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The anaphase-promoting complex/cyclosome (APC/C) ubiquitin ligase is tightly regulated to ensure programmed proteolysis in cells. The activity of the APC/C is positively controlled by cyclin-dependent kinase (CDK), but a second level of control must also exist because phosphorylation inactivates Cdc20, a mitotic APC/C co-activator. How Cdc20 is dephosphorylated specifically, when CDK is high, has remained unexplained. Here, we show that phosphatases are crucial to activate the APC/C. Cdc20 is phosphorylated at six conserved residues (S50/T64/T68/T79/S114/S165) by CDK in Xenopus egg extracts. When all the threonine residues are phosphorylated, Cdc20 binding to and activation of the APC/C are inhibited. Their dephosphorylation is regulated depending on the sites and protein phosphatase 2A, active in mitosis, is essential to dephosphorylate the threonine residues and activate the APC/C. Consistently, most of the Cdc20 bound to the APC/C in anaphase evades phosphorylation at T79. Furthermore, we show that the 'activation domain' of Cdc20 associates with the Apc6 and Apc8 core subunits. Our data suggest that dephosphorylation of Cdc20 is required for its loading and activation of the APC/C ubiquitin ligase.
Barford,
Structure, function and mechanism of the anaphase promoting complex (APC/C).
2011, Pubmed
Barford,
Structure, function and mechanism of the anaphase promoting complex (APC/C).
2011,
Pubmed Burton,
Assembly of an APC-Cdh1-substrate complex is stimulated by engagement of a destruction box.
2005,
Pubmed Buschhorn,
Substrate binding on the APC/C occurs between the coactivator Cdh1 and the processivity factor Doc1.
2011,
Pubmed Chung,
Phosphorylation of Cdc20 is required for its inhibition by the spindle checkpoint.
2003,
Pubmed
,
Xenbase Ciliberto,
Rewiring the exit from mitosis.
2005,
Pubmed
,
Xenbase da Fonseca,
Structures of APC/C(Cdh1) with substrates identify Cdh1 and Apc10 as the D-box co-receptor.
2011,
Pubmed D'Angiolella,
The spindle checkpoint requires cyclin-dependent kinase activity.
2003,
Pubmed
,
Xenbase Di Fiore,
Emi1 is needed to couple DNA replication with mitosis but does not regulate activation of the mitotic APC/C.
2007,
Pubmed Fang,
Direct binding of CDC20 protein family members activates the anaphase-promoting complex in mitosis and G1.
1998,
Pubmed
,
Xenbase Gharbi-Ayachi,
The substrate of Greatwall kinase, Arpp19, controls mitosis by inhibiting protein phosphatase 2A.
2010,
Pubmed
,
Xenbase Gmachl,
The RING-H2 finger protein APC11 and the E2 enzyme UBC4 are sufficient to ubiquitinate substrates of the anaphase-promoting complex.
2000,
Pubmed Grosskortenhaus,
Rca1 inhibits APC-Cdh1(Fzr) and is required to prevent cyclin degradation in G2.
2002,
Pubmed Harper,
The anaphase-promoting complex: it's not just for mitosis any more.
2002,
Pubmed Izawa,
How APC/C-Cdc20 changes its substrate specificity in mitosis.
2011,
Pubmed Janssens,
PP2A holoenzyme assembly: in cauda venenum (the sting is in the tail).
2008,
Pubmed Jaspersen,
Inhibitory phosphorylation of the APC regulator Hct1 is controlled by the kinase Cdc28 and the phosphatase Cdc14.
1999,
Pubmed Kimata,
A role for the Fizzy/Cdc20 family of proteins in activation of the APC/C distinct from substrate recruitment.
2008,
Pubmed
,
Xenbase Kraft,
The WD40 propeller domain of Cdh1 functions as a destruction box receptor for APC/C substrates.
2005,
Pubmed Kramer,
Mitotic regulation of the APC activator proteins CDC20 and CDH1.
2000,
Pubmed
,
Xenbase Kremmer,
Separation of PP2A core enzyme and holoenzyme with monoclonal antibodies against the regulatory A subunit: abundant expression of both forms in cells.
1997,
Pubmed Leverson,
The APC11 RING-H2 finger mediates E2-dependent ubiquitination.
2000,
Pubmed Liu,
Calcium elevation at fertilization coordinates phosphorylation of XErp1/Emi2 by Plx1 and CaMK II to release metaphase arrest by cytostatic factor.
2005,
Pubmed
,
Xenbase Matyskiela,
Analysis of activator-binding sites on the APC/C supports a cooperative substrate-binding mechanism.
2009,
Pubmed Mochida,
Calcineurin is required to release Xenopus egg extracts from meiotic M phase.
2007,
Pubmed
,
Xenbase Mochida,
Greatwall phosphorylates an inhibitor of protein phosphatase 2A that is essential for mitosis.
2010,
Pubmed
,
Xenbase Mochida,
Regulated activity of PP2A-B55 delta is crucial for controlling entry into and exit from mitosis in Xenopus egg extracts.
2009,
Pubmed
,
Xenbase Murray,
Cell cycle extracts.
1991,
Pubmed Ohsumi,
Oocyte extracts for the study of meiotic M-M transition.
2006,
Pubmed
,
Xenbase Passmore,
Doc1 mediates the activity of the anaphase-promoting complex by contributing to substrate recognition.
2003,
Pubmed Pesin,
Regulation of APC/C activators in mitosis and meiosis.
2008,
Pubmed Peters,
The anaphase promoting complex/cyclosome: a machine designed to destroy.
2006,
Pubmed Rauh,
Calcium triggers exit from meiosis II by targeting the APC/C inhibitor XErp1 for degradation.
2005,
Pubmed
,
Xenbase Rudner,
Phosphorylation by Cdc28 activates the Cdc20-dependent activity of the anaphase-promoting complex.
2000,
Pubmed Schreiber,
Structural basis for the subunit assembly of the anaphase-promoting complex.
2011,
Pubmed Schwab,
Yeast Hct1 recognizes the mitotic cyclin Clb2 and other substrates of the ubiquitin ligase APC.
2001,
Pubmed Shou,
Exit from mitosis is triggered by Tem1-dependent release of the protein phosphatase Cdc14 from nucleolar RENT complex.
1999,
Pubmed Shteinberg,
Phosphorylation of the cyclosome is required for its stimulation by Fizzy/cdc20.
1999,
Pubmed Tang,
APC2 Cullin protein and APC11 RING protein comprise the minimal ubiquitin ligase module of the anaphase-promoting complex.
2001,
Pubmed Thornton,
An architectural map of the anaphase-promoting complex.
2006,
Pubmed Thornton,
Precise destruction: an emerging picture of the APC.
2006,
Pubmed Tung,
A role for the anaphase-promoting complex inhibitor Emi2/XErp1, a homolog of early mitotic inhibitor 1, in cytostatic factor arrest of Xenopus eggs.
2005,
Pubmed
,
Xenbase Visintin,
The phosphatase Cdc14 triggers mitotic exit by reversal of Cdk-dependent phosphorylation.
1998,
Pubmed Vodermaier,
TPR subunits of the anaphase-promoting complex mediate binding to the activator protein CDH1.
2003,
Pubmed Yamano,
In vitro assays for the anaphase-promoting complex/cyclosome (APC/C) in Xenopus egg extracts.
2009,
Pubmed
,
Xenbase Yamano,
The role of proteolysis in cell cycle progression in Schizosaccharomyces pombe.
1996,
Pubmed
,
Xenbase Yu,
Cdc20: a WD40 activator for a cell cycle degradation machine.
2007,
Pubmed Yudkovsky,
Phosphorylation of Cdc20/fizzy negatively regulates the mammalian cyclosome/APC in the mitotic checkpoint.
2000,
Pubmed Zachariae,
Control of cyclin ubiquitination by CDK-regulated binding of Hct1 to the anaphase promoting complex.
1998,
Pubmed
