciaroA, SchiebelE (2010) Cdc14: a highly conserved family of phosphatases with non-conserved functions? J Cell Sci 123 : 2867–2876.

9. QueraltE, LehaneC, NovakB, UhlmannF (2006) Downregulation of PP2ACdc55 Phosphatase by Separase Initiates Mitotic Exit in Budding Yeast. Cell 125 : 719–732.

10. QueraltE, UhlmannF (2008) Separase cooperates with Zds1 and Zds2 to activate Cdc14 phosphatase in early anaphase. J Cell Biol 182 : 873–883.

11. CalabriaI, BaroB, Rodriguez-RodriguezJA, RussinolN, QueraltE (2012) Zds1 regulates PP2A(Cdc55) activity and Cdc14 activation during mitotic exit through its Zds_C motif. J Cell Sci 125 : 2875–2884.

12. ShirayamaM, MatsuiY, TohEA (1994) The yeast TEM1 gene, which encodes a GTP-binding protein, is involved in termination of M phase. Mol Cell Biol 14 : 7476–7482.

13. LucaFC, WineyM (1998) MOB1, an essential yeast gene required for completion of mitosis and maintenance of ploidy. Mol Biol Cell 9 : 29–46.

14. CenamorR, JimenezJ, CidVJ, NombelaC, SanchezM (1999) The budding yeast Cdc15 localizes to the spindle pole body in a cell-cycle-dependent manner. Mol Cell Biol Res Commun 2 : 178–184.

15. GrunebergU, CampbellK, SimpsonC, GrindlayJ, SchiebelE (2000) Nud1p links astral microtubule organization and the control of exit from mitosis. Embo J 19 : 6475–6488.

16. XuS, HuangHK, KaiserP, LatterichM, HunterT (2000) Phosphorylation and spindle pole body localization of the Cdc15p mitotic regulatory protein kinase in budding yeast. Curr Biol 10 : 329–332.

17. MenssenR, NeutznerA, SeufertW (2001) Asymmetric spindle pole localization of yeast Cdc15 kinase links mitotic exit and cytokinesis. Curr Biol 11 : 345–350.

18. PereiraG, SchiebelE (2001) The role of the yeast spindle pole body and the mammalian centrosome in regulating late mitotic events. Curr Opin Cell Biol 13 : 762–769.

19. StegmeierF, AmonA (2004) Closing mitosis: the functions of the Cdc14 phosphatase and its regulation. Annu Rev Genet 38 : 203–232.

20. MahAS, JangJ, DeshaiesRJ (2001) Protein kinase Cdc15 activates the Dbf2-Mob1 kinase complex. Proc Natl Acad Sci U S A 98 : 7325–7330.

21. RockJM, LimD, StachL, OgrodowiczRW, KeckJM, et al. (2013) Activation of the Yeast Hippo Pathway by Phosphorylation-Dependent Assembly of Signaling Complexes. Science 340 : 871–5.

22. MohlDA, HuddlestonMJ, CollingwoodTS, AnnanRS, DeshaiesRJ (2009) Dbf2-Mob1 drives relocalization of protein phosphatase Cdc14 to the cytoplasm during exit from mitosis. J Cell Biol 184 : 527–539.

23. PereiraG, SchiebelE (2005) Kin4 kinase delays mitotic exit in response to spindle alignment defects. Mol Cell 19 : 209–221.

24. HuF, WangY, LiuD, LiY, QinJ, et al. (2001) Regulation of the Bub2/Bfa1 GAP complex by Cdc5 and cell cycle checkpoints. Cell 107 : 655–665.

25. AtienzaJM, RothRB, RosetteC, SmylieKJ, KammererS, et al. (2005) Suppression of RAD21 gene expression decreases cell growth and enhances cytotoxicity of etoposide and bleomycin in human breast cancer cells. Mol Cancer Ther 4 : 361–368.

26. FraschiniR, D'AmbrosioC, VenturettiM, LucchiniG, PiattiS (2006) Disappearance of the budding yeast Bub2-Bfa1 complex from the mother-bound spindle pole contributes to mitotic exit. J Cell Biol 172 : 335–346.

27. MaekawaH, PriestC, LechnerJ, PereiraG, SchiebelE (2007) The yeast centrosome translates the positional information of the anaphase spindle into a cell cycle signal. J Cell Biol 179 : 423–436.

28. JaspersenSL, MorganDO (2000) Cdc14 activates cdc15 to promote mitotic exit in budding yeast. Curr Biol 10 : 615–618.

29. KonigC, MaekawaH, SchiebelE (2010) Mutual regulation of cyclin-dependent kinase and the mitotic exit network. J Cell Biol 188 : 351–368.

30. PereiraG, MansonC, GrindlayJ, SchiebelE (2002) Regulation of the Bfa1p-Bub2p complex at spindle pole bodies by the cell cycle phosphatase Cdc14p. J Cell Biol 157 : 367–379.

31. StegmeierF, VisintinR, AmonA (2002) Separase, Polo Kinase, the Kinetochore Protein Slk19, and Spo12 Function in a Network that Controls Cdc14 Localization during Early Anaphase. Cell 108 : 207–220.

32. GeymonatM, SpanosA, de BettigniesG, SedgwickSG (2009) Lte1 contributes to Bfa1 localization rather than stimulating nucleotide exchange by Tem1. J Cell Biol 187 : 497–511.

33. BardinAJ, VisintinR, AmonA (2000) A mechanism for coupling exit from mitosis to partitioning of the nucleus. Cell 102 : 21–31.

34. PereiraG, HofkenT, GrindlayJ, MansonC, SchiebelE (2000) The Bub2p spindle checkpoint links nuclear migration with mitotic exit. Mol Cell 6 : 1–10.

35. Monje-CasasF, AmonA (2009) Cell polarity determinants establish asymmetry in MEN signaling. Dev Cell 16 : 132–145.

36. PereiraG, TanakaTU, NasmythK, SchiebelE (2001) Modes of spindle pole body inheritance and segregation of the Bfa1p-Bub2p checkpoint protein complex. Embo J 20 : 6359–6370.

37. KimJ, LuoG, BahkYY, SongK (2012) Cdc5-dependent asymmetric localization of bfa1 fine-tunes timely mitotic exit. PLoS Genet 8: e1002450.

38. MolkJN, SchuylerSC, LiuJY, EvansJG, SalmonED, et al. (2004) The differential roles of budding yeast Tem1p, Cdc15p, and Bub2p protein dynamics in mitotic exit. Mol Biol Cell 15 : 1519–1532.

39. Valerio-SantiagoM, Monje-CasasF (2011) Tem1 localization to the spindle pole bodies is essential for mitotic exit and impairs spindle checkpoint function. The Journal of Cell Biology 192 : 599–614.

40. EvansDR, StarkMJ (1997) Mutations in the Saccharomyces cerevisiae type 2A protein phosphatase catalytic subunit reveal roles in cell wall integrity, actin cytoskeleton organization and mitosis. Genetics 145 : 227–241.

41. ChanLY, AmonA (2009) The protein phosphatase 2A functions in the spindle position checkpoint by regulating the checkpoint kinase Kin4. Genes Dev 23 : 1639–1649.

42. BouchouxC, UhlmannF (2011) A quantitative model for ordered Cdk substrate dephosphorylation during mitotic exit. Cell 147 : 803–814.

43. SchwabM, LutumAS, SeufertW (1997) Yeast Hct1 is a regulator of Clb2 cyclin proteolysis. Cell 90 : 683–693.

44. CharlesJF, JaspersenSL, Tinker-KulbergRL, HwangL, SzidonA, et al. (1998) The Polo-related kinase Cdc5 activates and is destroyed by the mitotic cyclin destruction machinery in S. cerevisiae. Curr Biol 8 : 497–507.

45. ShirayamaM, ZachariaeW, CioskR, NasmythK (1998) The Polo-like kinase Cdc5p and the WD-repeat protein Cdc20p/fizzy are regulators and substrates of the anaphase promoting complex in Saccharomyces cerevisiae. Embo J 17 : 1336–1349.

46. HildebrandtER, HoytMA (2001) Cell cycle-dependent degradation of the Saccharomyces cerevisiae spindle motor Cin8p requires APC(Cdh1) and a bipartite destruction sequence. Mol Biol Cell 12 : 3402–3416.

47. HuangJN, ParkI, EllingsonE, LittlepageLE, PellmanD (2001) Activity of the APC(Cdh1) form of the anaphase-promoting complex persists until S phase and prevents the premature expression of Cdc20p. J Cell Biol 154 : 85–94.

48. WoodburyEL, MorganDO (2007) Cdk and APC activities limit the spindle-stabilizing function of Fin1 to anaphase. Nat Cell Biol 9 : 106–112.

49. BenantiJA, MatyskielaME, MorganDO, ToczyskiDP (2009) Functionally distinct isoforms of Cik1 are differentially regulated by APC/C-mediated proteolysis. Mol Cell 33 : 581–590.

50. CaydasiAK, PereiraG (2009) Spindle alignment regulates the dynamic association of checkpoint proteins with yeast spindle pole bodies. Dev Cell 16 : 146–156.

51. MinshullJ, StraightA, RudnerAD, DernburgAF, BelmontA, et al. (1996) Protein phosphatase 2A regulates MPF activity and sister chromatid cohesion in budding yeast. Current Biology 6 : 1609–1620.

52. VisintinR, AmonA (2001) Regulation of the mitotic exit protein kinases Cdc15 and Dbf2. Mol Biol Cell 12 : 2961–2974.

53. LucaFC, ModyM, KurischkoC, RoofDM, GiddingsTH, et al. (2001) Saccharomyces cerevisiae Mob1p is required for cytokinesis and mitotic exit. Mol Cell Biol 21 : 6972–6983.

54. WickyS, TjandraH, SchieltzD, YatesJ3rd, KelloggDR The Zds proteins control entry into mitosis and target protein phosphatase 2A to the Cdc25 phosphatase. Mol Biol Cell 22 : 20–32.

55. YaakovG, ThornK, MorganDO (2012) Separase biosensor reveals that cohesin cleavage timing depends on phosphatase PP2A(Cdc55) regulation. Dev Cell 23 : 124–136.

56. HoltLJ, HuttiJE, CantleyLC, MorganDO (2007) Evolution of Ime2 phosphorylation sites on Cdk1 substrates provides a mechanism to limit the effects of the phosphatase Cdc14 in meiosis. Mol Cell 25 : 689–702.

57. Attila TothEQ (2007) Frank Uhlmann and Bela Novak (2007) Mitotic exit in two dimensions. Journal of Theoretical Biology Volume 248 : 560–573.

58. VinodPK, FreireP, RattaniA, CilibertoA, UhlmannF, et al. (2011) Computational modelling of mitotic exit in budding yeast: the role of separase and Cdc14 endocycles. J R Soc Interface 8 : 1128–1141.

59. VisintinC, TomsonBN, RahalR, PaulsonJ, CohenM, et al. (2008) APC/C-Cdh1-mediated degradation of the Polo kinase Cdc5 promotes the return of Cdc14 into the nucleolus. Genes Dev 22 : 79–90.

60. JaspersenSL, CharlesJF, Tinker-KulbergRL, MorganDO (1998) A late mitotic regulatory network controlling cyclin destruction in Saccharomyces cerevisiae. Mol Biol Cell 9 : 2803–2817.

61. Roberts-GalbraithRH, GouldKL (2008) Stepping into the ring: the SIN takes on contractile ring assembly. Genes Dev 22 : 3082–3088.

62. MeitingerF, PalaniS, PereiraG (2012) The power of MEN in cytokinesis. Cell Cycle 11 : 219–228.

63. LahozA, Alcaide-GavilanM, DagaRR, JimenezJ (2010) Antagonistic roles of PP2A-Pab1 and Etd1 in the control of cytokinesis in fission yeast. Genetics 186 : 1261–1270.

64. FrenzLM, LeeSE, FesquetD, JohnstonLH (2000) The budding yeast Dbf2 protein kinase localises to the centrosome and moves to the bud neck in late mitosis. J Cell Sci 113 (Pt 19) 3399–3408.

65. YoshidaS, Toh-eA (2001) Regulation of the localization of Dbf2 and mob1 during cell division of saccharomyces cerevisiae. Genes Genet Syst 76 : 141–147.

66. MeitingerF, PetrovaB, LombardiIM, BertazziDT, HubB, et al. (2010) Targeted localization of Inn1, Cyk3 and Chs2 by the mitotic-exit network regulates cytokinesis in budding yeast. J Cell Sci 123 : 1851–1861.

67. MeitingerF, BoehmME, HofmannA, HubB, ZentgrafH, et al. (2011) Phosphorylation-dependent regulation of the F-BAR protein Hof1 during cytokinesis. Genes Dev 25 : 875–888.

68. OhY, ChangKJ, OrleanP, WlokaC, DeshaiesR, et al. (2012) Mitotic exit kinase Dbf2 directly phosphorylates chitin synthase Chs2 to regulate cytokinesis in budding yeast. Mol Biol Cell 23 : 2445–2456.

69. HergovichA, HemmingsBA (2012) Hippo signalling in the G2/M cell cycle phase: lessons learned from the yeast MEN and SIN pathways. Semin Cell Dev Biol 23 : 794–802.

70. UhlmannF, LottspeichF, NasmythK (1999) Sister-chromatid separation at anaphase onset is promoted by cleavage of the cohesin subunit Scc1. Nature 400 : 37–42.

71. MascaraqueV, HernaezML, Jimenez-SanchezM, HansenR, GilC, et al. (2012) Phosphoproteomic analysis of protein kinase C signaling in Saccharomyces cerevisiae reveals Slt2 MAPK-dependent phosphorylation of eisosome core components. Mol Cell Proteomics 12 : 557–74.

72. MonteolivaL, Martinez-LopezR, PitarchA, HernaezML, SernaA, et al. (2011) Quantitative proteome and acidic subproteome profiling of Candida albicans yeast-to-hypha transition. J Proteome Res 10 : 502–517.