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PMID: 21937712 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Cdc15 integrates Tem1 GTPase-mediated spatial signals with Polo kinase-mediated temporal cues to activate mitotic exit.

Genes & development ·Vol. 25 ·No. 18 ·2011-09-15 ·Pages 1943-54

Rock JM, Amon A

Abstract

In budding yeast, a Ras-like GTPase signaling cascade known as the mitotic exit network (MEN) promotes exit from mitosis. To ensure the accurate execution of mitosis, MEN activity is coordinated with other cellular events and restricted to anaphase. The MEN GTPase Tem1 has been assumed to be the central switch in MEN regulation. We show here that during an unperturbed cell cycle, restricting MEN activity to anaphase can occur in a Tem1 GTPase-independent manner. We found that the anaphase-specific activation of the MEN in the absence of Tem1 is controlled by the Polo kinase Cdc5. We further show that both Tem1 and Cdc5 are required to recruit the MEN kinase Cdc15 to spindle pole bodies, which is both necessary and sufficient to induce MEN signaling. Thus, Cdc15 functions as a coincidence detector of two essential cell cycle oscillators: the Polo kinase Cdc5 synthesis/degradation cycle and the Tem1 G-protein cycle. The Cdc15-dependent integration of these temporal (Cdc5 and Tem1 activity) and spatial (Tem1 activity) signals ensures that exit from mitosis occurs only after proper genome partitioning.

MeSH Terms
Anaphase/physiology Cell Cycle Proteins/genetics,metabolism GTP-Binding Proteins/genetics,metabolism Mitosis/genetics,physiology Monomeric GTP-Binding Proteins/genetics,metabolism Protein Kinases/genetics,metabolism Protein Serine-Threonine Kinases Protein Transport Saccharomyces cerevisiae/cytology,enzymology,physiology Saccharomyces cerevisiae Proteins/genetics,metabolism Signal Transduction
Chemicals
CDC15 protein Cell Cycle Proteins Saccharomyces cerevisiae Proteins TEM1 protein, S cerevisiae Protein Kinases Protein Serine-Threonine Kinases CDC5 protein, S cerevisiae GTP-Binding Proteins Monomeric GTP-Binding Proteins
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Rock Jeremy M
David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
Amon Angelika
References (64)
64 references, click to expand
  1. KAR2, a karyogamy gene, is the yeast homolog of the mammalian BiP/GRP78 gene.
    Cell. 1989 Jun 30;57(7):1211-21 PMID: 2661018
  2. The FEAR network.
    Curr Biol. 2009 Dec 15;19(23):R1063-8 PMID: 20064401
  3. Plo1 kinase recruitment to the spindle pole body and its role in cell division in Schizosaccharomyces pombe.
    Mol Biol Cell. 1999 Aug;10(8):2771-85 PMID: 10436027
  4. A novel functional domain of Cdc15 kinase is required for its interaction with Tem1 GTPase in Saccharomyces cerevisiae.
    Genetics. 2001 Apr;157(4):1437-50 PMID: 11290702
  5. Mutual regulation of cyclin-dependent kinase and the mitotic exit network.
    J Cell Biol. 2010 Feb 8;188(3):351-68 PMID: 20123997
  6. Spindle position is coordinated with cell-cycle progression through establishment of mitotic exit-activating and -inhibitory zones.
    Mol Cell. 2010 Aug 13;39(3):444-54 PMID: 20705245
  7. Mitotic exit regulation through distinct domains within the protein kinase Cdc15.
    Mol Cell Biol. 2003 Jul;23(14):5018-30 PMID: 12832486
  8. Nud1p links astral microtubule organization and the control of exit from mitosis.
    EMBO J. 2000 Dec 1;19(23):6475-88 PMID: 11101520
  9. Cell cycle regulation of the Saccharomyces cerevisiae polo-like kinase cdc5p.
    Mol Cell Biol. 1998 Dec;18(12):7360-70 PMID: 9819423
  10. Regulation of the Bfa1p-Bub2p complex at spindle pole bodies by the cell cycle phosphatase Cdc14p.
    J Cell Biol. 2002 Apr 29;157(3):367-79 PMID: 11970961
  11. The role of Plo1 kinase in mitotic commitment and septation in Schizosaccharomyces pombe.
    EMBO J. 2001 Mar 15;20(6):1259-70 PMID: 11250892
  12. The role of the polo kinase Cdc5 in controlling Cdc14 localization.
    Mol Biol Cell. 2003 Nov;14(11):4486-98 PMID: 14551257
  13. Tem1 localization to the spindle pole bodies is essential for mitotic exit and impairs spindle checkpoint function.
    J Cell Biol. 2011 Feb 21;192(4):599-614 PMID: 21321099
  14. The differential roles of budding yeast Tem1p, Cdc15p, and Bub2p protein dynamics in mitotic exit.
    Mol Biol Cell. 2004 Apr;15(4):1519-32 PMID: 14718561
  15. Yeast polo-like kinases: functionally conserved multitask mitotic regulators.
    Oncogene. 2005 Jan 10;24(2):217-29 PMID: 15640837
  16. Asymmetric segregation on spindle poles of the Schizosaccharomyces pombe septum-inducing protein kinase Cdc7p.
    Genes Dev. 1998 Jan 1;12(1):84-94 PMID: 9420333
  17. Ubiquitin as a degradation signal.
    EMBO J. 1992 Feb;11(2):497-505 PMID: 1311250
  18. In vivo half-life of a protein is a function of its amino-terminal residue.
    Science. 1986 Oct 10;234(4773):179-86 PMID: 3018930
  19. The Dbf2 and Dbf20 protein kinases of budding yeast are activated after the metaphase to anaphase cell cycle transition.
    EMBO J. 1994 Mar 1;13(5):1103-13 PMID: 8131744
  20. Centrosome-associated NDR kinase regulates centrosome duplication.
    Mol Cell. 2007 Feb 23;25(4):625-34 PMID: 17317633
  21. Structural rearrangements of tubulin and actin during the cell cycle of the yeast Saccharomyces.
    J Cell Biol. 1984 Mar;98(3):922-33 PMID: 6365930
  22. Cfi1 prevents premature exit from mitosis by anchoring Cdc14 phosphatase in the nucleolus.
    Nature. 1999 Apr 29;398(6730):818-23 PMID: 10235265
  23. Lte1 promotes mitotic exit by controlling the localization of the spindle position checkpoint kinase Kin4.
    Proc Natl Acad Sci U S A. 2011 Aug 2;108(31):12584-90 PMID: 21709215
  24. Mitotic exit network controls the localization of Cdc14 to the spindle pole body in Saccharomyces cerevisiae.
    Curr Biol. 2002 Jun 4;12(11):944-50 PMID: 12062061
  25. Regulation of the Bub2/Bfa1 GAP complex by Cdc5 and cell cycle checkpoints.
    Cell. 2001 Nov 30;107(5):655-65 PMID: 11733064
  26. On the road to cancer: aneuploidy and the mitotic checkpoint.
    Nat Rev Cancer. 2005 Oct;5(10):773-85 PMID: 16195750
  27. Saccharomyces cerevisiae Mob1p is required for cytokinesis and mitotic exit.
    Mol Cell Biol. 2001 Oct;21(20):6972-83 PMID: 11564880
  28. Requirement for the budding yeast polo kinase Cdc5 in proper microtubule growth and dynamics.
    Eukaryot Cell. 2008 Mar;7(3):444-53 PMID: 18178775
  29. Hippo signaling: growth control and beyond.
    Development. 2011 Jan;138(1):9-22 PMID: 21138973
  30. Lte1 contributes to Bfa1 localization rather than stimulating nucleotide exchange by Tem1.
    J Cell Biol. 2009 Nov 16;187(4):497-511 PMID: 19948498
  31. Improved flow cytometric analysis of the budding yeast cell cycle.
    Cell Cycle. 2002 Mar-Apr;1(2):132-6 PMID: 12429922
  32. Phosphatase 2A negatively regulates mitotic exit in Saccharomyces cerevisiae.
    Mol Biol Cell. 2006 Jan;17(1):80-9 PMID: 16079183
  33. Separase, polo kinase, the kinetochore protein Slk19, and Spo12 function in a network that controls Cdc14 localization during early anaphase.
    Cell. 2002 Jan 25;108(2):207-20 PMID: 11832211
  34. A mechanism for coupling exit from mitosis to partitioning of the nucleus.
    Cell. 2000 Jul 7;102(1):21-31 PMID: 10929710
  35. Kin4 kinase delays mitotic exit in response to spindle alignment defects.
    Mol Cell. 2005 Jul 22;19(2):209-21 PMID: 16039590
  36. Cdc14 activates cdc15 to promote mitotic exit in budding yeast.
    Curr Biol. 2000 May 18;10(10):615-8 PMID: 10837230
  37. The yeast centrosome translates the positional information of the anaphase spindle into a cell cycle signal.
    J Cell Biol. 2007 Nov 5;179(3):423-36 PMID: 17967947
  38. A cell cycle phosphoproteome of the yeast centrosome.
    Science. 2011 Jun 24;332(6037):1557-61 PMID: 21700874
  39. Human LATS1 is a mitotic exit network kinase.
    Cancer Res. 2005 Aug 1;65(15):6568-75 PMID: 16061636
  40. Spindle orientation, asymmetric division and tumour suppression in Drosophila stem cells.
    Nat Rev Genet. 2007 Jun;8(6):462-72 PMID: 17510666
  41. The spindle position checkpoint: how to deal with spindle misalignment during asymmetric cell division in budding yeast.
    Biochem Soc Trans. 2008 Jun;36(Pt 3):416-20 PMID: 18481971
  42. The protein kinase Kin4 inhibits exit from mitosis in response to spindle position defects.
    Mol Cell. 2005 Jul 22;19(2):223-34 PMID: 16039591
  43. Spindle dynamics and cell cycle regulation of dynein in the budding yeast, Saccharomyces cerevisiae.
    J Cell Biol. 1995 Aug;130(3):687-700 PMID: 7622568
  44. Oscillations in Cdc14 release and sequestration reveal a circuit underlying mitotic exit.
    J Cell Biol. 2010 Jul 26;190(2):209-22 PMID: 20660629
  45. The phosphatase Cdc14 triggers mitotic exit by reversal of Cdk-dependent phosphorylation.
    Mol Cell. 1998 Dec;2(6):709-18 PMID: 9885559
  46. Control of cyclin ubiquitination by CDK-regulated binding of Hct1 to the anaphase promoting complex.
    Science. 1998 Nov 27;282(5394):1721-4 PMID: 9831566
  47. Dbf2-Mob1 drives relocalization of protein phosphatase Cdc14 to the cytoplasm during exit from mitosis.
    J Cell Biol. 2009 Feb 23;184(4):527-39 PMID: 19221193
  48. The Bub2p spindle checkpoint links nuclear migration with mitotic exit.
    Mol Cell. 2000 Jul;6(1):1-10 PMID: 10949022
  49. The Polo-related kinase Cdc5 activates and is destroyed by the mitotic cyclin destruction machinery in S. cerevisiae.
    Curr Biol. 1998 Apr 23;8(9):497-507 PMID: 9560342
  50. Mutual dependence of Mob1 and the chromosomal passenger complex for localization during mitosis.
    Mol Biol Cell. 2010 Feb 1;21(3):380-92 PMID: 19955215
  51. Closing mitosis: the functions of the Cdc14 phosphatase and its regulation.
    Annu Rev Genet. 2004;38:203-32 PMID: 15568976
  52. In vitro regulation of budding yeast Bfa1/Bub2 GAP activity by Cdc5.
    J Biol Chem. 2003 Apr 25;278(17):14591-4 PMID: 12637549
  53. Exit from mitosis is triggered by Tem1-dependent release of the protein phosphatase Cdc14 from nucleolar RENT complex.
    Cell. 1999 Apr 16;97(2):233-44 PMID: 10219244
  54. The cortical protein Lte1 promotes mitotic exit by inhibiting the spindle position checkpoint kinase Kin4.
    J Cell Biol. 2011 Jun 13;193(6):1033-48 PMID: 21670215
  55. A late mitotic regulatory network controlling cyclin destruction in Saccharomyces cerevisiae.
    Mol Biol Cell. 1998 Oct;9(10):2803-17 PMID: 9763445
  56. Identification of functional domains within the septation initiation network kinase, Cdc7.
    J Biol Chem. 2006 Apr 14;281(15):9935-41 PMID: 16469735
  57. Regulation of the mitotic exit protein kinases Cdc15 and Dbf2.
    Mol Biol Cell. 2001 Oct;12(10):2961-74 PMID: 11598184
  58. The Spg1p GTPase is an essential, dosage-dependent inducer of septum formation in Schizosaccharomyces pombe.
    Genes Dev. 1997 Jun 15;11(12):1519-34 PMID: 9203579
  59. Checkpoint control of mitotic exit--do budding yeast mind the GAP?
    J Cell Biol. 2006 Jan 30;172(3):331-3 PMID: 16431930
  60. 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. 1998 Mar 2;17(5):1336-49 PMID: 9482731
  61. Septins have a dual role in controlling mitotic exit in budding yeast.
    Curr Biol. 2003 Apr 15;13(8):654-8 PMID: 12699621
  62. The Polo kinase Plk4 functions in centriole duplication.
    Nat Cell Biol. 2005 Nov;7(11):1140-6 PMID: 16244668
  63. Anaphase spindle position is monitored by the BUB2 checkpoint.
    Nat Cell Biol. 2000 Aug;2(8):556-8 PMID: 10934478
  64. The spindle-assembly checkpoint in space and time.
    Nat Rev Mol Cell Biol. 2007 May;8(5):379-93 PMID: 17426725
Article Info
Journal
Genes & development
Abbr.
Genes Dev
ISSN
1549-5477
DOI
10.1101/gad.17257711
Published
2011-09-15
Pages
1943-54
Language
English
Region
United States
NLM ID
8711660
PMCID
PMC3185966
Subset
IM
Grants
NIGMS NIH HHS · R01 GM056800 · United States
NIGMS NIH HHS · R29 GM056800 · United States
Howard Hughes Medical Institute · United States
NIGMS NIH HHS · GM056800 · United States
External Links
PubMed source DOI: 10.1101/gad.17257711 PMC Full Text View journal details
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