Plafker SM, Plafker KS, Weissman AM, Macara IG.; ''Ubiquitin charging of human class III ubiquitin-conjugating enzymes triggers their nuclear import.''; PubMedEurope PMCScholia
Binné UK, Classon MK, Dick FA, Wei W, Rape M, Kaelin WG, Näär AM, Dyson NJ.; ''Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exit.''; PubMedEurope PMCScholia
Kraft C, Herzog F, Gieffers C, Mechtler K, Hagting A, Pines J, Peters JM.; ''Mitotic regulation of the human anaphase-promoting complex by phosphorylation.''; PubMedEurope PMCScholia
Wei SJ, Williams JG, Dang H, Darden TA, Betz BL, Humble MM, Chang FM, Trempus CS, Johnson K, Cannon RE, Tennant RW.; ''Identification of a specific motif of the DSS1 protein required for proteasome interaction and p53 protein degradation.''; PubMedEurope PMCScholia
Pfleger CM, Kirschner MW.; ''The KEN box: an APC recognition signal distinct from the D box targeted by Cdh1.''; PubMedEurope PMCScholia
Hsu JY, Reimann JD, Sørensen CS, Lukas J, Jackson PK.; ''E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1).''; PubMedEurope PMCScholia
Sudakin V, Chan GK, Yen TJ.; ''Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2.''; PubMedEurope PMCScholia
Fang G, Yu H, Kirschner MW.; ''The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiation.''; PubMedEurope PMCScholia
Hagting A, Den Elzen N, Vodermaier HC, Waizenegger IC, Peters JM, Pines J.; ''Human securin proteolysis is controlled by the spindle checkpoint and reveals when the APC/C switches from activation by Cdc20 to Cdh1.''; PubMedEurope PMCScholia
Wei W, Ayad NG, Wan Y, Zhang GJ, Kirschner MW, Kaelin WG.; ''Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complex.''; PubMedEurope PMCScholia
Jin L, Williamson A, Banerjee S, Philipp I, Rape M.; ''Mechanism of ubiquitin-chain formation by the human anaphase-promoting complex.''; PubMedEurope PMCScholia
Lukas C, Sørensen CS, Kramer E, Santoni-Rugiu E, Lindeneg C, Peters JM, Bartek J, Lukas J.; ''Accumulation of cyclin B1 requires E2F and cyclin-A-dependent rearrangement of the anaphase-promoting complex.''; PubMedEurope PMCScholia
Ohtoshi A, Maeda T, Higashi H, Ashizawa S, Hatakeyama M.; ''Human p55(CDC)/Cdc20 associates with cyclin A and is phosphorylated by the cyclin A-Cdk2 complex.''; PubMedEurope PMCScholia
Voges D, Zwickl P, Baumeister W.; ''The 26S proteasome: a molecular machine designed for controlled proteolysis.''; PubMedEurope PMCScholia
Peters JM.; ''The anaphase-promoting complex: proteolysis in mitosis and beyond.''; PubMedEurope PMCScholia
Golan A, Yudkovsky Y, Hershko A.; ''The cyclin-ubiquitin ligase activity of cyclosome/APC is jointly activated by protein kinases Cdk1-cyclin B and Plk.''; PubMedEurope PMCScholia
Hames RS, Wattam SL, Yamano H, Bacchieri R, Fry AM.; ''APC/C-mediated destruction of the centrosomal kinase Nek2A occurs in early mitosis and depends upon a cyclin A-type D-box.''; PubMedEurope PMCScholia
Rape M, Reddy SK, Kirschner MW.; ''The processivity of multiubiquitination by the APC determines the order of substrate degradation.''; PubMedEurope PMCScholia
Castro A, Bernis C, Vigneron S, Labbé JC, Lorca T.; ''The anaphase-promoting complex: a key factor in the regulation of cell cycle.''; PubMedEurope PMCScholia
Ji P, Jiang H, Rekhtman K, Bloom J, Ichetovkin M, Pagano M, Zhu L.; ''An Rb-Skp2-p27 pathway mediates acute cell cycle inhibition by Rb and is retained in a partial-penetrance Rb mutant.''; PubMedEurope PMCScholia
Hansen DV, Loktev AV, Ban KH, Jackson PK.; ''Plk1 regulates activation of the anaphase promoting complex by phosphorylating and triggering SCFbetaTrCP-dependent destruction of the APC Inhibitor Emi1.''; PubMedEurope PMCScholia
Castro A, Vigneron S, Bernis C, Labbé JC, Prigent C, Lorca T.; ''The D-Box-activating domain (DAD) is a new proteolysis signal that stimulates the silent D-Box sequence of Aurora-A.''; PubMedEurope PMCScholia
Listovsky T, Oren YS, Yudkovsky Y, Mahbubani HM, Weiss AM, Lebendiker M, Brandeis M.; ''Mammalian Cdh1/Fzr mediates its own degradation.''; PubMedEurope PMCScholia
Chang LF, Zhang Z, Yang J, McLaughlin SH, Barford D.; ''Molecular architecture and mechanism of the anaphase-promoting complex.''; PubMedEurope PMCScholia
Brown NG, VanderLinden R, Watson ER, Weissmann F, Ordureau A, Wu KP, Zhang W, Yu S, Mercredi PY, Harrison JS, Davidson IF, Qiao R, Lu Y, Dube P, Brunner MR, Grace CRR, Miller DJ, Haselbach D, Jarvis MA, Yamaguchi M, Yanishevski D, Petzold G, Sidhu SS, Kuhlman B, Kirschner MW, Harper JW, Peters JM, Stark H, Schulman BA.; ''Dual RING E3 Architectures Regulate Multiubiquitination and Ubiquitin Chain Elongation by APC/C.''; PubMedEurope PMCScholia
Sørensen CS, Lukas C, Kramer ER, Peters JM, Bartek J, Lukas J.; ''A conserved cyclin-binding domain determines functional interplay between anaphase-promoting complex-Cdh1 and cyclin A-Cdk2 during cell cycle progression.''; PubMedEurope PMCScholia
Margottin-Goguet F, Hsu JY, Loktev A, Hsieh HM, Reimann JD, Jackson PK.; ''Prophase destruction of Emi1 by the SCF(betaTrCP/Slimb) ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphase.''; PubMedEurope PMCScholia
Hayes MJ, Kimata Y, Wattam SL, Lindon C, Mao G, Yamano H, Fry AM.; ''Early mitotic degradation of Nek2A depends on Cdc20-independent interaction with the APC/C.''; PubMedEurope PMCScholia
Latres E, Chiaur DS, Pagano M.; ''The human F box protein beta-Trcp associates with the Cul1/Skp1 complex and regulates the stability of beta-catenin.''; PubMedEurope PMCScholia
Kramer ER, Scheuringer N, Podtelejnikov AV, Mann M, Peters JM.; ''Mitotic regulation of the APC activator proteins CDC20 and CDH1.''; PubMedEurope PMCScholia
Song MS, Song SJ, Ayad NG, Chang JS, Lee JH, Hong HK, Lee H, Choi N, Kim J, Kim H, Kim JW, Choi EJ, Kirschner MW, Lim DS.; ''The tumour suppressor RASSF1A regulates mitosis by inhibiting the APC-Cdc20 complex.''; PubMedEurope PMCScholia
Geley S, Kramer E, Gieffers C, Gannon J, Peters JM, Hunt T.; ''Anaphase-promoting complex/cyclosome-dependent proteolysis of human cyclin A starts at the beginning of mitosis and is not subject to the spindle assembly checkpoint.''; PubMedEurope PMCScholia
Bembenek J, Yu H.; ''Regulation of the anaphase-promoting complex by the dual specificity phosphatase human Cdc14a.''; PubMedEurope PMCScholia
Ballabeni A, Park IH, Zhao R, Wang W, Lerou PH, Daley GQ, Kirschner MW.; ''Cell cycle adaptations of embryonic stem cells.''; PubMedEurope PMCScholia
In the direct inhibition model, association of the MCC with APCC results in the inactivation of APC/C. However, the affinity between MCC and APC/C is not high, so that the inhibition is readily reversible. The role of unattached kinetochores is to sensitize the APC/C to prolonged inhibition by the MCC.
In the sequestration model, the Mad2 molecules that dissociate from unattached kinetochores are perceived to bind to Cdc20, a protein that recruits specific substrates to the APC/C. Consequently, Mad2 indirectly inhibits the APC/C by sequestering its activator, Cdc20. This requires interaction between Mad1 and Mad2. Cdc20 and Mad1 bind to the same site on Mad2.
Upon release from the kinetochore, Mad2 associates with Cdc20, hBUBR1, and hBUB3 to form the Mitotic Checkpoint Complex (MCC). Assembly of this complex does not depend on kinetochores but this complex can only inhibit APC/C that has undergone mitotic modifications.
At the beginning of this reaction, 1 molecule of 'multiubiquitinated Cdh1 associated with APC/C' is present. At the end of this reaction, 1 molecule of 'phosphorylated anaphase promoting complex (APC/C)', and 3 molecules of 'ubiquitin' are present.
This reaction takes place in the 'nucleoplasm' and is mediated by the 'endopeptidase activity' of '26S proteasome'.
At the G1/S transition, the Cdh1 subunit of the APC:Cdh1 complex is phosphorylated by Cyclin A:Cdk2 and dissociates from APC/C. This inactivates APC/C and permits the accumulation of cell cycle proteins required for DNA synthesis and entry into mitosis.
The APC/C:Cdh1 complex recognizes substrates containing a D box, a KEN box (Pfleger and Kirschner, 2000) or a D box activated (DAD) domain (Castro et al., 2002).
Rape et al. have recently demonstrated that the order in which APC/C targeted proteins are degraded is determined by the processivity of multiubiquitination of these substrates. Processive substrates acquire a polyubiquitin chain upon binding to the APC/C once and are degraded. Distributive substrates bind, dissociate and reassociate with the APC/C multiple times before acquiring an ubiquitin chain of sufficient length to insure degradation. In addition, distributive substrates that dissociate from the APC/C with short ubiquitin chains are targeted for deubiquitination (Rape et al., 2006). Paradoxically, although the multiubiquitination of cyclin A is distributive and later substrates of APC-Cdc20 such as Securin are processive (Rape et al., 2006), Cyclin A is degraded prior to Securin and Cyclin B. The mechanisms insuring this order have not yet be determined.
Phosphorylation of the APC/C is believed to be required for its activation. While the identity of the essential phosphorylation sites and the kinase(s) responsible are not known with certainty, in vitro studies have shown that the Apc1 and the tetratricopeptide repeat (TPR) subunits Cdc27, Cdc16, Cdc23 and Apc7 are phosphorylated and that the Cdk1 and Plk1 kinases may play a role.
Emi1 is also believed to be phosphorylated by Cyclin B:Cdc2 on a CDK consensus site at Ser 182. While Plk1 mediated phosphorylation of Emi1 at the DSGxxS (ßTrCP recognition) motif is essential for Emi1 destruction in mitosis, Cdk phosphorylation has been shown to play an important regulatory role.
Phosphorylation by mitotic kinases is believed to alter the conformation of Cdh1 preventing it from associating with the APC/C. Cdc14 is thought to contribute to the dephosphorylation of Cdh1 in late mitosis. Dephosphorylated Cdh1 then associates with and activates the APC/C.
Phosphorylation of the APC/C is believed to be required for its activation. While the identity of the essential phosphorylation sites and the kinase(s) responsible are not known with certainty, in vitro studies have shown that the Apc1 and the tetratricopeptide repeat (TPR) subunits Cdc27, Cdc16, Cdc23 and Apc7 are phosphorylated and that the Cdk1 and Plk1 kinases may play a role.
Following its phosphorylation, Cdh1 dissociates from the APC/C, rendering the APC/C inactive. This allows the stabilization of proteins required for subsequent cell cycle progression.
Cyclin A is believed to be recognized by the APC/C:Cdc20 complex through its D-box sequence, which is 10-20 residues longer than the D-box of cyclin B (Geley et al., 2001).
The phosphorylation of Emi1 by Plk1 is believed to be involved in the degradation of Emi1 during mitosis. Plk1 phosphorylates serine residues in the DSGxxS degron sequence of Emi1 recruiting the SCF(betaTrCP) ubiquitin ligase.
At the beginning of this reaction, 3 molecules of 'ubiquitin', and 1 molecule of 'cell cycle proteins:phospho-APC/C:Cdh1 complex' are present. At the end of this reaction, 1 molecule of 'multiubiquitinated cell cycle protein:APC/C:Cdh1 complex' is present.
This reaction takes place in the 'cytosol' and is mediated by the 'ubiquitin-protein ligase activity' of 'cell cycle proteins:phospho-APC/C:Cdh1 complex' (Rape et al.1996).
At the beginning of this reaction, 1 molecule of 'Cdc20:phospho-APC/C:Cyclin B:Cdc2 complex', and 3 molecules of 'ubiquitin' are present. At the end of this reaction, 1 molecule of 'multiubiquitinated Cyclin B:Cdc2:Cdc20:phospho-APC/C complex' is present.
This reaction takes place in the 'cytosol' and is mediated by the 'ubiquitin-protein ligase activity' of 'Cdc20:Phospho-APC/C'.
In addition to its association with Cdh1 in G1 phase, Emi1 further contributes the inactivation of the APC/C between G2 and prophase by associating with another APC/C activator, Cdc20.
One model ( the direct inhibition model) describing the inhibition of the APC/C during the mitotic spindle checkpoint suggests that the association of the hBUBR1:hBUB3:MAD2*:CDC20 mitotic checkpoint complex (MCC) with APC/C results in the inactivation of APC/C. The affinity between MCC and APC/C is not high, thus inhibition is readily reversible when the mitotic spindle checkpoint has been satisfied.
Nek2A does not appear to be recruited to the APC/C by Cdc20 but rather binds directly to the APC/C in an interaction involving the NEK2A C-terminal methionine–arginine (MR) dipeptide tail (Hayes et al., 2006).
SKP2 is degraded by the anaphase promoting complex/Cyclosome and its activator FZR1 (Cdh1) [APC/C(Cdh1)] (Bashir et al, 2004; Wei et al, 2004). The tight regulation of APC/C(Cdh1) activity ensures the timely elimination SKP2 and, thus, plays a critical role in controlling the M/G1 transition (mitotic exit). APC/C:Cdh1-mediated degradation of SKP2 depends on RB1, as RB1 recruits SKP2 to the APC/C:Cdh1 complex, by simultaneously interacting with SKP2 and FZR1. RB1 does not undergo APC/C:Cdh1-mediated ubiquitination (Binne et al. 2007).
Cyclin A-Cdk2 prevents unscheduled APC reactivation during S phase by binding and subsequently phosphorylating Cdh1. Phosphorylation-dependent dissociation of the Cdh1-activating subunit inhibits the APC/C.
RB1-dependent polyubiquitination of SKP2 by the APC/C:Cdh1 complex is an important mechanism of RB1-mediated cell cycle exit, which contributes to the RB1 tumor suppressive role. ABC/C:Cdh1-mediated polyubiquitination targets SKP2 for proteasome-mediated degradation. RB1 and APC/C:Cdh1-dependent degradation of SKP2 allows accumulation of CDKN1B (p27Kip1) in the cell, as CDKN1B is a target of the SKP2-containing SCF ubiquitin ligase complex. CDKN1B acts as a CDK inhibitor, enabling mitotic exit (Ji et al. 2004, Binne et al. 2007).
The pocket domain of the RB1 tumor suppressor protein binds to the N-terminal domain of SKP2, a component of the SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex, whose targets include the cyclin-dependent kinase (CDK) inhibitor p27Kip1 (CDKN1B) (Ji et al. 2004, Binne et al. 2007). RB1 is able to simultanously interact with SKP2 and with FZR1 (Cdh1). FZR1 is a substrate-specific adapter for the anaphase promoting complex/cyclosome (APC/C). The interaction with FZR1 involves a different subregion of the pocket domain than the interaction with SKP2, and is partially dependent on the LxCxE binding cleft (Binne et al. 2007).
Try the New WikiPathways
View approved pathways at the new wikipathways.org.Quality Tags
Ontology Terms
Bibliography
History
External references
DataNodes
A:phospho-Cdc2(Thr
161) complexA:phospho-Cdk(Thr
160):Cdh1:phosho-APC/C complexA:phospho-Cdk2(Thr
160):phospho-Cdh1:phospho-APC/C complex182):Cdc20/Cdh1
complexesmultiubiquitinated
Emi1complexescycle
proteins:phospho-APC/C:Cdh1 complexCdh1 associated
with APC/CCyclin
B:Cdc2:Cdc20:phospho-APC/C complexCyclin A associated with MCC:APC/C
complexcell cycle protein:APC/C:Cdh1
complex145, Ser 149):Cdc20/Cdh1
complexesanaphase promoting
complex (APC/C)anaphase promoting
complex (APC/C)Annotated Interactions
A:phospho-Cdc2(Thr
161) complexA:phospho-Cdk(Thr
160):Cdh1:phosho-APC/C complexA:phospho-Cdk(Thr
160):Cdh1:phosho-APC/C complexA:phospho-Cdk(Thr
160):Cdh1:phosho-APC/C complexA:phospho-Cdk2(Thr
160):phospho-Cdh1:phospho-APC/C complex182):Cdc20/Cdh1
complexesThis reaction takes place in the 'nucleoplasm' and is mediated by the 'endopeptidase activity' of '26S proteasome'.
This reaction takes place in the 'cytosol' and is mediated by the 'ubiquitin-protein ligase activity' of 'cell cycle proteins:phospho-APC/C:Cdh1 complex' (Rape et al.1996).
This reaction takes place in the 'cytosol' and is mediated by the 'ubiquitin-protein ligase activity' of 'Cdc20:Phospho-APC/C'.
multiubiquitinated
Emi1complexesmultiubiquitinated
Emi1complexescycle
proteins:phospho-APC/C:Cdh1 complexcycle
proteins:phospho-APC/C:Cdh1 complexcycle
proteins:phospho-APC/C:Cdh1 complexCdh1 associated
with APC/CCdh1 associated
with APC/CCyclin
B:Cdc2:Cdc20:phospho-APC/C complexCyclin
B:Cdc2:Cdc20:phospho-APC/C complexCyclin A associated with MCC:APC/C
complexCyclin A associated with MCC:APC/C
complexcell cycle protein:APC/C:Cdh1
complexcell cycle protein:APC/C:Cdh1
complex145, Ser 149):Cdc20/Cdh1
complexesanaphase promoting
complex (APC/C)anaphase promoting
complex (APC/C)anaphase promoting
complex (APC/C)anaphase promoting
complex (APC/C)anaphase promoting
complex (APC/C)anaphase promoting
complex (APC/C)anaphase promoting
complex (APC/C)