title: Switches and latches: a biochemical tug-of-war between the kinases and phosphatases that control mitosis.
abstract: Activation of the cyclin-dependent kinase (Cdk1) cyclin B (CycB) complex (Cdk1:CycB) in mitosis brings about a remarkable extent of protein phosphorylation. Cdk1:CycB activation is switch-like, controlled by two auto-amplification loops--Cdk1:CycB activates its activating phosphatase, Cdc25, and inhibits its inhibiting kinase, Wee1. Recent experimental evidence suggests that parallel to Cdk1:CycB activation during mitosis, there is inhibition of its counteracting phosphatase activity. We argue that the downregulation of the phosphatase is not just a simple latch that suppresses futile cycles of phosphorylation/dephosphorylation during mitosis. Instead, we propose that phosphatase regulation creates coherent feed-forward loops and adds extra amplification loops to the Cdk1:CycB regulatory network, thus forming an integral part of the mitotic switch. These network motifs further strengthen the bistable characteristic of the mitotic switch, which is based on the antagonistic interaction of two groups of proteins: M-phase promoting factors (Cdk1:CycB, Cdc25, Greatwall and Endosulfine/Arpp19) and interphase promoting factors (Wee1, PP2A-B55 and a Greatwall counteracting phosphatase, probably PP1). The bistable character of the switch implies the existence of a CycB threshold for entry into mitosis. The end of G2 phase is determined by the point where CycB level crosses the CycB threshold for Cdk1 activation.
authors.affiliation: Department of Biochemistry, Oxford Centre for Integrative Systems Biology, University of Oxford, South Parks Road, Oxford OX1 3QU, UK.
authors.forename: Maria Rosa
authors.initials: MR
authors.lastname: Domingo-Sananes
authors.forename: Orsolya
authors.initials: O
authors.lastname: Kapuy
authors.forename: Tim
authors.initials: T
authors.lastname: Hunt
authors.forename: Bela
authors.initials: B
authors.lastname: Novak
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000737:chemistry*; D059447:Cell Cycle Checkpoints; D019926:Cyclin B / Q000737:chemistry*; D004789:Enzyme Activation; D005656:Fungal Proteins / Q000737:chemistry; D007399:Interphase; D008938:Mitosis; D010766:Phosphorylation; D015003:Yeasts / Q000737:chemistry / Q000166:cytology; D020687:cdc25 Phosphatases / Q000737:chemistry
chemical_list: D019926:Cyclin B; D005656:Fungal Proteins; D016203:CDC2 Protein Kinase; D020687:cdc25 Phosphatases
references.citation: Cell. 1983 Jun;33(2):389-96
references.pmid: 6134587
references.citation: Nature. 2007 Sep 20;449(7160):336-40
references.pmid: 17882219
references.citation: Mol Cell. 2009 Mar 13;33(5):537-45
references.pmid: 19285938
references.citation: Nat Cell Biol. 2003 Apr;5(4):346-51
references.pmid: 12629549
references.citation: Cell. 1991 Mar 22;64(6):1111-22
references.pmid: 1706223
references.citation: EMBO J. 2009 Sep 16;28(18):2786-93
references.pmid: 19680222
references.citation: Nat Cell Biol. 2009 May;11(5):644-51
references.pmid: 19396163
references.citation: Mol Biol Cell. 2008 Apr;19(4):1317-27
references.pmid: 18199678
references.citation: Cell Cycle. 2010 Sep 1;9(17):3591-601
references.pmid: 20818157
references.citation: Adv Enzyme Regul. 2010;50(1):375-99
references.pmid: 20045433
references.citation: Cell. 1995 Apr 21;81(2):279-88
references.pmid: 7736580
references.citation: Science. 2010 Dec 17;330(6011):1670-3
references.pmid: 21164013
references.citation: Mol Cell Biol. 1991 Feb;11(2):1171-5
references.pmid: 1846666
references.citation: Nat Cell Biol. 2010 Sep;12(9):886-93
references.pmid: 20711181
references.citation: Proc Natl Acad Sci U S A. 2003 Feb 4;100(3):975-80
references.pmid: 12509509
references.citation: Cell. 2005 Aug 26;122(4):565-78
references.pmid: 16122424
references.citation: Science. 2009 Sep 25;325(5948):1682-6
references.pmid: 19779198
references.citation: Cell. 1988 Jul 29;54(3):433-9
references.pmid: 3293803
references.citation: J Cell Sci. 2005 Jun 1;118(Pt 11):2485-94
references.pmid: 15923661
references.citation: Nature. 1990 Apr 5;344(6266):503-8
references.pmid: 2138713
references.citation: Cell. 1988 Jul 29;54(3):423-31
references.pmid: 3293802
references.citation: Mol Biol Cell. 1995 Feb;6(2):185-97
references.pmid: 7787245
references.citation: Nat Rev Genet. 2007 Jun;8(6):450-61
references.pmid: 17510665
references.citation: Mol Cell. 2006 Apr 7;22(1):83-91
references.pmid: 16600872
references.citation: EMBO J. 2009 Sep 16;28(18):2777-85
references.pmid: 19696736
references.citation: Proc Natl Acad Sci U S A. 1988 May;85(9):3009-13
references.pmid: 3283736
references.citation: J Exp Zool. 1971 Jun;177(2):129-45
references.pmid: 5106340
references.citation: Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6408-12
references.pmid: 8022797
references.citation: J Cell Sci Suppl. 1989;12:39-51
references.pmid: 2561426
references.citation: EMBO J. 1993 Sep;12(9):3427-36
references.pmid: 7504624
references.citation: Cell. 1992 Jul 10;70(1):139-51
references.pmid: 1623517
references.citation: Mol Cell. 2011 Nov 4;44(3):437-50
references.pmid: 22055189
references.citation: Nature. 1989 Nov 2;342(6245):39-45
references.pmid: 2682257
references.citation: Mol Cell. 2011 Feb 4;41(3):263-74
references.pmid: 21292159
references.citation: Mol Gen Genet. 1976 Jul 23;146(2):167-78
references.pmid: 958201
references.citation: Nature. 1975 Aug 14;256(5518):547-51
references.pmid: 1165770
references.citation: Cell. 1990 Nov 30;63(5):1013-24
references.pmid: 2147872
references.citation: J Virol. 2011 Jan;85(1):286-95
references.pmid: 21047956
references.citation: Cell. 1986 Apr 25;45(2):261-8
references.pmid: 3516412
references.citation: J Cell Biol. 1989 Dec;109(6 Pt 2):3347-54
references.pmid: 2574724
references.citation: EMBO J. 1987 Oct;6(10):2987-95
references.pmid: 2826125
references.citation: Proc Natl Acad Sci U S A. 2010 Jul 13;107(28):12564-9
references.pmid: 20538976
references.citation: Mol Biol Cell. 2009 Nov;20(22):4777-89
references.pmid: 19793917
references.citation: Cell. 2007 Mar 23;128(6):1133-45
references.pmid: 17382882
references.citation: Nature. 1987 May 7-13;327(6117):31-5
references.pmid: 3553962
references.citation: Cell. 1989 Jul 28;58(2):361-72
references.pmid: 2665944
references.citation: Cell. 1986 Apr 11;45(1):145-53
references.pmid: 3955656
references.citation: Curr Opin Cell Biol. 2010 Dec;22(6):801-8
references.pmid: 20678910
references.citation: J Cell Sci. 1993 Dec;106 ( Pt 4):1153-68
references.pmid: 8126097
references.citation: Nature. 1989 May 25;339(6222):275-80
references.pmid: 2566917
references.citation: Mol Biol Cell. 2011 Jul 1;22(13):2157-64
references.pmid: 21551066
references.citation: Mol Biol Cell. 1993 Dec;4(12):1337-50
references.pmid: 7513216
references.citation: Cell. 1990 Feb 9;60(3):487-94
references.pmid: 1967981
references.citation: Cancer Cell. 2010 Dec 14;18(6):641-54
references.pmid: 21156286
references.citation: J Cell Sci. 2010 Jul 1;123(Pt 13):2281-91
references.pmid: 20554897
references.citation: Science. 1974 Jan 11;183(4120):46-51
references.pmid: 4587263
references.citation: Science. 2010 Dec 17;330(6011):1673-7
references.pmid: 21164014
references.citation: Science. 1995 Oct 6;270(5233):86-90
references.pmid: 7569953
references.citation: J Cell Biol. 2004 Feb 16;164(4):487-92
references.pmid: 14970188
references.citation: Proc Natl Acad Sci U S A. 2008 Aug 5;105(31):10762-7
references.pmid: 18669648
references.citation: Mol Gen Genet. 1978 May 3;161(2):215-20
references.pmid: 672898
references.citation: Prog Biophys Mol Biol. 2009 Sep-Oct;100(1-3):47-56
references.pmid: 19523976
references.citation: Curr Opin Cell Biol. 2003 Apr;15(2):221-31
references.pmid: 12648679
references.citation: Philos Trans R Soc Lond B Biol Sci. 1991 Jun 29;332(1264):271-6
references.pmid: 1680238