BioPAX pathway converted from "APC/C-mediated degradation of cell cycle proteins" in the Reactome database.APC/C-mediated degradation of cell cycle proteinsAPC/C-mediated degradation of cell cycle proteinsThe Anaphase Promoting Complex or Cyclosome (APC/C) functions during mitosis to promote sister chromatid separation and mitotic exit through the degradation of mitotic cyclins and securin. This complex is also active in interphase insuring the appropriate length of the G1 phase (reviewed in Peters, 2002). The APC/C contains at least 12 subunits and functions as an ubiquitin-protein ligase (E3) promoting the multiubiquitination of its target proteins (see Gieffers et al., 2001). <br>In the ubiquitination reaction, ubiquitin is activated by the formation of a thioester bond with the (E1) ubiquitin activating enzyme then transferred to a cysteine residue within the ubiquitin conjugating enzyme (E2) and ultimately to a lysine residue within the target protein, with the aid of ubiquitin-protein ligase activity of the APC/C. The ubiquitin chains generated are believed to target proteins for destruction by the 26S proteasome (Reviewed in Peters, 1994 ) <br>The activity of the APC/C is highly periodic during the cell cycle and is controlled by a combination of regulatory events. The APC/C is activated by phosphorylation and the regulated recruitment of activating subunits and is negatively regulated by sequestration by kinetochore-associated checkpoint proteins. The Emi1 protein associates with Cdh1 and Cdc20, inhibiting the APC/C between G1/S and prophase. RSSA1 may play a similar role in ihibiting the APC during early mitosis.<br>Following phosphorylation of the APC/C core subunits by mitotic kinases, the activating subunit, Cdc20 is recruited to the APC/C and is responsible for mitotic activities, including the initiation of sister chromatid separation and the timing of exit from mitosis (See Zachariae and Nasmyth, 1999). Substrates of the Cdc20:APC/C complex, which are recognized by a motif known as the destruction box (D box) include Cyclin A, Nek2, Securin and Cyclin B. Degradation of Securin and Cyclin B does not occur until the mitotic spindle checkpoint has been satisfied (see Castro et al. 2005).<br>Cdc20 is degraded late in mitosis (Reviewed in Owens and Hoyt, 2005). At this time the activating subunit, Cdh1, previously maintained in an inactive phosphorylated state by mitotic kinases, is dephosphorylated and associates with and activates the APC/C. 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) sequence and promotes the ordered degration of mitotic cyclins and other mitotic proteins culminating with its own ubiquitin-conjugating enzyme (E2) subunit UbcH10 (Rape et al., 2006). This ordered degradation promotes the stability of Cyclin A at the end of G1. This stabilization, in turn, promotes the phosphorylation of Cdh1 and its abrupt dissociation from the APC/C, allowing accumulation of cyclins for the next G1/S transition (Sorensen et al., 2001). <br><br>Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Regulation of APC/C activators between G1/S and early anaphaseRegulation of APC/C activators between G1/S and early anaphaseThe APC/C is activated by either Cdc20 or Cdh1. While both activators associate with the APC/C, they do so at different points in the cell cycle and their binding is regulated differently (see Zachariae and Nasmyth, 1999). Cdc20, whose protein levels increase as cells enter into mitosis and decrease upon mitotic exit, only associates with the APC/C during M phase. Cdh1 associates with the APC/C in G1. This interaction is inhibited at other times by Cdk1 phosphorylation.Reviewed: Peters, JM, 2006-03-27 22:55:09Association of Cyclin A:Cdk2 with Cdh1Association of Cyclin A:Cdk2 with Cdh1Cyclin 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.Authored: Lorca, T, Castro, A, 2006-10-10 10:03:43Reviewed: Peters, JM, 2006-10-10 10:07:26Edited: Matthews, L, 2006-10-10 08:05:07Reactome DB_ID: 1879521nucleoplasmGO0005654CCNA:p-T160-CDK2 [nucleoplasm]CCNA:p-T160-CDK2Cyclin A:phospho-Cdk2(Thr160) complexConverted from EntitySet in ReactomeReactome DB_ID: 752021CCNA [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityReactomehttp://www.reactome.orgReactome DB_ID: 1879671UniProt:P24941 CDK2CDK2CDK2CDKN2FUNCTION Serine/threonine-protein kinase involved in the control of the cell cycle; essential for meiosis, but dispensable for mitosis. Phosphorylates CTNNB1, USP37, p53/TP53, NPM1, CDK7, RB1, BRCA2, MYC, NPAT, EZH2. Triggers duplication of centrosomes and DNA. Acts at the G1-S transition to promote the E2F transcriptional program and the initiation of DNA synthesis, and modulates G2 progression; controls the timing of entry into mitosis/meiosis by controlling the subsequent activation of cyclin B/CDK1 by phosphorylation, and coordinates the activation of cyclin B/CDK1 at the centrosome and in the nucleus. Crucial role in orchestrating a fine balance between cellular proliferation, cell death, and DNA repair in human embryonic stem cells (hESCs). Activity of CDK2 is maximal during S phase and G2; activated by interaction with cyclin E during the early stages of DNA synthesis to permit G1-S transition, and subsequently activated by cyclin A2 (cyclin A1 in germ cells) during the late stages of DNA replication to drive the transition from S phase to mitosis, the G2 phase. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. Phosphorylates CABLES1 (By similarity). Cyclin E/CDK2 prevents oxidative stress-mediated Ras-induced senescence by phosphorylating MYC. Involved in G1-S phase DNA damage checkpoint that prevents cells with damaged DNA from initiating mitosis; regulates homologous recombination-dependent repair by phosphorylating BRCA2, this phosphorylation is low in S phase when recombination is active, but increases as cells progress towards mitosis. In response to DNA damage, double-strand break repair by homologous recombination a reduction of CDK2-mediated BRCA2 phosphorylation. Phosphorylation of RB1 disturbs its interaction with E2F1. NPM1 phosphorylation by cyclin E/CDK2 promotes its dissociates from unduplicated centrosomes, thus initiating centrosome duplication. Cyclin E/CDK2-mediated phosphorylation of NPAT at G1-S transition and until prophase stimulates the NPAT-mediated activation of histone gene transcription during S phase. Required for vitamin D-mediated growth inhibition by being itself inactivated. Involved in the nitric oxide- (NO) mediated signaling in a nitrosylation/activation-dependent manner. USP37 is activated by phosphorylation and thus triggers G1-S transition. CTNNB1 phosphorylation regulates insulin internalization. Phosphorylates FOXP3 and negatively regulates its transcriptional activity and protein stability (By similarity). Phosphorylates CDK2AP2 (PubMed:12944431). Phosphorylates ERCC6 which is essential for its chromatin remodeling activity at DNA double-strand breaks (PubMed:29203878).ACTIVITY REGULATION Phosphorylation at Thr-14 or Tyr-15 inactivates the enzyme, while phosphorylation at Thr-160 activates it (PubMed:1396589). Inhibited by 1,25-dihydroxyvitamin D(3) (1,25-(OH)(2)D(3)), AG-024322, N-(4-Piperidinyl)-4-(2,6-dichlorobenzoylamino)-1H-pyrazole-3-carboxamide (AT7519), R547 (Ro-4584820), purine, pyrimidine and pyridine derivatives, 2-aminopyrimidines, paullones, thiazo derivatives, macrocyclic quinoxalin-2-one, pyrazolo[1,5-a]-1,3,5-triazine, pyrazolo[1,5-a]pyrimidine, 2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine (roscovitine, seliciclib and CYC202), SNS-032 (BMS-387032), triazolo[1,5-a]pyrimidines, staurosporine and olomoucine. Stimulated by MYC. Inactivated by CDKN1A (p21).SUBUNIT Found in a complex with CABLES1, CCNA1 and CCNE1. Interacts with CABLES1 (By similarity). Interacts with UHRF2. Part of a complex consisting of UHRF2, CDK2 and CCNE1. Interacts with the Speedy/Ringo proteins SPDYA and SPDYC (PubMed:15611625). Interaction with SPDYA promotes kinase activation via a conformation change that alleviates obstruction of the substrate-binding cleft by the T-loop (PubMed:28666995). Found in a complex with both SPDYA and CDKN1B/KIP1 (PubMed:12972555, PubMed:28666995). Binds to RB1 and CDK7. Binding to CDKN1A (p21) leads to CDK2/cyclin E inactivation at the G1-S phase DNA damage checkpoint, thereby arresting cells at the G1-S transition during DNA repair. Associated with PTPN6 and beta-catenin/CTNNB1. Interacts with CACUL1. May interact with CEP63. Interacts with ANKRD17. Interacts with CEBPA (when phosphorylated) (PubMed:15107404). Forms a ternary complex with CCNA2 and CDKN1B; CDKN1B inhibits the kinase activity of CDK2 through conformational rearrangements (PubMed:8684460). Interacts with cyclins A, B1, B3, D, or E (PubMed:10499802, PubMed:10884347, PubMed:12185076, PubMed:23781148). Interacts with CDK2AP2 (PubMed:23781148).INDUCTION Induced transiently by TGFB1 at an early phase of TGFB1-mediated apoptosis.PTM Phosphorylated at Thr-160 by CDK7 in a CAK complex (PubMed:28666995). Phosphorylation at Thr-160 promotes kinase activity, whereas phosphorylation at Tyr-15 by WEE1 reduces slightly kinase activity. Phosphorylated on Thr-14 and Tyr-15 during S and G2 phases before being dephosphorylated by CDC25A.PTM Nitrosylated after treatment with nitric oxide (DETA-NO).SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.Homo sapiensNCBI Taxonomy9606UniProtP24941O-phospho-L-threonine at 160160EQUALO-phospho-L-threonine [MOD:00047]Chain Coordinates1EQUAL298EQUALReactome Database ID Release 75187952Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=187952ReactomeR-HSA-1879521Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-187952.1Reactome DB_ID: 1742501Cdh1:phospho-APC/C complex [nucleoplasm]Cdh1:phospho-APC/C complexReactome DB_ID: 1740991UniProt:Q9UM11 FZR1FZR1FZR1CDH1KIAA1242FYRFZRFUNCTION Substrate-specific adapter for the anaphase promoting complex/cyclosome (APC/C) E3 ubiquitin-protein ligase complex. Associates with the APC/C in late mitosis, in replacement of CDC20, and activates the APC/C during anaphase and telophase. The APC/C remains active in degrading substrates to ensure that positive regulators of the cell cycle do not accumulate prematurely. At the G1/S transition FZR1 is phosphorylated, leading to its dissociation from the APC/C. Following DNA damage, it is required for the G2 DNA damage checkpoint: its dephosphorylation and reassociation with the APC/C leads to the ubiquitination of PLK1, preventing entry into mitosis. Acts as an adapter for APC/C to target the DNA-end resection factor RBBP8/CtIP for ubiquitination and subsequent proteasomal degradation. Through the regulation of RBBP8/CtIP protein turnover, may play a role in DNA damage response, favoring DNA double-strand repair through error-prone non-homologous end joining (NHEJ) over error-free, RBBP8-mediated homologous recombination (HR) (PubMed:25349192).PATHWAY Protein modification; protein ubiquitination.SUBUNIT The unphosphorylated form interacts with APC/C during mitosis (PubMed:26083744, PubMed:9734353). Interacts with NINL (PubMed:17403670). Interacts (in complex with the anaphase promoting complex APC) with MAD2L2; inhibits FZR1-mediated APC/C activation (PubMed:11459825, PubMed:11459826). Interacts with SIRT2 and USP37 (PubMed:21596315, PubMed:22014574). Interacts (via WD repeats) with MAK (PubMed:21986944). Interacts with RBBP8/CtIP; this interaction leads to RBBP8 proteasomal degradation (PubMed:25349192). Interacts with HECW2 (PubMed:24163370). Interacts with SASS6; the interaction is regulated by CENATAC and leads to SASS6 proteasomal degradation (PubMed:31722219).TISSUE SPECIFICITY Isoform 2 is expressed at high levels in heart, liver, spleen and some cancer cell lines whereas isoform 3 is expressed only at low levels in these tissues.PTM Acetylated. Deacetylated by SIRT2 at Lys-69 and Lys-159; deacetylation enhances the interaction of FZR1 with CDC27, leading to activation of anaphase promoting complex/cyclosome (APC/C).PTM Phosphorylated during mitosis, probably by maturation promoting factor (MPF), leading to its dissociation of the APC/C. Following DNA damage, it is dephosphorylated by CDC14B in G2 phase, leading to its reassociation with the APC/C, and allowing an efficient G2 DNA damage checkpoint. Phosphorylated by MAK.SIMILARITY Belongs to the WD repeat CDC20/Fizzy family.UniProtQ9UM111EQUAL496EQUALReactome DB_ID: 1741091phosphorylated anaphase promoting complex (APC/C) [nucleoplasm]phosphorylated anaphase promoting complex (APC/C)Reactome DB_ID: 1741531UniProt:Q9UJX4 ANAPC5ANAPC5ANAPC5APC5FUNCTION Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.PATHWAY Protein modification; protein ubiquitination.SUBUNIT The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5.DOMAIN The TPR repeats are six to seven residues longer than a canonical TPR motif.SIMILARITY Belongs to the APC5 family.UniProtQ9UJX41EQUAL755EQUALReactome DB_ID: 1742041UniProt:Q9UJX3 ANAPC7ANAPC7ANAPC7APC7FUNCTION Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.PATHWAY Protein modification; protein ubiquitination.SUBUNIT V-shaped homodimer. The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5 (PubMed:25043029, PubMed:26083744).SIMILARITY Belongs to the APC7 family.CAUTION It is uncertain whether Met-1 or Met-35 is the initiator.UniProtQ9UJX31EQUAL599EQUALReactome DB_ID: 68051361UniProt:P60006 ANAPC15ANAPC15ANAPC15C11orf51HSPC020FUNCTION Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. In the complex, plays a role in the release of the mitotic checkpoint complex (MCC) from the APC/C: not required for APC/C activity itself, but promotes the turnover of CDC20 and MCC on the APC/C, thereby participating in the responsiveness of the spindle assembly checkpoint. Also required for degradation of CDC20.SUBUNIT The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5.SIMILARITY Belongs to the APC15 family.UniProtP600061EQUAL121EQUALReactome DB_ID: 1741881UniProt:O00762 UBE2CUBE2CUBE2CUBCH10FUNCTION Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. In vitro catalyzes 'Lys-11'- and 'Lys-48'-linked polyubiquitination. Acts as an essential factor of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated ubiquitin ligase that controls progression through mitosis. Acts by initiating 'Lys-11'-linked polyubiquitin chains on APC/C substrates, leading to the degradation of APC/C substrates by the proteasome and promoting mitotic exit.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Component of the APC/C complex, composed of at least 14 distinct subunits that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa. Within this complex, directly interacts with ANAPC2.PTM Autoubiquitinated by the APC/C complex, leading to its degradation by the proteasome. Its degradation plays a central role in APC/C regulation, allowing cyclin-A accumulation before S phase entry. APC/C substrates inhibit the autoubiquitination of UBE2C/UBCH10 but not its E2 function, hence APC/C remaining active until its substrates have been destroyed.SIMILARITY Belongs to the ubiquitin-conjugating enzyme family.UniProtO007622EQUAL179EQUALReactome DB_ID: 1741151UniProt:Q9UJX5 ANAPC4ANAPC4ANAPC4APC4FUNCTION Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.PATHWAY Protein modification; protein ubiquitination.SUBUNIT The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5 (PubMed:25043029, PubMed:27259151, PubMed:9469815, PubMed:26083744). In the context of the APC/C complex, directly interacts with UBE2S (PubMed:27259151).SIMILARITY Belongs to the APC4 family.UniProtQ9UJX51EQUAL808EQUALReactome DB_ID: 1742161UniProt:Q8NHZ8 CDC26CDC26ANAPC12C9orf17CDC26FUNCTION Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains. May recruit the E2 ubiquitin-conjugating enzymes to the complex.PATHWAY Protein modification; protein ubiquitination.SUBUNIT V-shaped homodimer. Interacts with CDC16. The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5.SIMILARITY Belongs to the CDC26 family.UniProtQ8NHZ81EQUAL85EQUALReactome DB_ID: 1741631UniProt:Q9NYG5 ANAPC11ANAPC11HSPC214ANAPC11FUNCTION Together with the cullin protein ANAPC2, constitutes the catalytic component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains. May recruit the E2 ubiquitin-conjugating enzymes to the complex.PATHWAY Protein modification; protein ubiquitination.SUBUNIT The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5 (PubMed:26083744, PubMed:10922056, PubMed:25043029). Interacts with the cullin domain of ANAPC2 (PubMed:11739784). Interacts with UBE2D2 (PubMed:11739784).TISSUE SPECIFICITY Expressed at high levels in skeletal muscle and heart; in moderate levels in brain, kidney, and liver; and at low levels in colon, thymus, spleen, small intestine, placenta, lung and peripheral blood leukocyte.DOMAIN The RING-type zinc finger domain coordinates an additional third zinc ion.PTM Auto-ubiquitinated.SIMILARITY Belongs to the RING-box family.UniProtQ9NYG51EQUAL84EQUALReactome DB_ID: 1741411UniProt:Q9UJX6 ANAPC2ANAPC2APC2KIAA1406ANAPC2FUNCTION Together with the RING-H2 protein ANAPC11, constitutes the catalytic component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains. The CDC20-APC/C complex positively regulates the formation of synaptic vesicle clustering at active zone to the presynaptic membrane in postmitotic neurons. CDC20-APC/C-induced degradation of NEUROD2 drives presynaptic differentiation.PATHWAY Protein modification; protein ubiquitination.SUBUNIT The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5 (PubMed:25043029, PubMed:26083744). In the context of the APC/C complex, directly interacts with UBE2C and UBE2S (PubMed:27259151). Interacts (via cullin domain) with ANAPC11 and with UBCH10 (PubMed:11739784). Interacts with NEUROD2 (By similarity).SIMILARITY Belongs to the cullin family.UniProtQ9UJX61EQUAL822EQUALReactome DB_ID: 1741751UniProt:P30260 CDC27CDC27D0S1430ECDC27ANAPC3D17S978EFUNCTION Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homodimer. The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5 (PubMed:26083744, PubMed:25043029). Interacts with RB. Interacts with FAM168B/MANI (By similarity). Interacts with MCPH1 (PubMed:22139841).PTM Phosphorylated. Phosphorylation on Ser-426 and Thr-446 occurs specifically during mitosis.SIMILARITY Belongs to the APC3/CDC27 family.UniProtP302601EQUAL824EQUALReactome DB_ID: 1742281UniProt:Q9UJX2 CDC23CDC23CDC23ANAPC8FUNCTION Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.PATHWAY Protein modification; protein ubiquitination.SUBUNIT The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5.PTM Phosphorylated. Phosphorylation on Thr-562 occurs specifically during mitosis.SIMILARITY Belongs to the APC8/CDC23 family.UniProtQ9UJX21EQUAL597EQUALReactome DB_ID: 1740631UniProt:P51965 UBE2E1UBE2E1UBE2E1UBCH6FUNCTION Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. Catalyzes the covalent attachment of ISG15 to other proteins. Mediates the selective degradation of short-lived and abnormal proteins. In vitro also catalyzes 'Lys-48'-linked polyubiquitination.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with RNF14.PTM ISGylation suppresses ubiquitin E2 enzyme activity.PTM Autoubiquitinated in vitro.SIMILARITY Belongs to the ubiquitin-conjugating enzyme family.UniProtP519652EQUAL193EQUALReactome DB_ID: 1740471UniProt:Q9UM13 ANAPC10ANAPC10APC10ANAPC10FUNCTION Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.PATHWAY Protein modification; protein ubiquitination.SUBUNIT The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5 (PubMed:26083744, PubMed:25043029). The C-terminus of APC10 binds to CDC27/APC3 (PubMed:11524682). Interacts with PIWIL1; interaction only takes place when PIWIL1 binds piRNA (By similarity).SIMILARITY Belongs to the APC10 family.UniProtQ9UM131EQUAL185EQUALReactome DB_ID: 1740491UniProt:Q13042 CDC16CDC16CDC16ANAPC6FUNCTION Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.PATHWAY Protein modification; protein ubiquitination.SUBUNIT V-shaped homodimer. The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5 (PubMed:26083744, PubMed:25043029). Interacts with PPP5C and CDC20 (PubMed:9628895, PubMed:9405394). Interacts with CDC26 (PubMed:19668213).DOMAIN TPR repeats 1-7 mediate homodimerization, while the C-terminal TPR repeats bind to CDC26, burying its hydrophobic N-terminus.PTM Phosphorylated. Phosphorylation on Ser-560 occurs specifically during mitosis.SIMILARITY Belongs to the APC6/CDC16 family.UniProtQ130421EQUAL620EQUALReactome DB_ID: 1741971UniProt:P51668 UBE2D1UBE2D1SFTUBCH5AUBE2D1UBC5AUBCH5FUNCTION Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins (PubMed:22496338). In vitro catalyzes 'Lys-48'-linked polyubiquitination (PubMed:20061386). Mediates the selective degradation of short-lived and abnormal proteins. Functions in the E6/E6-AP-induced ubiquitination of p53/TP53. Mediates ubiquitination of PEX5 and auto-ubiquitination of STUB1, TRAF6 and TRIM63/MURF1 (PubMed:18042044, PubMed:18359941). Ubiquitinates STUB1-associated HSP90AB1 in vitro (PubMed:18042044). Lacks inherent specificity for any particular lysine residue of ubiquitin (PubMed:18042044). Essential for viral activation of IRF3 (PubMed:19854139). Mediates polyubiquitination of CYP3A4 (PubMed:19103148).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Component of a E3 ubiquitin ligase complex containing UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC and TBL1X. Interacts with RNF11.TISSUE SPECIFICITY Ubiquitous. Up-regulated in livers of iron-overloaded patients with hereditary hemochromatosis.PTM Autoubiquitinated in vitro.SIMILARITY Belongs to the ubiquitin-conjugating enzyme family.CAUTION PubMed:9362508 cloned and sequenced SFT which consisted of UBE2D1 last coding exon along with intronic sequences on the 5'-end of this exon. A function in iron transport has been described.UniProtP516681EQUAL147EQUALReactome DB_ID: 88520511UniProt:Q16763 UBE2SUBE2SUBE2SE2EPFOK/SW-cl.73FUNCTION Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins (PubMed:22496338). Catalyzes 'Lys-11'-linked polyubiquitination. Acts as an essential factor of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated ubiquitin ligase that controls progression through mitosis. Acts by specifically elongating 'Lys-11'-linked polyubiquitin chains initiated by the E2 enzyme UBE2C/UBCH10 on APC/C substrates, enhancing the degradation of APC/C substrates by the proteasome and promoting mitotic exit (PubMed:19820702, PubMed:19822757, PubMed:27259151). Also acts by elongating ubiquitin chains initiated by the E2 enzyme UBE2D1/UBCH5 in vitro; it is however unclear whether UBE2D1/UBCH5 acts as an E2 enzyme for the APC/C in vivo. Also involved in ubiquitination and subsequent degradation of VHL, resulting in an accumulation of HIF1A (PubMed:16819549). In vitro able to promote polyubiquitination using all 7 ubiquitin Lys residues, except 'Lys-48'-linked polyubiquitination (PubMed:20061386, PubMed:20622874).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Component of the APC/C complex, composed of at least 14 distinct subunits that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa. Within this complex, directly interacts with ANAPC2 and ANAPC4 (PubMed:27259151). Interacts with CDC20, FZR1/CDH1 and VHL (PubMed:16819549, PubMed:19822757).PTM Autoubiquitinated by the APC/C complex during G1, leading to its degradation by the proteasome.SIMILARITY Belongs to the ubiquitin-conjugating enzyme family.UniProtQ167631EQUAL222EQUALReactome DB_ID: 1742171UniProt:Q9H1A4 ANAPC1ANAPC1TSG24ANAPC1FUNCTION Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.PATHWAY Protein modification; protein ubiquitination.SUBUNIT The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5.PTM Phosphorylated. Phosphorylation on Ser-355 occurs specifically during mitosis.SIMILARITY Belongs to the APC1 family.UniProtQ9H1A41EQUAL1944EQUALReactome DB_ID: 68051371UniProt:Q96DE5 ANAPC16ANAPC16ANAPC16C10orf104CENP-27FUNCTION Component of the anaphase promoting complex/cyclosome (APC/C), a cell cycle-regulated E3 ubiquitin ligase that controls progression through mitosis and the G1 phase of the cell cycle. The APC/C complex acts by mediating ubiquitination and subsequent degradation of target proteins: it mainly mediates the formation of 'Lys-11'-linked polyubiquitin chains and, to a lower extent, the formation of 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains.PATHWAY Protein modification; protein ubiquitination.SUBUNIT The mammalian APC/C is composed at least of 14 distinct subunits ANAPC1, ANAPC2, CDC27/APC3, ANAPC4, ANAPC5, CDC16/APC6, ANAPC7, CDC23/APC8, ANAPC10, ANAPC11, CDC26/APC12, ANAPC13, ANAPC15 and ANAPC16 that assemble into a complex of at least 19 chains with a combined molecular mass of around 1.2 MDa; APC/C interacts with FZR1 and FBXO5 (PubMed:26083744, PubMed:25043029). ANAPC16 associates with the rest of the complex independently of ANAPC2 and ANAPC11.SIMILARITY Belongs to the APC16 family.UniProtQ96DE52EQUAL110EQUALReactome Database ID Release 75174109Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174109ReactomeR-HSA-1741093Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174109.3Reactome Database ID Release 75174250Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174250ReactomeR-HSA-1742501Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174250.1Reactome DB_ID: 1883741Cyclin A:phospho-Cdk(Thr 160):Cdh1:phosho-APC/C complex [nucleoplasm]Cyclin A:phospho-Cdk(Thr 160):Cdh1:phosho-APC/C complexReactome DB_ID: 1879521Reactome DB_ID: 1742501Reactome Database ID Release 75188374Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=188374ReactomeR-HSA-1883741Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-188374.1Reactome Database ID Release 75188371Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=188371ReactomeR-HSA-1883712Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-188371.211340163Pubmed2001A conserved cyclin-binding domain determines functional interplay between anaphase-promoting complex-Cdh1 and cyclin A-Cdk2 during cell cycle progressionSorensen, CSLukas, CKramer, ERPeters, JMLukas, JMol Cell Biol 21:3692-7032.7.11.22Phosphorylation of Cdh1 by Cyclin A:Cdk2Phosphorylation of Cdh1 by Cyclin A:Cdk2At 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.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Reactome DB_ID: 1883741Reactome DB_ID: 293581ATP(4-) [ChEBI:30616]ATP(4-)Adenosine 5'-triphosphateatpATPChEBI30616Reactome DB_ID: 1883871Cyclin A:phospho-Cdk2(Thr 160):phospho-Cdh1:phospho-APC/C complex [nucleoplasm]Cyclin A:phospho-Cdk2(Thr 160):phospho-Cdh1:phospho-APC/C complexReactome DB_ID: 1741671phospho-Cdh1:phospho-APC/C complex [nucleoplasm]phospho-Cdh1:phospho-APC/C complexReactome DB_ID: 1742571phosphorylated residue at unknown positionphosphorylated residue [MOD:00696]1EQUAL496EQUALReactome DB_ID: 1741091Reactome Database ID Release 75174167Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174167ReactomeR-HSA-1741671Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174167.1Reactome DB_ID: 1879521Reactome Database ID Release 75188387Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=188387ReactomeR-HSA-1883871Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-188387.1Reactome DB_ID: 1135821ADP(3-) [ChEBI:456216]ADP(3-)ADP trianion5&apos;-O-[(phosphonatooxy)phosphinato]adenosineADPChEBI456216PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 188374GO0004693GO molecular functionReactome Database ID Release 75188394Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=188394Reactome Database ID Release 75174079Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174079ReactomeR-HSA-1740793Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174079.310548110Pubmed1999Accumulation of cyclin B1 requires E2F and cyclin-A-dependent rearrangement of the anaphase-promoting complexLukas, CSorensen, CSKramer, ESantoni-Rugiu, ELindeneg, CPeters, JMLukas, JNature 401:815-8Dissociation of phospho-Cdh1 from the APC/C complexDissociation of phospho-Cdh1 from the APC/C complexFollowing 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.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Reactome DB_ID: 1741671Reactome DB_ID: 1742571phosphorylated residue at unknown position1EQUAL496EQUALReactome DB_ID: 1741091Reactome Database ID Release 75174139Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174139ReactomeR-HSA-1741393Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174139.3Association of Emi1 with Cdh1Association of Emi1 with Cdh1Emi1 promotes the accumulation of Cyclin A and entry into S phase by associating with and inhibiting the APC/C:Cdh1 complex at G1/S.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Converted from EntitySet in ReactomeReactome DB_ID: 1764291Cdh1 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-FZR1 [nucleoplasm]FZR1 [nucleoplasm]Reactome DB_ID: 1740601UniProt:Q9UKT4 FBXO5FBXO5EMI1FBX5FBXO5FUNCTION Regulator of APC activity during mitotic and meiotic cell cycle (PubMed:17485488, PubMed:17234884, PubMed:17875940, PubMed:23708001, PubMed:23708605, PubMed:16921029). During mitotic cell cycle plays a role as both substrate and inhibitor of APC-FZR1 complex (PubMed:29875408, PubMed:17485488, PubMed:17234884, PubMed:17875940, PubMed:23708001, PubMed:23708605, PubMed:16921029). During G1 phase, plays a role as substrate of APC-FZR1 complex E3 ligase (PubMed:29875408). Then switches as an inhibitor of APC-FZR1 complex during S and G2 leading to cell-cycle commitment (PubMed:29875408). As APC inhibitor, prevents the degradation of APC substrates at multiple levels: by interacting with APC and blocking access of APC substrates to the D-box coreceptor, formed by FZR1 and ANAPC10; by suppressing ubiquitin ligation and chain elongation by APC by preventing the UBE2C and UBE2S activities (PubMed:23708605, PubMed:23708001, PubMed:16921029). Plays a role in genome integrity preservation by coordinating DNA replication with mitosis through APC inhibition in interphase to stabilize CCNA2 and GMNN in order to promote mitosis and prevent rereplication and DNA damage-induced cellular senescence (PubMed:17234884, PubMed:17485488, PubMed:17875940). During oocyte maturation, plays a role in meiosis through inactivation of APC-FZR1 complex. Inhibits APC through RPS6KA2 interaction that increases FBXO5 affiniy for CDC20 leading to the metaphase arrest of the second meiotic division before fertilization (By similarity). Controls entry into the first meiotic division through inactivation of APC-FZR1 complex (By similarity). Promotes migration and osteogenic differentiation of mesenchymal stem cells (PubMed:29850565).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Part of a SCF (SKP1-cullin-F-box) protein ligase complex (By similarity). Interacts with BTRC; mediates proteolysis by the SCF ubiquitin ligase complex leading to activation of APC in late mitosis and subsequent mitotic progression (PubMed:12791267). Interacts with FZR1/CDH1 and the N-terminal substrate-binding domain of CDC20; prevents APC activation (PubMed:11988738). Also interacts with EVI5 which blocks its phosphorylation by PLK1 and prevents its subsequent binding to BTRC and degradation (PubMed:16439210). Interacts simultaneously with anaphase promoting complex (APC), through at least ANAPC2, CDC23, CDC27, the APC substrate GMNN and the APC activator FZR1 (PubMed:23708001, PubMed:26083744). Interacts with UBE2S; interferes with the activity of UBE2S mainly by disrupting the dynamic electrostatic association between the C-terminal tail of UBE2S and ANAPC2 (PubMed:23708001). Interacts with RPS6KA2; cooperates to induce the metaphase arrest of early blastomeres; increases and stabilizes interaction of FBXO5 with CDC20 (By similarity).DEVELOPMENTAL STAGE Accumulates in late G1 phase, levels rise during S phase and drop in early mitosis.INDUCTION Up-regulated at 7 days after osteogenic induction (PubMed:29850565). Down-regulated in late G2 phase or mitosis (PubMed:17485488). Down-regulated in G2 phase after DNA damage in a CDKN1A-dependent manner (PubMed:19211842). Down-regulated in G1 phase when APC-FZR1 complex is active and accumulates at the G1-S transition, coincident with the inactivation of APC-FZR1 complex (PubMed:29875408). At the G1-S transition, transcriptionally induced by the E2F transcription factor (PubMed:11988738).PTM Phosphorylation by CDK2 and subsequently by PLK1 triggers degradation during early mitosis through ubiquitin-mediated proteolysis by the SCF ubiquitin ligase complex containing the F-box protein BTRC. This degradation is necessary for the activation of APC in late mitosis and subsequent mitotic progression (PubMed:12791267, PubMed:15469984). Phosphorylated by RPS6KA2; increases and stabilizes interaction with CDC20 (By similarity).PTM Ubiquitinated by the SCF(BTRC) complex following phosphorylation by PLK1 (PubMed:15469984). Undergoes both 'Lys-11' and 'Lys-48'-linked polyubiquitination by APC-FZR1 complex leading to degradation by proteasome during G1 phase (PubMed:29875408). Degraded through the SCF(BTRC) complex; degradation occurs during oocyte maturation, between germinal vesicle breakdown (GVBD) and meiosis I, and is required for the meiosis I-meiosis II transition (By similarity).UniProtQ9UKT41EQUAL447EQUALReactome DB_ID: 1742471Emi1:Cdh1 complex [nucleoplasm]Emi1:Cdh1 complexConverted from EntitySet in ReactomeReactome DB_ID: 1764291Reactome DB_ID: 17406011EQUAL447EQUALReactome Database ID Release 75174247Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174247ReactomeR-HSA-1742471Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174247.1Reactome Database ID Release 75174097Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174097ReactomeR-HSA-1740974Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174097.411988738Pubmed2002E2F-dependent accumulation of hEmi1 regulates S phase entry by inhibiting APC(Cdh1)Hsu, JYReimann, JDSorensen, CSLukas, JJackson, PKNat Cell Biol 4:358-66Association of Emi1 with Cdc20Association of Emi1 with Cdc20In 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.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Reactome DB_ID: 17406011EQUAL447EQUALReactome DB_ID: 1741121UniProt:Q12834 CDC20CDC20CDC20FUNCTION Required for full ubiquitin ligase activity of the anaphase promoting complex/cyclosome (APC/C) and may confer substrate specificity upon the complex. Is regulated by MAD2L1: in metaphase the MAD2L1-CDC20-APC/C ternary complex is inactive and in anaphase the CDC20-APC/C binary complex is active in degrading substrates. The CDC20-APC/C complex positively regulates the formation of synaptic vesicle clustering at active zone to the presynaptic membrane in postmitotic neurons. CDC20-APC/C-induced degradation of NEUROD2 induces presynaptic differentiation.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Found in a complex with CDC20, CDC27, SPATC1 and TUBG1. Interacts with NEUROD2 and SPATC1 (By similarity). Interacts with MAD2L1 and BUB1B. The phosphorylated form interacts with APC/C. Interacts with NINL. May interact with MAD2L2. Interacts with CDK5RAP2 and SIRT2. Interacts with isoform 1 of NEK2. Interacts with HSF1 (via phosphorylated form); this interaction occurs in mitosis in a MAD2L1-dependent manner and prevents PLK1-stimulated degradation of HSF1 by blocking the recruitment of the SCF(BTRC) ubiquitin ligase complex (PubMed:18794143). Interacts (via the N-terminal substrate-binding domain) with FBXO5 (By similarity).DEVELOPMENTAL STAGE Synthesis is initiated at G1/S, protein level peaks in M phase and protein is abruptly degraded at M/G1 transition.PTM Acetylated. Deacetylated at Lys-66 by SIRT2; deacetylation enhances the interaction of CDC20 with CDC27, leading to activation of anaphase promoting complex/cyclosome (APC/C).PTM Phosphorylated during mitosis, probably by maturation promoting factor (MPF). Phosphorylated by BUB1 at Ser-41; Ser-72; Ser-92; Ser-153; Thr-157 and Ser-161. Phosphorylated by NEK2.PTM Dephosphorylated by CTDP1.PTM Ubiquitinated and degraded by the proteasome during spindle assembly checkpoint. Deubiquitinated by USP44, leading to stabilize the MAD2L1-CDC20-APC/C ternary complex, thereby preventing premature activation of the APC/C. Ubiquitinated at Lys-490 during prometaphase. Ubiquitination at Lys-485 and Lys-490 has no effect on its ability to bind the APC/C complex.SIMILARITY Belongs to the WD repeat CDC20/Fizzy family.UniProtQ128341EQUAL499EQUALReactome DB_ID: 1741861Emi1:Cdc20 complex [nucleoplasm]Emi1:Cdc20 complexReactome DB_ID: 17406011EQUAL447EQUALReactome DB_ID: 17411211EQUAL499EQUALReactome Database ID Release 75174186Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174186ReactomeR-HSA-1741861Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174186.1Reactome Database ID Release 75174235Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174235ReactomeR-HSA-1742353Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174235.314743218Pubmed2004The tumour suppressor RASSF1A regulates mitosis by inhibiting the APC-Cdc20 complexSong, MSSong, SJAyad, NGChang, JSLee, JHHong, HKLee, HChoi, NKim, JKim, HKim, JWChoi, EJKirschner, Marc WLim, DSNat Cell Biol 6:129-37Phosphorylation of Emi1Phosphorylation of Emi1The phosphorylation of Emi1, which is required for its degradation in mitosis, appears to involve both Plk1 and Cdk1.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:092.7.11.22Phosphorylation of the Emi1 DSGxxS degron by Cyclin B:Cdc2Phosphorylation of the Emi1 DSGxxS degron by Cyclin B:Cdc2Emi1 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.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-02-17 05:21:42Reactome DB_ID: 1886791Emi1:Cdc20/Cdh1 complex [nucleoplasm]Emi1:Cdc20/Cdh1 complexReactome DB_ID: 17406011EQUAL447EQUALConverted from EntitySet in ReactomeReactome DB_ID: 1869771Cdc20/Cdh1 [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityp-FZR1 [nucleoplasm]FZR1 [nucleoplasm]CDC20 [nucleoplasm]Reactome Database ID Release 75188679Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=188679ReactomeR-HSA-1886791Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-188679.1Reactome DB_ID: 293581Reactome DB_ID: 1869751Phospho-Emi1(Ser 182):Cdc20/Cdh1 complexes [nucleoplasm]Phospho-Emi1(Ser 182):Cdc20/Cdh1 complexesReactome DB_ID: 1764471O-phospho-L-serine at 182182EQUALO-phospho-L-serine [MOD:00046]1EQUAL447EQUALConverted from EntitySet in ReactomeReactome DB_ID: 1869771Reactome Database ID Release 75186975Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=186975ReactomeR-HSA-1869751Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-186975.1Reactome DB_ID: 1135821PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 170160CCNB1:p-T161-CDK1 [nucleoplasm]CCNB1:p-T161-CDK1Cyclin B1:phospho-Cdc2(Thr 161)Reactome DB_ID: 1700661UniProt:P06493 CDK1CDK1P34CDC2CDK1CDC28ACDKN1CDC2FUNCTION Plays a key role in the control of the eukaryotic cell cycle by modulating the centrosome cycle as well as mitotic onset; promotes G2-M transition, and regulates G1 progress and G1-S transition via association with multiple interphase cyclins. Required in higher cells for entry into S-phase and mitosis. Phosphorylates PARVA/actopaxin, APC, AMPH, APC, BARD1, Bcl-xL/BCL2L1, BRCA2, CALD1, CASP8, CDC7, CDC20, CDC25A, CDC25C, CC2D1A, CENPA, CSNK2 proteins/CKII, FZR1/CDH1, CDK7, CEBPB, CHAMP1, DMD/dystrophin, EEF1 proteins/EF-1, EZH2, KIF11/EG5, EGFR, FANCG, FOS, GFAP, GOLGA2/GM130, GRASP1, UBE2A/hHR6A, HIST1H1 proteins/histone H1, HMGA1, HIVEP3/KRC, LMNA, LMNB, LMNC, LBR, LATS1, MAP1B, MAP4, MARCKS, MCM2, MCM4, MKLP1, MYB, NEFH, NFIC, NPC/nuclear pore complex, PITPNM1/NIR2, NPM1, NCL, NUCKS1, NPM1/numatrin, ORC1, PRKAR2A, EEF1E1/p18, EIF3F/p47, p53/TP53, NONO/p54NRB, PAPOLA, PLEC/plectin, RB1, TPPP, UL40/R2, RAB4A, RAP1GAP, RCC1, RPS6KB1/S6K1, KHDRBS1/SAM68, ESPL1, SKI, BIRC5/survivin, STIP1, TEX14, beta-tubulins, MAPT/TAU, NEDD1, VIM/vimentin, TK1, FOXO1, RUNX1/AML1, SAMHD1, SIRT2 and RUNX2. CDK1/CDC2-cyclin-B controls pronuclear union in interphase fertilized eggs. Essential for early stages of embryonic development. During G2 and early mitosis, CDC25A/B/C-mediated dephosphorylation activates CDK1/cyclin complexes which phosphorylate several substrates that trigger at least centrosome separation, Golgi dynamics, nuclear envelope breakdown and chromosome condensation. Once chromosomes are condensed and aligned at the metaphase plate, CDK1 activity is switched off by WEE1- and PKMYT1-mediated phosphorylation to allow sister chromatid separation, chromosome decondensation, reformation of the nuclear envelope and cytokinesis. Inactivated by PKR/EIF2AK2- and WEE1-mediated phosphorylation upon DNA damage to stop cell cycle and genome replication at the G2 checkpoint thus facilitating DNA repair. Reactivated after successful DNA repair through WIP1-dependent signaling leading to CDC25A/B/C-mediated dephosphorylation and restoring cell cycle progression. In proliferating cells, CDK1-mediated FOXO1 phosphorylation at the G2-M phase represses FOXO1 interaction with 14-3-3 proteins and thereby promotes FOXO1 nuclear accumulation and transcription factor activity, leading to cell death of postmitotic neurons. The phosphorylation of beta-tubulins regulates microtubule dynamics during mitosis. NEDD1 phosphorylation promotes PLK1-mediated NEDD1 phosphorylation and subsequent targeting of the gamma-tubulin ring complex (gTuRC) to the centrosome, an important step for spindle formation. In addition, CC2D1A phosphorylation regulates CC2D1A spindle pole localization and association with SCC1/RAD21 and centriole cohesion during mitosis. The phosphorylation of Bcl-xL/BCL2L1 after prolongated G2 arrest upon DNA damage triggers apoptosis. In contrast, CASP8 phosphorylation during mitosis prevents its activation by proteolysis and subsequent apoptosis. This phosphorylation occurs in cancer cell lines, as well as in primary breast tissues and lymphocytes. EZH2 phosphorylation promotes H3K27me3 maintenance and epigenetic gene silencing. CALD1 phosphorylation promotes Schwann cell migration during peripheral nerve regeneration. CDK1-cyclin-B complex phosphorylates NCKAP5L and mediates its dissociation from centrosomes during mitosis (PubMed:26549230). Regulates the amplitude of the cyclic expression of the core clock gene ARNTL/BMAL1 by phosphorylating its transcriptional repressor NR1D1, and this phosphorylation is necessary for SCF(FBXW7)-mediated ubiquitination and proteasomal degradation of NR1D1 (PubMed:27238018).FUNCTION (Microbial infection) Acts as a receptor for hepatitis C virus (HCV) in hepatocytes and facilitates its cell entry.ACTIVITY REGULATION Phosphorylation at Thr-14 or Tyr-15 inactivates the enzyme, while phosphorylation at Thr-161 activates it. Activated through a multistep process; binding to cyclin-B is required for relocation of cyclin-kinase complexes to the nucleus, activated by CAK/CDK7-mediated phosphorylation on Thr-161, and CDC25-mediated dephosphorylation of inhibitory phosphorylation on Thr-14 and Tyr-15. Inhibited by flavopiridol and derivatives, pyrimidine derivatives, pyridine derivatives, purine derivatives, staurosporine, paullones, oxoindoles, indazole analogs, indolin-2-ones, pyrazolo[3,4-b]pyridines, imidazo[1,2-a]pyridine (AZ703), thiazolinone analogs(RO-3306), thiazol urea, macrocyclic quinoxalin-2-one, pyrrolo[2,3-a]carbazole, pyrazolo[1,5-a]-1,3,5-triazine, pyrazolo[1,5-a]pyrimidine (Dinaciclib, SCH 727965), 2-(1-ethyl-2-hydroxyethylamino)-6-benzylamino-9-isopropylpurine (roscovitine), olomoucine, AG-024322, AT-7519, P276-00, R547/Ro-4584820 and SNS-032/BMS-387032. Repressed by the CDK inhibitors CDKN1A/p21 and CDKN1B/p27 during the G1 phase and by CDKN1A/p21 at the G1-S checkpoint upon DNA damage. Transient activation by rapid and transient dephosphorylation at Tyr-15 triggered by TGFB1.SUBUNIT Forms a stable but non-covalent complex with a regulatory subunit and with a cyclin. Interacts with cyclins-B (CCNB1, CCNB2 and CCNB3) to form a serine/threonine kinase holoenzyme complex also known as maturation promoting factor (MPF). The cyclin subunit imparts substrate specificity to the complex. Can also form CDK1-cylin-D and CDK1-cyclin-E complexes that phosphorylate RB1 in vitro. Binds to RB1 and other transcription factors such as FOXO1 and RUNX2. Promotes G2-M transition when in complex with a cyclin-B. Interacts with DLGAP5. Binds to the CDK inhibitors CDKN1A/p21 and CDKN1B/p27. Isoform 2 is unable to complex with cyclin-B1 and also fails to bind to CDKN1A/p21. Interacts with catalytically active CCNB1 and RALBP1 during mitosis to form an endocytotic complex during interphase. Associates with cyclins-A and B1 during S-phase in regenerating hepatocytes. Interacts with FANCC. Interacts with CEP63; this interaction recruits CDK1 to centrosomes. Interacts with CENPA (PubMed:25556658). Interacts with NR1D1 (PubMed:27238018). Interacts with proteasome subunit PSMA8; to participate in meiosis progression during spermatogenesis (By similarity).TISSUE SPECIFICITY Isoform 2 is found in breast cancer tissues.INDUCTION Follows a cyclic expression; during interphase, accumulates gradually following G1, S to reach a critical threshold at the end of G2, which promotes self-activation and triggers onset of mitosis. Induced transiently by TGFB1 at an early phase of TGFB1-mediated apoptosis, but later repressed. Triggered by CKS1B during mitotic entry in breast cancer cells. Down-regulated under genotoxic stresses triggered by PKR/EIF2AK2-mediated phosphorylation.PTM Phosphorylation at Thr-161 by CAK/CDK7 activates kinase activity. Phosphorylation at Thr-14 and Tyr-15 by PKMYT1 prevents nuclear translocation. Phosphorylation at Tyr-15 by WEE1 and WEE2 inhibits the protein kinase activity and acts as a negative regulator of entry into mitosis (G2 to M transition). Phosphorylation by PKMYT1 and WEE1 takes place during mitosis to keep CDK1-cyclin-B complexes inactive until the end of G2. By the end of G2, PKMYT1 and WEE1 are inactivated, but CDC25A and CDC25B are activated. Dephosphorylation by active CDC25A and CDC25B at Thr-14 and Tyr-15, leads to CDK1 activation at the G2-M transition. Phosphorylation at Tyr-15 by WEE2 during oogenesis is required to maintain meiotic arrest in oocytes during the germinal vesicle (GV) stage, a long period of quiescence at dictyate prophase I, leading to prevent meiotic reentry. Phosphorylation by WEE2 is also required for metaphase II exit during egg activation to ensure exit from meiosis in oocytes and promote pronuclear formation. Phosphorylated at Tyr-4 by PKR/EIF2AK2 upon genotoxic stress. This phosphorylation triggers CDK1 polyubiquitination and subsequent proteolysis, thus leading to G2 arrest. In response to UV irradiation, phosphorylation at Tyr-15 by PRKCD activates the G2/M DNA damage checkpoint.PTM Polyubiquitinated upon genotoxic stress.MISCELLANEOUS As a key regulator of the cell cycle, CDK1 is a potent therapeutic target for inhibitors in cancer treatment.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily.UniProtP06493O-phospho-L-threonine at 161161EQUAL1EQUAL297EQUALReactome DB_ID: 689011UniProt:P14635 CCNB1CCNB1CCNB1CCNBFUNCTION Essential for the control of the cell cycle at the G2/M (mitosis) transition.SUBUNIT Interacts with the CDC2 protein kinase to form a serine/threonine kinase holoenzyme complex also known as maturation promoting factor (MPF). The cyclin subunit imparts substrate specificity to the complex. Binds HEI10. Interacts with catalytically active RALBP1 and CDC2 during mitosis to form an endocytotic complex during interphase. Interacts with CCNF; interaction is required for nuclear localization. Interacts with CDK5RAP3 (PubMed:15790566). Interacts with RFPL4A and UBE2A (By similarity). Interacts with INCA1 (PubMed:21540187).DEVELOPMENTAL STAGE Accumulates steadily during G2 and is abruptly destroyed at mitosis.PTM Ubiquitinated by the SCF(NIPA) complex during interphase, leading to its destruction. Not ubiquitinated during G2/M phases.PTM Phosphorylated by PLK1 at Ser-133 on centrosomes during prophase: phosphorylation by PLK1 does not cause nuclear import. Phosphorylation at Ser-147 was also reported to be mediated by PLK1 but Ser-133 seems to be the primary phosphorylation site.SIMILARITY Belongs to the cyclin family. Cyclin AB subfamily.UniProtP146351EQUAL433EQUALReactome Database ID Release 75170160Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=170160ReactomeR-HSA-1701601Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-170160.1Reactome Database ID Release 75174240Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174240Reactome Database ID Release 75174122Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174122ReactomeR-HSA-1741222Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174122.212791267Pubmed2003Prophase destruction of Emi1 by the SCF(betaTrCP/Slimb) ubiquitin ligase activates the anaphase promoting complex to allow progression beyond prometaphaseMargottin-Goguet, FHsu, JYLoktev, AHsieh, HMReimann, JDJackson, PKDev Cell 4:813-262.7.11Phosphorylation of the Emi1 DSGxxS degron by Plk1Phosphorylation of the Emi1 DSGxxS degron by Plk1The 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.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-02-17 05:22:55Reactome DB_ID: 1886791Reactome DB_ID: 293582Reactome DB_ID: 1764461phospho-Emi1(Ser 145, Ser 149):Cdc20/Cdh1 complexes [nucleoplasm]phospho-Emi1(Ser 145, Ser 149):Cdc20/Cdh1 complexesReactome DB_ID: 1742201O-phospho-L-serine at 145145EQUALO-phospho-L-serine at 149149EQUAL1EQUAL447EQUALConverted from EntitySet in ReactomeReactome DB_ID: 1869771Reactome Database ID Release 75176446Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176446ReactomeR-HSA-1764461Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176446.1Reactome DB_ID: 1135822PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 3002800UniProt:P53350 PLK1PLK1PLK1PLKFUNCTION Serine/threonine-protein kinase that performs several important functions throughout M phase of the cell cycle, including the regulation of centrosome maturation and spindle assembly, the removal of cohesins from chromosome arms, the inactivation of anaphase-promoting complex/cyclosome (APC/C) inhibitors, and the regulation of mitotic exit and cytokinesis. Polo-like kinase proteins acts by binding and phosphorylating proteins are that already phosphorylated on a specific motif recognized by the POLO box domains. Phosphorylates BORA, BUB1B/BUBR1, CCNB1, CDC25C, CEP55, ECT2, ERCC6L, FBXO5/EMI1, FOXM1, KIF20A/MKLP2, CENPU, NEDD1, NINL, NPM1, NUDC, PKMYT1/MYT1, KIZ, PPP1R12A/MYPT1, PRC1, RACGAP1/CYK4, SGO1, STAG2/SA2, TEX14, TOPORS, p73/TP73, TPT1, WEE1 and HNRNPU. Plays a key role in centrosome functions and the assembly of bipolar spindles by phosphorylating KIZ, NEDD1 and NINL. NEDD1 phosphorylation promotes subsequent targeting of the gamma-tubulin ring complex (gTuRC) to the centrosome, an important step for spindle formation. Phosphorylation of NINL component of the centrosome leads to NINL dissociation from other centrosomal proteins. Involved in mitosis exit and cytokinesis by phosphorylating CEP55, ECT2, KIF20A/MKLP2, CENPU, PRC1 and RACGAP1. Recruited at the central spindle by phosphorylating and docking PRC1 and KIF20A/MKLP2; creates its own docking sites on PRC1 and KIF20A/MKLP2 by mediating phosphorylation of sites subsequently recognized by the POLO box domains. Phosphorylates RACGAP1, thereby creating a docking site for the Rho GTP exchange factor ECT2 that is essential for the cleavage furrow formation. Promotes the central spindle recruitment of ECT2. Plays a central role in G2/M transition of mitotic cell cycle by phosphorylating CCNB1, CDC25C, FOXM1, CENPU, PKMYT1/MYT1, PPP1R12A/MYPT1 and WEE1. Part of a regulatory circuit that promotes the activation of CDK1 by phosphorylating the positive regulator CDC25C and inhibiting the negative regulators WEE1 and PKMYT1/MYT1. Also acts by mediating phosphorylation of cyclin-B1 (CCNB1) on centrosomes in prophase. Phosphorylates FOXM1, a key mitotic transcription regulator, leading to enhance FOXM1 transcriptional activity. Involved in kinetochore functions and sister chromatid cohesion by phosphorylating BUB1B/BUBR1, FBXO5/EMI1 and STAG2/SA2. PLK1 is high on non-attached kinetochores suggesting a role of PLK1 in kinetochore attachment or in spindle assembly checkpoint (SAC) regulation. Required for kinetochore localization of BUB1B. Regulates the dissociation of cohesin from chromosomes by phosphorylating cohesin subunits such as STAG2/SA2. Phosphorylates SGO1: required for spindle pole localization of isoform 3 of SGO1 and plays a role in regulating its centriole cohesion function. Mediates phosphorylation of FBXO5/EMI1, a negative regulator of the APC/C complex during prophase, leading to FBXO5/EMI1 ubiquitination and degradation by the proteasome. Acts as a negative regulator of p53 family members: phosphorylates TOPORS, leading to inhibit the sumoylation of p53/TP53 and simultaneously enhance the ubiquitination and subsequent degradation of p53/TP53. Phosphorylates the transactivation domain of the transcription factor p73/TP73, leading to inhibit p73/TP73-mediated transcriptional activation and pro-apoptotic functions. Phosphorylates BORA, and thereby promotes the degradation of BORA. Contributes to the regulation of AURKA function. Also required for recovery after DNA damage checkpoint and entry into mitosis. Phosphorylates MISP, leading to stabilization of cortical and astral microtubule attachments required for proper spindle positioning (PubMed:8991084, PubMed:11202906, PubMed:12207013, PubMed:12447691, PubMed:12524548, PubMed:12738781, PubMed:12852856, PubMed:12939256, PubMed:14532005, PubMed:14734534, PubMed:15070733, PubMed:15148369, PubMed:15469984, PubMed:16198290, PubMed:16247472, PubMed:16980960, PubMed:17081991, PubMed:17351640, PubMed:17376779, PubMed:17617734, PubMed:18174154, PubMed:18331714, PubMed:18418051, PubMed:18477460, PubMed:18521620, PubMed:18615013, PubMed:19160488, PubMed:19351716, PubMed:19468300, PubMed:19468302, PubMed:19473992, PubMed:19509060, PubMed:19597481, PubMed:23455478, PubMed:23509069). Together with MEIKIN, acts as a regulator of kinetochore function during meiosis I: required both for mono-orientation of kinetochores on sister chromosomes and protection of centromeric cohesin from separase-mediated cleavage (By similarity). Phosphorylates CEP68 and is required for its degradation (PubMed:25503564). Regulates nuclear envelope breakdown during prophase by phosphorylating DCTN1 resulting in its localization in the nuclear envelope (PubMed:20679239). Phosphorylates the heat shock transcription factor HSF1, promoting HSF1 nuclear translocation upon heat shock (PubMed:15661742). Phosphorylates HSF1 also in the early mitotic period; this phosphorylation regulates HSF1 localization to the spindle pole, the recruitment of the SCF(BTRC) ubiquitin ligase complex induicing HSF1 degradation, and hence mitotic progression (PubMed:18794143). Regulates mitotic progression by phosphorylating RIOK2 (PubMed:21880710).ACTIVITY REGULATION Activated by phosphorylation of Thr-210 by AURKA; phosphorylation by AURKA is enhanced by BORA. Once activated, activity is stimulated by binding target proteins. Binding of target proteins has no effect on the non-activated kinase. Several inhibitors targeting PLKs are currently in development and are under investigation in a growing number of clinical trials, such as BI 2536, an ATP-competitive PLK1 inhibitor or BI 6727, a dihydropteridinone that specifically inhibits the catalytic activity of PLK1.SUBUNIT Interacts with CEP170 and EVI5. Interacts and phosphorylates ERCC6L. Interacts with FAM29A. Interacts with SLX4/BTBD12 and TTDN1. Interacts with BUB1B. Interacts (via POLO-box domain) with the phosphorylated form of BUB1, CENPU and CDC25C. Interacts with isoform 3 of SGO1. Interacts with BORA, KIF2A and AURKA. Interacts with TOPORS and CYLD. Interacts with ECT2; the interaction is stimulated upon phosphorylation of ECT2 on 'Thr-444'. Interacts with PRC1. Interacts with KIF20A/MKLP2 (when phosphorylated), leading to the recruitment at the central spindle. Interacts (via POLO box domains) with PPP1R12A/MYPT1 (when previously phosphorylated by CDK1). Part of an astrin (SPAG5)-kinastrin (SKAP) complex containing KNSTRN, SPAG5, PLK1, DYNLL1 and SGO2. Interacts with BIRC6/bruce. Interacts with CDK1-phosphorylated FRY; this interaction occurs in mitotic cells, but not in interphase cells. FRY interaction facilitates AURKA-mediated PLK1 phosphorylation. Interacts with CDK1-phosphorylated DCTN6 during mitotic prometaphase; the interaction facilitates recruitment to kinetochores. Interacts with CEP68; the interaction phosphorylates CEP68 (PubMed:25503564). Interacts (via POLO-box domain) with DCTN1 (PubMed:20679239). Interacts with CEP20 in later G1, S, G2 and M phases of the cell cycle; this interaction recruits PLK1 to centrosomes, a step required for S phase progression (PubMed:24018379). Interacts with HSF1; this interaction increases upon heat shock but does not modulate neither HSF1 homotrimerization nor DNA-binding activities (PubMed:15661742, PubMed:18794143). Interacts with HNRNPU; this interaction induces phosphorylation of HNRNPU in mitosis (PubMed:25986610). Interacts (via its N-terminus) to RIOK2 (PubMed:21880710). Interacts with KLHL22 (PubMed:24067371, PubMed:23455478).TISSUE SPECIFICITY Placenta and colon.DEVELOPMENTAL STAGE Accumulates to a maximum during the G2 and M phases, declines to a nearly undetectable level following mitosis and throughout G1 phase, and then begins to accumulate again during S phase.INDUCTION By growth-stimulating agents.DOMAIN The POLO box domains act as phosphopeptide-binding module that recognize and bind serine-[phosphothreonine/phosphoserine]-(proline/X) motifs. PLK1 recognizes and binds docking proteins that are already phosphorylated on these motifs, and then phosphorylates them. PLK1 can also create its own docking sites by mediating phosphorylation of serine-[phosphothreonine/phosphoserine]-(proline/X) motifs subsequently recognized by the POLO box domains.PTM Catalytic activity is enhanced by phosphorylation of Thr-210. Phosphorylation at Thr-210 is first detected on centrosomes in the G2 phase of the cell cycle, peaks in prometaphase and gradually disappears from centrosomes during anaphase. Dephosphorylation at Thr-210 at centrosomes is probably mediated by protein phosphatase 1C (PP1C), via interaction with PPP1R12A/MYPT1. Autophosphorylation and phosphorylation of Ser-137 may not be significant for the activation of PLK1 during mitosis, but may enhance catalytic activity during recovery after DNA damage checkpoint. Phosphorylated in vitro by STK10.PTM Ubiquitinated by the anaphase promoting complex/cyclosome (APC/C) in anaphase and following DNA damage, leading to its degradation by the proteasome. Ubiquitination is mediated via its interaction with FZR1/CDH1. Ubiquitination and subsequent degradation prevents entry into mitosis and is essential to maintain an efficient G2 DNA damage checkpoint. Monoubiquitination at Lys-492 by the BCR(KLHL22) ubiquitin ligase complex does not lead to degradation: it promotes PLK1 dissociation from phosphoreceptor proteins and subsequent removal from kinetochores, allowing silencing of the spindle assembly checkpoint (SAC) and chromosome segregation.DISEASE Defects in PLK1 are associated with some cancers, such as gastric, thyroid or B-cell lymphomas. Expression is cancer increased in tumor tissues with a poor prognosis, suggesting a role in malignant transformations and carcinogenesis.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. CDC5/Polo subfamily.UniProtP53350O-phospho-L-threonine at 210210EQUAL1EQUAL603EQUALGO0004674GO molecular functionReactome Database ID Release 75156714Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=156714Reactome Database ID Release 75174174Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174174ReactomeR-HSA-1741742Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174174.215469984Pubmed2004Plk1 regulates activation of the anaphase promoting complex by phosphorylating and triggering SCFbetaTrCP-dependent destruction of the APC Inhibitor Emi1Hansen, DVLoktev, AVBan, KHMol Biol Cell 15:5623-34Reactome Database ID Release 75176417Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176417ReactomeR-HSA-1764172Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176417.2SCF-beta-TrCP mediated degradation of Emi1SCF-beta-TrCP mediated degradation of Emi1Emi1 destruction in early mitosis requires the SCF beta-TrCP ubiquitin ligase complex. Binding of beta-TrCP to Emi1 occurs in late prophase and requires phosphorylation at the DSGxxS consensus motif as well as Cdk mediated phosphorylation. A two-step mechanism has been proposed in which the phosphorylation of Emi1 by Cdc2 occurs after the G2-M transition followed soon after by binding of beta-TrCP to the DSGxxS phosphorylation sites. Emi1 is then poly-ubiquitinated and degraded by the 26S proteasome.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Phosphorylated Emi1 binds the beta-TrCP in the SCF complexPhosphorylated Emi1 binds the beta-TrCP in the SCF complexCdk mediated phosphorylation of Emi1 is believed to promotes its phospho- Ser145-Ser149 dependent association with beta-TrCP.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-02-17 05:46:22Reactome DB_ID: 1741551cytosolGO0005829BTRC:CUL1:SKP1 [cytosol]BTRC:CUL1:SKP1SCF-beta-TrCP1 complexReactome DB_ID: 1741501UniProt:P63208 SKP1SKP1TCEB1LOCP2EMC19SKP1ASKP1FUNCTION Essential component of the SCF (SKP1-CUL1-F-box protein) ubiquitin ligase complex, which mediates the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. In the SCF complex, serves as an adapter that links the F-box protein to CUL1. The functional specificity of the SCF complex depends on the F-box protein as substrate recognition component. SCF(BTRC) and SCF(FBXW11) direct ubiquitination of CTNNB1 and participate in Wnt signaling. SCF(FBXW11) directs ubiquitination of phosphorylated NFKBIA. SCF(BTRC) directs ubiquitination of NFKBIB, NFKBIE, ATF4, SMAD3, SMAD4, CDC25A, FBXO5, CEP68 and probably NFKB2 (PubMed:25704143). SCF(SKP2) directs ubiquitination of phosphorylated CDKN1B/p27kip and is involved in regulation of G1/S transition. SCF(SKP2) directs ubiquitination of ORC1, CDT1, RBL2, ELF4, CDKN1A, RAG2, FOXO1A, and probably MYC and TAL1. SCF(FBXW7) directs ubiquitination of cyclin E, NOTCH1 released notch intracellular domain (NICD), and probably PSEN1. SCF(FBXW2) directs ubiquitination of GCM1. SCF(FBXO32) directs ubiquitination of MYOD1. SCF(FBXO7) directs ubiquitination of BIRC2 and DLGAP5. SCF(FBXO33) directs ubiquitination of YBX1. SCF(FBXO11) directs ubiquitination of BCL6 and DTL but does not seem to direct ubiquitination of TP53. SCF(BTRC) mediates the ubiquitination of NFKBIA at 'Lys-21' and 'Lys-22'; the degradation frees the associated NFKB1-RELA dimer to translocate into the nucleus and to activate transcription. SCF(CCNF) directs ubiquitination of CCP110. SCF(FBXL3) and SCF(FBXL21) direct ubiquitination of CRY1 and CRY2. SCF(FBXO9) directs ubiquitination of TTI1 and TELO2. SCF(FBXO10) directs ubiquitination of BCL2.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with KDM2B, forming heterodimers (PubMed:27568929). The KDM2B-SKP1 heterodimeric complex interacts with the PCGF1-BCORL heterodimeric complex to form a homotetrameric polycomb repression complex 1 (PRC1.1) (PubMed:27568929). Component of multiple SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complexes formed of CUL1, SKP1, RBX1 and a variable F-box domain-containing protein as substrate-specific subunit. Component of the SCF(FBXW11) complex containing FBXW11. Component of the SCF(SKP2) complex containing SKP2, in which it interacts directly with SKP1, SKP2 and RBX1. Component of the SCF(FBXW2) complex containing FBXw2. Component of the SCF(FBXO32) complex containing FBXO32. Component of the probable SCF(FBXO7) complex containing FBXO7. Component of the SCF(FBXO10) complex containing FBXO10. Component of the SCF(FBXO11) complex containing FBXO11. Component of the SCF(FBXO25) complex containing FBXO25. Component of the SCF(FBXO33) complex containing FBXO33. Component of the probable SCF(FBXO4) complex containing FBXO4. Component of the SCF(FBXO44) complex, composed of SKP1, CUL1 and FBXO44. Component of the SCF(BTRC) complex, composed of SKP1, CUL1 and BTRC. This complex binds phosphorylated NFKBIA. Part of a SCF complex consisting of CUL1, RBX1, SKP1 and FBXO2. Component of a SCF(SKP2)-like complex containing CUL1, SKP1, TRIM21 and SKP2. Component of the SCF(FBXO17) complex, composed of SKP1, CUL1 and FBXO17. Component of the SCF(FBXO27) complex, composed of SKP1, CUL1 and FBXO27. Component of the SCF(CCNF) complex consisting of CUL1, RBX1, SKP1 and CCNF. Component of the SCF(FBXL3) complex composed of CUL1, SKP1, RBX1 and FBXL3. Component of the SCF(FBXL21) complex composed of CUL1, SKP1, RBX1 and FBXL21. Component of the SCF(FBXO9) composed of CUL1, SKP1, RBX1 and FBXO9. Component of the SCF(FBXW7) composed of CUL1, SKP1, RBX1 and FBXW7 (PubMed:28727686). Interacts with CEP68 (PubMed:25503564). Interacts with NOTCH2 (PubMed:29149593). Interacts with FBXW15 (By similarity). The SKP1-KDM2A and SKP1-KDM2B complexes interact with UBB (PubMed:30033217).SUBUNIT (Microbial infection) Interacts with vaccinia virus protein C9L.PTM Undergoes autophagy-mediated degradation in the liver in a time-dependent manner.SIMILARITY Belongs to the SKP1 family.UniProtP632082EQUAL163EQUALReactome DB_ID: 1742371UniProt:Q9Y297 BTRCBTRCFBW1ABTRCPFBXW1ABTRCFUNCTION Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins. Recognizes and binds to phosphorylated target proteins (PubMed:10066435, PubMed:10497169, PubMed:10644755, PubMed:10835356, PubMed:11238952, PubMed:11359933, PubMed:11994270, PubMed:12791267, PubMed:12902344, PubMed:14603323, PubMed:14681206, PubMed:14988407, PubMed:15448698, PubMed:15917222, PubMed:16371461, PubMed:25503564, PubMed:25704143, PubMed:9859996, PubMed:22087322). SCF(BTRC) mediates the ubiquitination of CTNNB1 and participates in Wnt signaling (PubMed:12077367, PubMed:12820959). SCF(BTRC) mediates the ubiquitination of phosphorylated NFKB1, ATF4, CDC25A, DLG1, FBXO5, PER1, SMAD3, SMAD4, SNAI1 and probably NFKB2 (PubMed:10835356, PubMed:11238952, PubMed:14681206, PubMed:14603323). SCF(BTRC) mediates the ubiquitination of NFKBIA, NFKBIB and NFKBIE; the degradation frees the associated NFKB1 to translocate into the nucleus and to activate transcription (PubMed:10066435, PubMed:10497169, PubMed:10644755). Ubiquitination of NFKBIA occurs at 'Lys-21' and 'Lys-22' (PubMed:10066435). SCF(BTRC) mediates the ubiquitination of CEP68; this is required for centriole separation during mitosis (PubMed:25704143, PubMed:25503564). SCF(BTRC) mediates the ubiquitination and subsequent degradation of nuclear NFE2L1 (By similarity). Has an essential role in the control of the clock-dependent transcription via degradation of phosphorylated PER1 and PER2 (PubMed:15917222). May be involved in ubiquitination and subsequent proteasomal degradation through a DBB1-CUL4 E3 ubiquitin-protein ligase. Required for activation of NFKB-mediated transcription by IL1B, MAP3K14, MAP3K1, IKBKB and TNF. Required for proteolytic processing of GLI3 (PubMed:16371461). Mediates ubiquitination of REST, thereby leading to its proteasomal degradation (PubMed:21258371, PubMed:18354482).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Homodimer. Self-associates. Component of the SCF(BTRC) complex formed of CUL1, SKP1, RBX1 and a BTRC dimer. Direct interaction with SKP1 occurs via the F-box domain. Interacts with phosphorylated ubiquitination substrates SMAD3 and SMAD4. Interacts with phosphorylated ubiquitination substrates CTNNB1, NFKBIA, NFKBIB, NFKBIE, NFKB1/nuclear factor NF-kappa-B p105 subunit, ATF4, CDC25A, DLG1, FBXO5 and SNAI1; the interaction requires the phosphorylation of the 2 serine residues in the substrate destruction motif D-S-G-X(2,3,4)-S. Binds UBQLN1. Interacts with CDC34 and UBE2R2. Interacts with FBXW11. Interacts with CUL4A and DDB1. Part of a SCF(BTRC)-like complex lacking CUL1, which is associated with phosphorylated NKBIA and RELA; RELA interacts directly with NFKBIA. Interacts with the phosphorylated form of GLI3. Interacts with CLU. Interacts with PER1 (phosphorylated), PER2 (phosphorylated) and PER3. Interacts with phosphorylated ubiquitination substrate CEP68 (PubMed:25704143, PubMed:25503564). Interacts with ZC3H12A; this interaction occurs when ZC3H12A is phosphorylated in a IKBKB/IKKB-dependent manner (By similarity). Interacts with HSF1; this interaction occurs during mitosis and induces HSF1 ubiquitin-dependent degradation, a process inhibited by CDC20 (PubMed:18794143). Interacts with NFE2L1 (By similarity). Interacts with INAVA (PubMed:29420262). Interacts with IL10RA; this interaction leads to IL10RA ubiquitination and subsequent degradation (PubMed:22087322). Interacts with REST (PubMed:18354482).SUBUNIT (Microbial infection) Interacts with vaccinia virus A49; this interaction inhibits NF-kappa-B activation.SUBUNIT (Microbial infection) Interacts with HIV-1 Vpu.TISSUE SPECIFICITY Expressed in epididymis (at protein level).DOMAIN The N-terminal D domain mediates homodimerization.UniProtQ9Y2971EQUAL605EQUALReactome DB_ID: 1742301UniProt:Q13616 CUL1CUL1CUL1FUNCTION Core component of multiple cullin-RING-based SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complexes, which mediate the ubiquitination of proteins involved in cell cycle progression, signal transduction and transcription. SCF complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins (PubMed:27565346). In the SCF complex, serves as a rigid scaffold that organizes the SKP1-F-box protein and RBX1 subunits. May contribute to catalysis through positioning of the substrate and the ubiquitin-conjugating enzyme. The E3 ubiquitin-protein ligase activity of the complex is dependent on the neddylation of the cullin subunit and exchange of the substrate recognition component is mediated by TIP120A/CAND1. The functional specificity of the SCF complex depends on the F-box protein as substrate recognition component. SCF(BTRC) and SCF(FBXW11) direct ubiquitination of CTNNB1 and participate in Wnt signaling. SCF(FBXW11) directs ubiquitination of phosphorylated NFKBIA. SCF(BTRC) directs ubiquitination of NFKBIB, NFKBIE, ATF4, SMAD3, SMAD4, CDC25A, FBXO5 and probably NFKB2. SCF(BTRC) and/or SCF(FBXW11) direct ubiquitination of CEP68 (PubMed:25704143, PubMed:25503564). SCF(SKP2) directs ubiquitination of phosphorylated CDKN1B/p27kip and is involved in regulation of G1/S transition. SCF(SKP2) directs ubiquitination of ORC1, CDT1, RBL2, ELF4, CDKN1A, RAG2, FOXO1A, and probably MYC and TAL1. SCF(FBXW7) directs ubiquitination of CCNE1, NOTCH1 released notch intracellular domain (NICD), and probably PSEN1. SCF(FBXW2) directs ubiquitination of GCM1. SCF(FBXO32) directs ubiquitination of MYOD1. SCF(FBXO7) directs ubiquitination of BIRC2 and DLGAP5. SCF(FBXO33) directs ubiquitination of YBX1. SCF(FBXO1) directs ubiquitination of BCL6 and DTL but does not seem to direct ubiquitination of TP53. SCF(BTRC) mediates the ubiquitination of NFKBIA at 'Lys-21' and 'Lys-22'; the degradation frees the associated NFKB1-RELA dimer to translocate into the nucleus and to activate transcription. SCF(CCNF) directs ubiquitination of CCP110. SCF(FBXL3) and SCF(FBXL21) direct ubiquitination of CRY1 and CRY2. SCF(FBXO9) directs ubiquitination of TTI1 and TELO2. SCF(FBXO10) directs ubiquitination of BCL2.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Component of multiple SCF (SKP1-CUL1-F-box) E3 ubiquitin-protein ligase complexes formed of CUL1, SKP1, RBX1 and a variable F-box domain-containing protein as substrate-specific subunit (PubMed:10230406, PubMed:15145941, PubMed:15531760, PubMed:16714087, PubMed:16797541, PubMed:17098746, PubMed:18203720, PubMed:20596027, PubMed:22405651, PubMed:22113614, PubMed:23263282, PubMed:23431138, PubMed:25503564, PubMed:11961546, PubMed:22748924). Component of the SCF(FBXW11) complex containing FBXW11. Component of the SCF(SKP2) complex containing SKP2, in which it interacts directly with SKP1, SKP2 and RBX1. Component of the SCF(FBXW2) complex containing FBXW2. Component of the SCF(FBXO32) complex containing FBXO32. Component of the probable SCF(FBXO7) complex containing FBXO7. Component of the SCF(FBXO10) complex containing FBXO10. Component of the SCF(FBXO11) complex containing FBXO11. Component of the SCF(FBXO25) complex containing FBXO25. Component of the SCF(FBXO33) complex containing FBXO33. Component of the probable SCF(FBXO4) complex containing FBXO4. Component of the SCF(FBXO44) complex, composed of SKP1, CUL1 and FBXO44. Component of the SCF(BTRC) complex, composed of SKP1, CUL1 and BTRC. This complex binds phosphorylated NFKBIA. Part of a SCF complex consisting of CUL1, RBX1, SKP1 and FBXO2. Component of a SCF(SKP2)-like complex containing CUL1, SKP1, TRIM21 and SKP2. Component of the SCF(FBXO17) complex, composed of SKP1, CUL1 and FBXO17. Component of the SCF(FBXO27) complex, composed of SKP1, CUL1 and FBXO27. Component of the SCF(CCNF) complex consisting of CUL1, RBX1, SKP1 and CCNF. Component of the SCF(FBXL3) complex composed of CUL1, SKP1, RBX1 and FBXL3. Component of the SCF(FBXL21) complex composed of CUL1, SKP1, RBX1 and FBXL21. Component of the SCF(FBXO9) composed of CUL1, SKP1, RBX1 and FBXO9. Component of the SCF(FBXW7) composed of CUL1, SKP1, RBX1 and FBXW7 (PubMed:22405651). Interacts with CHEK2; mediates CHEK2 ubiquitination and regulates its function. Part of a complex with TIP120A/CAND1 and RBX1. The unneddylated form interacts with TIP120A/CAND1 and the interaction mediates the exchange of the F-box substrate-specific subunit. Can self-associate. Interacts with FBXW8. Interacts with RNF7. Interacts with CUL7; the interaction seems to be mediated by FBXW8. Interacts with TRIM21. Interacts with COPS2. Interacts with DCUN1D1 and UBE2M (PubMed:21940857). Interacts with DCUN1D3 (PubMed:25349211). Interacts with DCUN1D4 (PubMed:28581483). Identified in a complex with RBX1 and GLMN (PubMed:22405651, PubMed:22748924). Interacts with CEP68 as part of the SCF(FBXW11) complex; the interaction is probably mediated by FBXW11 and the complex also contains CDK5RAP2 and PCNT (PubMed:25503564). Interacts (when neddylated) with ARIH1; leading to activate the E3 ligase activity of ARIH1 (PubMed:24076655, PubMed:27565346). Interacts with COPS9 isoform 2 (PubMed:23776465). Interacts with UBXN1 (PubMed:28152074). Interacts with KAT7, probably as part of an SCF complex; the interaction mediates KAT7 ubiquitination (By similarity). Interacts with NOTCH2 (PubMed:29149593).SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus BPLF1.SUBUNIT (Microbial infection) Interacts with Human adenovirus early E1A protein; this interaction inhibits RBX1-CUL1-dependent elongation reaction of ubiquitin chains by the SCF(FBXW7) complex.SUBUNIT (Microbial infection) Interacts with vaccinia virus protein C9L.TISSUE SPECIFICITY Expressed in lung fibroblasts.PTM Neddylated; which enhances the ubiquitination activity of SCF and prevents binding of the inhibitor CAND1. Deneddylated via its interaction with the COP9 signalosome (CSN) complex (PubMed:10597293, PubMed:10713156, PubMed:15537541, PubMed:18805092).PTM (Microbial infection) Deneddylated by Epstein-Barr virus BPLF1 leading to a S-phase-like environment that is required for efficient replication of the viral genome (PubMed:20190741).SIMILARITY Belongs to the cullin family.UniProtQ136161EQUAL776EQUALReactome Database ID Release 75174155Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174155ReactomeR-HSA-1741552Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174155.2Converted from EntitySet in ReactomeReactome DB_ID: 1773321phospho-Emi1:Cdc20/Cdh1 complexes [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityReactome DB_ID: 1741381SCF-beta-TrCP:phospho-Emi1 complexes [cytosol]SCF-beta-TrCP:phospho-Emi1 complexesReactome DB_ID: 1741551Converted from EntitySet in ReactomeReactome DB_ID: 1773321Reactome Database ID Release 75174138Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174138ReactomeR-HSA-1741381Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174138.1Reactome Database ID Release 75174209Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174209ReactomeR-HSA-1742092Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174209.210023660Pubmed1999The human F box protein beta-Trcp associates with the Cul1/Skp1 complex and regulates the stability of beta-cateninLatres, EChiaur, DSPagano, MicheleOncogene 18:849-546.3.2.19Ubiquitination of Emi1 by SCF-beta-TrCPUbiquitination of Emi1 by SCF-beta-TrCPFollowing its association with SCF-ßTrCP, phospho-Emi1 is poly-ubiquitinated.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Reactome DB_ID: 1741381Converted from EntitySet in ReactomeReactome DB_ID: 1135953Ub [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUBC(77-152) [cytosol]UBB(153-228) [cytosol]UBC(305-380) [cytosol]UBB(1-76) [cytosol]UBB(77-152) [cytosol]UBA52(1-76) [cytosol]UBC(533-608) [cytosol]UBC(381-456) [cytosol]UBC(457-532) [cytosol]UBC(609-684) [cytosol]UBC(153-228) [cytosol]RPS27A(1-76) [cytosol]UBC(1-76) [cytosol]UBC(229-304) [cytosol]UniProtP0CG48UniProtP0CG47UniProtP62987UniProtP62979Reactome DB_ID: 1740611SCF-associated multiubiquitinated Emi1complexes [cytosol]SCF-associated multiubiquitinated Emi1complexesReactome DB_ID: 1741381Converted from EntitySet in ReactomeReactome DB_ID: 1135953Reactome Database ID Release 75174061Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174061ReactomeR-HSA-1740611Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174061.1PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 174155GO0004842GO molecular functionReactome Database ID Release 75174077Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174077Reactome Database ID Release 75174159Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174159ReactomeR-HSA-1741592Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174159.2SCF-mediated degradation of Emi1SCF-mediated degradation of Emi1Multiubiquitinated Emi1 is degraded by the 26S proteasome.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Reactome DB_ID: 1740611Reactome DB_ID: 1741551Converted from EntitySet in ReactomeReactome DB_ID: 1135954Converted from EntitySet in ReactomeReactome DB_ID: 1773201Cdc20/Cdh1 [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityFZR1 [cytosol]CDC20 [cytosol]PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 6881926S proteasome [cytosol]26S proteasomeReactome DB_ID: 688001UniProt:P55036 PSMD4PSMD4MCB1PSMD4FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMD4 acts as an ubiquitin receptor subunit through ubiquitin-interacting motifs and selects ubiquitin-conjugates for destruction. Displays a preferred selectivity for longer polyubiquitin chains.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD4 (PubMed:27428775, PubMed:27342858). Interacts with NUB1 (PubMed:11585840). Interacts with SQSTM1 (PubMed:15340068). Interacts with UBQLN4 (PubMed:15280365). Interacts with UBE3A (PubMed:22645313). Interacts with UBQLN1 (via ubiquitin-like domain) (PubMed:15147878). Interacts with DDI2 (PubMed:29290612).DOMAIN The 2 UIM motifs are involved in the binding to a multi-ubiquitin chain in a cooperative way.SIMILARITY Belongs to the proteasome subunit S5A family.UniProtP550361EQUAL377EQUALReactome DB_ID: 688021UniProt:Q16401 PSMD5PSMD5PSMD5KIAA0072FUNCTION Acts as a chaperone during the assembly of the 26S proteasome, specifically of the base subcomplex of the PA700/19S regulatory complex (RC). In the initial step of the base subcomplex assembly is part of an intermediate PSMD5:PSMC2:PSMC1:PSMD2 module which probably assembles with a PSMD10:PSMC4:PSMC5:PAAF1 module followed by dissociation of PSMD5.SUBUNIT Interacts with PSMC1, PSMC2, PSMD1 and PSMD6. Part of transient complex containing PSMD5, PSMC2, PSMC1 and PSMD2 formed during the assembly of the 26S proteasome.DOMAIN Rich in dileucine repeats, which have been implicated in trafficking of a variety of transmembrane proteins.SIMILARITY Belongs to the proteasome subunit S5B/HSM3 family.CAUTION Was initially identified as a genuine component of the 26S proteasome.UniProtQ164012EQUAL504EQUALReactome DB_ID: 688101UniProt:O00233 PSMD9PSMD9PSMD9FUNCTION Acts as a chaperone during the assembly of the 26S proteasome, specifically of the base subcomplex of the PA700/19S regulatory complex (RC). During the base subcomplex assembly is part of an intermediate PSMD9:PSMC6:PSMC3 module, also known as modulator trimer complex; PSMD9 is released during the further base assembly process.SUBUNIT Interacts with PSMC3. Part of a transient complex (modulator) containing PSMD9, PSMC6 and PSMC3 formed during the assembly of the 26S proteasome.TISSUE SPECIFICITY Expressed in all tissues tested, highly expressed in liver and kidney.SIMILARITY Belongs to the proteasome subunit p27 family.CAUTION Was initially identified as a component of the 26S proteasome.UniProtO002331EQUAL223EQUALReactome DB_ID: 9476071UniProt:A5LHX3 PSMB11PSMB11PSMB11FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. Incorporated instead of PSMB5 or PSMB8, this unit reduces the chymotrypsin-like activity of the proteasome (By similarity). Plays a pivotal role in development of CD8-positive T cells (By similarity).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Incorporated instead of PSMB5 and PSMB8.SIMILARITY Belongs to the peptidase T1B family.UniProtA5LHX350EQUAL300EQUALReactome DB_ID: 9476101UniProt:Q8TAA3 PSMA8PSMA8PSMA7LPSMA8FUNCTION Component of the spermatoproteasome, a proteasome specifically found in testis that promotes acetylation-dependent degradation of histones, thereby participating actively to the exchange of histones during spermatogenesis. The proteasome is a protein complexe that degrades unneeded or damaged proteins by proteolysis, a chemical reaction that breaks peptide bonds. Required for 20S core proteasome assembly, essential for the degradation of meiotic proteins RAD51 and RPA1 at late prophase I and the progression of meiosis I during spermatogenesis. Localizes to the synaptonemal complex, a 'zipper'-like structure that holds homologous chromosome pairs in synapsis during meiotic prophase I.SUBUNIT Component of the outer alpha-ring of the 20S proteasome core which is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The catalytic chamber with the active sites is on the inside of the barrel. Interacts with canonical subunits of the spermatoproteasome, including proteasome activators PSME4 (also called PA200) and PSME3 (also called PA28-gamma). Interacts with proteasome-interacting proteins chaperones, ubiquitin ligases and ubiquitin specific proteases. Interacts with meiotic proteins cyclin dependent kinase CDK1 and the ATPase TRIP13 as well as proteins of the synaptonemal complex SIX6OS1 and SYCE3.SIMILARITY Belongs to the peptidase T1A family.UniProtQ8TAA31EQUAL256EQUALReactome DB_ID: 687711UniProt:P35998 PSMC2PSMC2MSS1PSMC2FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC2 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC2 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with NDC80/HEC; this interaction is detected only during M phase. Interacts and SQSTM1 (PubMed:15340068). Interacts with PAAF1 (PubMed:15831487). Directly interacts with TRIM5 (PubMed:22078707).INDUCTION Expression is not cell cycle-dependent and occurs throughout the cell cycle.SIMILARITY Belongs to the AAA ATPase family.UniProtP359982EQUAL433EQUALReactome DB_ID: 688041UniProt:Q15008 PSMD6PSMD6PSMD6KIAA0107PFAAP4FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD6, a base containing 6 ATPases and few additional components.SIMILARITY Belongs to the proteasome subunit S10 family.UniProtQ150081EQUAL389EQUALReactome DB_ID: 9476061UniProt:Q14997 PSME4PSME4PSME4KIAA0077FUNCTION Associated component of the proteasome that specifically recognizes acetylated histones and promotes ATP- and ubiquitin-independent degradation of core histones during spermatogenesis and DNA damage response. Recognizes and binds acetylated histones via its bromodomain-like (BRDL) region and activates the proteasome by opening the gated channel for substrate entry. Binds to the core proteasome via its C-terminus, which occupies the same binding sites as the proteasomal ATPases, opening the closed structure of the proteasome via an active gating mechanism. Component of the spermatoproteasome, a form of the proteasome specifically found in testis: binds to acetylated histones and promotes degradation of histones, thereby participating actively to the exchange of histones during spermatogenesis. Also involved in DNA damage response in somatic cells, by promoting degradation of histones following DNA double-strand breaks.SUBUNIT Homodimer. Interacts with the 20S and 26S proteasomes. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.DOMAIN The bromodomain-like (BRDL) region specifically recognizes and binds acetylated histones.SIMILARITY Belongs to the BLM10 family.UniProtQ149971EQUAL1843EQUALReactome DB_ID: 687861UniProt:Q99460 PSMD1PSMD1PSMD1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD1 (PubMed:27428775, PubMed:27342858). Interacts with ADRM1 (PubMed:16990800, PubMed:16906146). Interacts with ZFAND1 (PubMed:29804830).SIMILARITY Belongs to the proteasome subunit S1 family.UniProtQ994601EQUAL953EQUALReactome DB_ID: 687981UniProt:O43242 PSMD3PSMD3PSMD3FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD3, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Interacts with UBQLN1 (via ubiquitin-like domain) (PubMed:15147878). Interacts with ERCC6 (PubMed:26030138).SIMILARITY Belongs to the proteasome subunit S3 family.UniProtO432421EQUAL534EQUALReactome DB_ID: 688141UniProt:Q9UL46 PSME2PSME2PSME2FUNCTION Implicated in immunoproteasome assembly and required for efficient antigen processing. The PA28 activator complex enhances the generation of class I binding peptides by altering the cleavage pattern of the proteasome.SUBUNIT Heterodimer of PSME1 and PSME2, which forms a hexameric ring.INDUCTION By IFNG/IFN-gamma.SIMILARITY Belongs to the PA28 family.UniProtQ9UL462EQUAL239EQUALReactome DB_ID: 88666741UniProt:P60896 SEM1SEM1SEM1C7orf76SHFDG1SHFM1DSS1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair (PubMed:15117943). Component of the TREX-2 complex (transcription and export complex 2), composed of at least ENY2, GANP, PCID2, SEM1, and either centrin CETN2 or CETN3 (PubMed:22307388). The TREX-2 complex functions in docking export-competent ribonucleoprotein particles (mRNPs) to the nuclear entrance of the nuclear pore complex (nuclear basket). TREX-2 participates in mRNA export and accurate chromatin positioning in the nucleus by tethering genes to the nuclear periphery. Binds and stabilizes BRCA2 and is thus involved in the control of R-loop-associated DNA damage and thus transcription-associated genomic instability. R-loop accumulation increases in SEM1-depleted cells.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including SEM1, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Belongs to the TREX-2 complex (transcription and export complex 2), composed of at least ENY2, GANP, PCID2, SEM1, and either centrin CETN2 or CETN3 (PubMed:22307388). Interacts with the C-terminal of BRCA2 (PubMed:10373512, PubMed:21719596).TISSUE SPECIFICITY Expressed in limb bud, craniofacial primordia and skin.SIMILARITY Belongs to the DSS1/SEM1 family.UniProtP608961EQUAL70EQUALReactome DB_ID: 687651UniProt:P28065 PSMB9PSMB9LMP2PSMB6iRING12PSMB9FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Replacement of PSMB6 by PSMB9 increases the capacity of the immunoproteasome to cleave model peptides after hydrophobic and basic residues.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB6. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.DEVELOPMENTAL STAGE Highly expressed in immature dendritic cells (at protein level).INDUCTION Up-regulated by interferon gamma (at protein level). Up-regulated by IRF1. Up-regulated by tumor necrosis factor-alpha (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Up-regulated by heat shock treatment. Up-regulated by CD40L via the NFKB1 pathway in cancer cells.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.MISCELLANEOUS Encoded in the MHC class II region.MISCELLANEOUS A model for self-activation in which residue Thr-21 serves as nucleophile and Lys-53 as proton donor/acceptor has been proposed. Subunit processing of mammalian beta-subunits proceeds via a novel ordered two-step mechanism involving autocatalysis.SIMILARITY Belongs to the peptidase T1B family.UniProtP2806521EQUAL219EQUALReactome DB_ID: 687921UniProt:O00232 PSMD12PSMD12PSMD12FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex (PubMed:27428775,PubMed:27342858). The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP) (PubMed:27428775,PubMed:27342858). The regulatory particle is made of a lid composed of 9 subunits including PSMD12, a base containing 6 ATPases and few additional components (PubMed:27428775,PubMed:27342858). Interacts with ERCC6 (PubMed:26030138).SIMILARITY Belongs to the proteasome subunit p55 family.UniProtO002322EQUAL456EQUALReactome DB_ID: 688181UniProt:Q92530 PSMF1PSMF1PSMF1FUNCTION Plays an important role in control of proteasome function. Inhibits the hydrolysis of protein and peptide substrates by the 20S proteasome. Also inhibits the activation of the proteasome by the proteasome regulatory proteins PA700 and PA28.SUBUNIT Monomer and homodimer. Interacts with FBXO7. Interacts with the 20S proteasome.SIMILARITY Belongs to the proteasome inhibitor PI31 family.UniProtQ925301EQUAL271EQUALReactome DB_ID: 687321UniProt:P28066 PSMA5PSMA5PSMA5FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. PSMA5 interacts directly with the PSMG1-PSMG2 heterodimer which promotes 20S proteasome assembly.TISSUE SPECIFICITY Expressed in fetal brain (at protein level).INDUCTION Up-regulated in colon cancer cell lines. Up-regulated in fetal Down syndrome (DS) brain (at protein level). May be the target of the transcriptional activator NFE2L2.SIMILARITY Belongs to the peptidase T1A family.UniProtP280661EQUAL241EQUALReactome DB_ID: 687771UniProt:P43686 PSMC4PSMC4TBP7PSMC4MIP224FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC4 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC4 and few additional components (PubMed:27428775,PubMed:27342858). Interacts with NR1I3. Interacts with PAAF1 (PubMed:15831487). Interacts with TRIM5 (PubMed:22078707). Interacts with ZFAND1 (PubMed:29804830).SIMILARITY Belongs to the AAA ATPase family.UniProtP436861EQUAL418EQUALReactome DB_ID: 687591UniProt:Q99436 PSMB7PSMB7PSMB7ZFUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB7 displays a trypsin-like activity.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 Tat protein.TISSUE SPECIFICITY Expressed at a low level in colonic mucosa. Up-regulated in colorectal cancer tissues.SIMILARITY Belongs to the peptidase T1B family.UniProtQ9943644EQUAL277EQUALReactome DB_ID: 687801UniProt:P62195 PSMC5PSMC5PSMC5SUG1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC5 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC5 and few additional components (PubMed:27428775, PubMed:27342858). Component of a complex with USP49 and RUVBL1 (PubMed:23824326). Interacts with PRPF19. Interacts with TRIM5 (PubMed:22078707). Interacts with NDC80 (PubMed:9295362, PubMed:10409732). Interacts with PAAF1 (PubMed:15831487). Interacts, in vitro, with the thyroid hormone receptor (in a thyroid hormone T3-dependent manner) and with retinoid X receptor (RXR) (By similarity). Interacts with ERCC6 (PubMed:26030138).SIMILARITY Belongs to the AAA ATPase family.UniProtP621952EQUAL406EQUALReactome DB_ID: 688161UniProt:P61289 PSME3PSME3PSME3FUNCTION Subunit of the 11S REG-gamma (also called PA28-gamma) proteasome regulator, a doughnut-shaped homoheptamer which associates with the proteasome. 11S REG-gamma activates the trypsin-like catalytic subunit of the proteasome but inhibits the chymotrypsin-like and postglutamyl-preferring (PGPH) subunits. Facilitates the MDM2-p53/TP53 interaction which promotes ubiquitination- and MDM2-dependent proteasomal degradation of p53/TP53, limiting its accumulation and resulting in inhibited apoptosis after DNA damage. May also be involved in cell cycle regulation. Mediates CCAR2 and CHEK2-dependent SIRT1 inhibition (PubMed:25361978).SUBUNIT Homoheptamer; the stability of the heptamer is essential for the specific activation of the trypsine-like subunit and inhibition of the chymotrypsin-like and postglutamyl-preferring (PGPH) subunits of the proteasome. Interacts with p53/TP53 and MDM2. Interacts with MAP3K3 (By similarity). Associates with the proteasome. Interacts with CCAR2. Interacts with PSME3IP1 (via C-terminus); the interaction is direct and promotes the association of PSME3 with the 20S proteasome (PubMed:29934401). Interacts with COIL; the interaction is inhibited by PSME3IP1 (PubMed:29934401).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus UL27.INDUCTION Up-regulated in thyroid carcinoma cells.DOMAIN The C-terminal sequences affect heptamer stability and proteasome affinity.PTM Phosphorylated by MAP3K3 (By similarity). Phosphorylation at Ser-247 promotes its association with CCAR2.PTM Acetylation at the major site Lys-195 is important for oligomerization and ability to degrade its target substrates. Deacetylated by SIRT1.SIMILARITY Belongs to the PA28 family.UniProtP612892EQUAL254EQUALReactome DB_ID: 687361UniProt:O14818 PSMA7PSMA7PSMA7HSPCFUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Inhibits the transactivation function of HIF-1A under both normoxic and hypoxia-mimicking conditions. The interaction with EMAP2 increases the proteasome-mediated HIF-1A degradation under the hypoxic conditions. Plays a role in hepatitis C virus internal ribosome entry site-mediated translation. Mediates nuclear translocation of the androgen receptor (AR) and thereby enhances androgen-mediated transactivation. Promotes MAVS degradation and thereby negatively regulates MAVS-mediated innate immune response.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. PSMA7 interacts directly with the PSMG1-PSMG2 heterodimer which promotes 20S proteasome assembly (PubMed:16251969). Interacts with HIF1A. Interacts with RAB7A (PubMed:14998988). Interacts with PRKN (PubMed:15987638). Interacts with ABL1 and ABL2 (PubMed:16678104). Interacts with EMAP2 (PubMed:19362550). Interacts with MAVS (PubMed:19734229).SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.SUBUNIT (Microbial infection) Interacts with hepatitis B virus X protein (HBX).INDUCTION Down-regulated by the ribozyme Rz3'X. Up-regulated in colorectal cancer tissues.PTM Phosphorylation by ABL1 or ABL2 leads to an inhibition of proteasomal activity and cell cycle transition blocks.SIMILARITY Belongs to the peptidase T1A family.UniProtO148181EQUAL248EQUALReactome DB_ID: 687741UniProt:P17980 PSMC3PSMC3PSMC3TBP1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC3 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC3 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with PAAF1 (PubMed:15831487).SUBUNIT (Microbial infection) Interacts with HIV-1 Tat.PTM Sumoylated by UBE2I in response to MEKK1-mediated stimuli.SIMILARITY Belongs to the AAA ATPase family.UniProtP179801EQUAL439EQUALReactome DB_ID: 687681UniProt:P62191 PSMC1PSMC1PSMC1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC1 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC1 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with SCA7 (PubMed:11734547). Interacts with NGLY1 (PubMed:15358861). Interacts with PAAF1 (PubMed:15831487).SIMILARITY Belongs to the AAA ATPase family.UniProtP621912EQUAL440EQUALReactome DB_ID: 687941UniProt:Q9UNM6 PSMD13PSMD13PSMD13FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD13, a base containing 6 ATPases and few additional components.SIMILARITY Belongs to the proteasome subunit S11 family.UniProtQ9UNM61EQUAL376EQUALReactome DB_ID: 687241UniProt:P25786 PSMA1PSMA1PSMA1HC2NUPSC2PROS30FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with NOTCH3. Interacts with ZFAND1 (PubMed:29804830).INDUCTION Induced in breast cancer tissue (at protein level). Up-regulated in liver tumor tissues.SIMILARITY Belongs to the peptidase T1A family.UniProtP257861EQUAL263EQUALReactome DB_ID: 687261UniProt:P25787 PSMA2PSMA2PSMA2PSC3HC3FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.INDUCTION Down-regulated by antioxidants BO-653 and probucol. Down-regulated in response to enterovirus 71 (EV71) infection (at protein level).PTM Phosphorylated on tyrosine residues; which may be important for nuclear import.SIMILARITY Belongs to the peptidase T1A family.UniProtP257872EQUAL234EQUALReactome DB_ID: 687281UniProt:P25788 PSMA3PSMA3PSMA3HC8PSC8FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Binds to the C-terminus of CDKN1A and thereby mediates its degradation. Negatively regulates the membrane trafficking of the cell-surface thromboxane A2 receptor (TBXA2R) isoform 2.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with AURKB. Interacts with CDKN1A (PubMed:11350925). Interacts with MDM2 and RB1 (PubMed:16337594). Interacts with the C-terminus of TBXA2R isoform 2 (PubMed:17499743). Interacts with DNAJB2 (PubMed:15936278).SUBUNIT (Microbial infection) Interacts with HIV-1 Tat protein.SUBUNIT (Microbial infection) Interacts with hepatitis C virus (HCV) F protein.SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus EBNA3 proteins.INDUCTION Down-regulated by antioxidants BO-653 and probucol. Up-regulated by bacterial lipopolysaccharides (LPS) and TNF.SIMILARITY Belongs to the peptidase T1A family.UniProtP257882EQUAL255EQUALReactome DB_ID: 687881UniProt:O75832 PSMD10PSMD10PSMD10FUNCTION Acts as a chaperone during the assembly of the 26S proteasome, specifically of the PA700/19S regulatory complex (RC). In the initial step of the base subcomplex assembly is part of an intermediate PSMD10:PSMC4:PSMC5:PAAF1 module which probably assembles with a PSMD5:PSMC2:PSMC1:PSMD2 module. Independently of the proteasome, regulates EGF-induced AKT activation through inhibition of the RHOA/ROCK/PTEN pathway, leading to prolonged AKT activation. Plays an important role in RAS-induced tumorigenesis.FUNCTION Acts as an proto-oncoprotein by being involved in negative regulation of tumor suppressors RB1 and p53/TP53. Overexpression is leading to phosphorylation of RB1 and proteasomal degradation of RB1. Regulates CDK4-mediated phosphorylation of RB1 by competing with CDKN2A for binding with CDK4. Facilitates binding of MDM2 to p53/TP53 and the mono- and polyubiquitination of p53/TP53 by MDM2 suggesting a function in targeting the TP53:MDM2 complex to the 26S proteasome. Involved in p53-independent apoptosis. Involved in regulation of NF-kappa-B by retaining it in the cytoplasm. Binds to the NF-kappa-B component RELA and accelerates its XPO1/CRM1-mediated nuclear export.SUBUNIT Part of transient complex containing PSMD10, PSMC4, PSMC5 and PAAF1 formed during the assembly of the 26S proteasome. Stays associated throughout the assembly of the PA700/19S RC and is released upon association with the 20S core. Interacts with PSMC4. Interacts with RB1. Interacts with CDK4. Interacts with MDM2. Interacts with RELA. Associates with a CDK4:CCND2 serine/threonine kinase complex. Interacts with ARHGDIA and increases the interaction between ARHGDIA and RHOA, hence promotes ARHGDIA inactivation of RHOA and ROCK.TISSUE SPECIFICITY Tends to be up-regulated in cancer cells with RAS mutations, including lung cancers and adenocarconimas (at protein level).CAUTION Was initially identified as a genuine component of the 26S proteasome.UniProtO758321EQUAL226EQUALReactome DB_ID: 687301UniProt:P25789 PSMA4PSMA4PSMA4PSC9HC9FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interaction with HTLV-1 TAX protein favors NFKB1 activation.INDUCTION Down-regulated by antioxidants BO-653 and probucol.SIMILARITY Belongs to the peptidase T1A family.UniProtP257891EQUAL261EQUALReactome DB_ID: 687341UniProt:P60900 PSMA6PSMA6PSMA6PROS27FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with ALKBH4 (PubMed:23145062).SIMILARITY Belongs to the peptidase T1A family.UniProtP609001EQUAL246EQUALReactome DB_ID: 687501UniProt:P28070 PSMB4PSMB4PSMB4PROS26FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). SMAD1/OAZ1/PSMB4 complex mediates the degradation of the CREBBP/EP300 repressor SNIP1.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Forms a ternary complex with SMAD1 and OAZ1 before PSMB4 is incorporated into the 20S proteasome. Interacts with PRPF19 (PubMed:11571290, PubMed:12097147).SUBUNIT (Microbial infection) Interacts with HTLV-1 Tax protein.SUBUNIT (Microbial infection) Interacts with HIV-1 Nef and Tat proteins.INDUCTION Up-regulated in fibrolamellar carcinomas.SIMILARITY Belongs to the peptidase T1B family.CAUTION A report observed N-glycosylation at Asn-83 (PubMed:19139490). However, as the protein does not localize in an extracellular compartment of the cell, additional evidence is required to confirm this result.UniProtP2807046EQUAL264EQUALReactome DB_ID: 687621UniProt:P28062 PSMB8PSMB8PSMB5iRING10Y2LMP7PSMB8FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides. Replacement of PSMB5 by PSMB8 increases the capacity of the immunoproteasome to cleave model peptides after hydrophobic and basic residues. Involved in the generation of spliced peptides resulting from the ligation of two separate proteasomal cleavage products that are not contiguous in the parental protein (PubMed:27049119). Acts as a major component of interferon gamma-induced sensitivity. Plays a key role in apoptosis via the degradation of the apoptotic inhibitor MCL1. May be involved in the inflammatory response pathway. In cancer cells, substitution of isoform 1 (E2) by isoform 2 (E1) results in immunoproteasome deficiency. Required for the differentiation of preadipocytes into adipocytes.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB5. Component of the spermatoproteasome, a form of the proteasome specifically found in testis. Directly interacts with POMP. Interacts with TAP1.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.DEVELOPMENTAL STAGE Highly expressed in immature dendritic cells (at protein level).INDUCTION Up-regulated by IFNG/IFN-gamma and IRF1 (at protein level). Up-regulated by TNF (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Down-regulated by the selective inhibitor PR-957. Down-regulated in mature dendritic cells by HSV-1 infection. Up-regulated by heat shock treatment.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.SIMILARITY Belongs to the peptidase T1B family.UniProtP2806273EQUAL276EQUALReactome DB_ID: 687961UniProt:Q13200 PSMD2PSMD2TRAP2PSMD2FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.FUNCTION Binds to the intracellular domain of tumor necrosis factor type 1 receptor. The binding domain of TRAP1 and TRAP2 resides outside the death domain of TNFR1.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases and few additional components including PSMD2 (PubMed:27428775, PubMed:27342858). Interacts with RPGRIP1L (By similarity). Interacts with CRY1 in a KDM8-dependent manner (By similarity).TISSUE SPECIFICITY Found in skeletal muscle, liver, heart, brain, kidney, pancreas, lung and placenta.SIMILARITY Belongs to the proteasome subunit S2 family.UniProtQ132001EQUAL908EQUALReactome DB_ID: 687221UniProt:O00487 PSMD14PSMD14PSMD14POH1FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. The PSMD14 subunit is a metalloprotease that specifically cleaves 'Lys-63'-linked polyubiquitin chains within the complex. Plays a role in response to double-strand breaks (DSBs): acts as a regulator of non-homologous end joining (NHEJ) by cleaving 'Lys-63'-linked polyubiquitin, thereby promoting retention of JMJD2A/KDM4A on chromatin and restricting TP53BP1 accumulation. Also involved in homologous recombination repair by promoting RAD51 loading.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD4, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Within the complex, PSMD4 interacts with subunit PSMD7 through their respective MPN domain. Interacts with TXNL1 (PubMed:19349277).TISSUE SPECIFICITY Widely expressed. Highest levels in heart and skeletal muscle.SIMILARITY Belongs to the peptidase M67A family. PSMD14 subfamily.UniProtO004871EQUAL310EQUALReactome DB_ID: 687561UniProt:P28072 PSMB6PSMB6PSMB6LMPYYFUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB6 displays a peptidylglutamyl-hydrolizing activity also termed postacidic or caspase-like activity, meaning that the peptides bond hydrolysis occurs directly after acidic residues.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 protein Tat.INDUCTION Down-regulated by IFNG/IFN-gamma (at protein level). Up-regulated in anaplastic thyroid cancer cell lines.SIMILARITY Belongs to the peptidase T1B family.UniProtP2807235EQUAL239EQUALReactome DB_ID: 687381UniProt:P20618 PSMB1PSMB1PSC5PSMB1FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Interacts with SERPINB2. Interacts with RFPL4A (By similarity).SUBUNIT (Microbial infection) Interacts with HIV-1 protein Tat.SIMILARITY Belongs to the peptidase T1B family.UniProtP2061829EQUAL241EQUALReactome DB_ID: 688061UniProt:P51665 PSMD7PSMD7MOV34LPSMD7FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD7, a base containing 6 ATPases and few additional components (PubMed:27428775, PubMed:27342858). Within the complex, PSMD7 interacts with subunit PSMD4 through their respective MPN domain. Interacts with TRIM5 (PubMed:22078707).MISCELLANEOUS Does not bind a metal ion.SIMILARITY Belongs to the peptidase M67A family.UniProtP516651EQUAL324EQUALReactome DB_ID: 687901UniProt:O00231 PSMD11PSMD11PSMD11FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. In the complex, PSMD11 is required for proteasome assembly. Plays a key role in increased proteasome activity in embryonic stem cells (ESCs): its high expression in ESCs promotes enhanced assembly of the 26S proteasome, followed by higher proteasome activity.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD11, a base containing 6 ATPases and few additional components.TISSUE SPECIFICITY Highly expressed in embryonic stem cells (ESCs). Expression decreases as ESCs differentiate.INDUCTION By FOXO4; expression in embryonic stem cells (ESCs) is mediated by FOXO4.PTM Phosphorylated by AMPK.SIMILARITY Belongs to the proteasome subunit S9 family.UniProtO002312EQUAL422EQUALReactome DB_ID: 687441UniProt:P49721 PSMB2PSMB2PSMB2FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 protein Tat.INDUCTION Up-regulated in ovarian cancer cell lines.SIMILARITY Belongs to the peptidase T1B family.UniProtP497211EQUAL201EQUALReactome DB_ID: 687411UniProt:P40306 PSMB10PSMB10LMP10MECL1PSMB10FUNCTION The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. This subunit is involved in antigen processing to generate class I binding peptides.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is composed of 28 subunits that are arranged in four stacked rings, resulting in a barrel-shaped structure. The two end rings are each formed by seven alpha subunits, and the two central rings are each formed by seven beta subunits. The catalytic chamber with the active sites is on the inside of the barrel. Component of the immunoproteasome, where it displaces the equivalent housekeeping subunit PSMB7. Component of the spermatoproteasome, a form of the proteasome specifically found in testis.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.DEVELOPMENTAL STAGE Highly expressed in immature dendritic cells (at protein level).INDUCTION Up-regulated by IFNG/IFN-gamma (at protein level). Up-regulated by IRF1. Up-regulated by TNF (at protein level). Up-regulated by tetrodotoxin (TTX) in glial cells. Up-regulated in Crohn's bowel disease (CD). Up-regulated by CD40L via the NFKB1 pathway in cancer cells.PTM Autocleaved. The resulting N-terminal Thr residue of the mature subunit is responsible for the nucleophile proteolytic activity.SIMILARITY Belongs to the peptidase T1B family.UniProtP4030640EQUAL273EQUALReactome DB_ID: 687831UniProt:P62333 PSMC6PSMC6PSMC6SUG2FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair. PSMC6 belongs to the heterohexameric ring of AAA (ATPases associated with diverse cellular activities) proteins that unfolds ubiquitinated target proteins that are concurrently translocated into a proteolytic chamber and degraded into peptides.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits, a base containing 6 ATPases including PSMC6 and few additional components (PubMed:27428775, PubMed:27342858). Interacts with PAAF1 (PubMed:15831487).SIMILARITY Belongs to the AAA ATPase family.CAUTION Alternative initiation from an upstream conserved methionine cannot be fully excluded but is not experimentally supported while initiation from the displayed methionine is supported by PubMed:17323924.UniProtP623331EQUAL389EQUALReactome DB_ID: 688081UniProt:P48556 PSMD8PSMD8PSMD8FUNCTION Component of the 26S proteasome, a multiprotein complex involved in the ATP-dependent degradation of ubiquitinated proteins. This complex plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins, which could impair cellular functions, and by removing proteins whose functions are no longer required. Therefore, the proteasome participates in numerous cellular processes, including cell cycle progression, apoptosis, or DNA damage repair.SUBUNIT Component of the 19S proteasome regulatory particle complex. The 26S proteasome consists of a 20S core particle (CP) and two 19S regulatory subunits (RP). The regulatory particle is made of a lid composed of 9 subunits including PSMD8, a base containing 6 ATPases and few additional components. Interacts with DDI2 (PubMed:29290612). Interacts with TASOR (By similarity).SIMILARITY Belongs to the proteasome subunit S14 family.CAUTION It is uncertain whether Met-1 or Met-64 is the initiator.UniProtP485561EQUAL350EQUALReactome DB_ID: 688121UniProt:Q06323 PSME1PSME1PSME1IFI5111FUNCTION Implicated in immunoproteasome assembly and required for efficient antigen processing. The PA28 activator complex enhances the generation of class I binding peptides by altering the cleavage pattern of the proteasome.SUBUNIT Heterodimer of PSME1 and PSME2, which forms a hexameric ring. PSME1 can form homoheptamers.INDUCTION By IFNG/IFN-gamma.SIMILARITY Belongs to the PA28 family.UniProtQ063231EQUAL249EQUALReactome DB_ID: 687471UniProt:P49720 PSMB3PSMB3PSMB3FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex).SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7.SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.INDUCTION Up-regulated in asthenozoospermic sperm.SIMILARITY Belongs to the peptidase T1B family.UniProtP497202EQUAL205EQUALReactome DB_ID: 687531UniProt:P28074 PSMB5PSMB5PSMB5XLMPXMB1FUNCTION Component of the 20S core proteasome complex involved in the proteolytic degradation of most intracellular proteins. This complex plays numerous essential roles within the cell by associating with different regulatory particles. Associated with two 19S regulatory particles, forms the 26S proteasome and thus participates in the ATP-dependent degradation of ubiquitinated proteins. The 26S proteasome plays a key role in the maintenance of protein homeostasis by removing misfolded or damaged proteins that could impair cellular functions, and by removing proteins whose functions are no longer required. Associated with the PA200 or PA28, the 20S proteasome mediates ubiquitin-independent protein degradation. This type of proteolysis is required in several pathways including spermatogenesis (20S-PA200 complex) or generation of a subset of MHC class I-presented antigenic peptides (20S-PA28 complex). Within the 20S core complex, PSMB5 displays a chymotrypsin-like activity.SUBUNIT The 26S proteasome consists of a 20S proteasome core and two 19S regulatory subunits. The 20S proteasome core is a barrel-shaped complex made of 28 subunits that are arranged in four stacked rings. The two outer rings are each formed by seven alpha subunits, and the two inner rings are formed by seven beta subunits. The proteolytic activity is exerted by three beta-subunits PSMB5, PSMB6 and PSMB7. Directly interacts with POMP (PubMed:15944226). Interacts with ABCB1 and TAP1 (PubMed:15488952).SUBUNIT (Microbial infection) Interacts with HIV-1 TAT protein.INDUCTION Down-regulated by IFNG/IFN-gamma (at protein level). Induced in breast cancer tissue. Up-regulated by sulforaphane in breast cancer cells.SIMILARITY Belongs to the peptidase T1B family.UniProtP2807460EQUAL263EQUALReactome Database ID Release 7568819Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=68819ReactomeR-HSA-688192Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-68819.2GO0004175GO molecular functionReactome Database ID Release 7568824Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=68824Reactome Database ID Release 75174203Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174203ReactomeR-HSA-1742032Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174203.2Reactome Database ID Release 75174113Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174113ReactomeR-HSA-1741133Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174113.3GO1901990GO biological process2.7.11.22Phosphorylation of Cdh1 by Cyclin B1:Cdc2Phosphorylation of Cdh1 by Cyclin B1:Cdc2At the onset of mitosis, Cdh1 is phosphorylated by Cyclin B-Cdc2 resulting in a conformational change that prevents Cdh1 from activating the APC/C. Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Reactome DB_ID: 17409911EQUAL496EQUALReactome DB_ID: 293581Reactome DB_ID: 1742571phosphorylated residue at unknown position1EQUAL496EQUALReactome DB_ID: 1135821PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 170160Reactome Database ID Release 75174251Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174251ReactomeR-HSA-1742513Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174251.311598127Pubmed2001Regulation of the anaphase-promoting complex by the dual specificity phosphatase human Cdc14aBembenek, JYu, HJ Biol Chem 276:48237-42Inhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint componentsInhibition of the proteolytic activity of APC/C required for the onset of anaphase by mitotic spindle checkpoint componentsThe target of the mitotic checkpoint is the Anaphase Promoting Complex/Cyclosome (APC/C) an E3 ubiquitin ligase that targets proteins whose destruction is essential for mitotic exit. Currently, there are two proposed mechanism by which inhibition of the APC/C is achieved. These mechanisms differ depending on the mechanism of signal transduction. The APC/C may be inhibited directly by association with the Mitotic Checkpoint Complex (MCC) or through the sequestration of its activator, Cdc20. Authored: Yen, T, 2004-05-05 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Inactivation of APC/C via CDC20 sequestrationInactivation of APC/C via CDC20 sequestrationIn 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.Authored: Yen, T, 2004-05-05 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-02-17 05:19:32Reactome DB_ID: 1414471UniProt:Q13257 MAD2L1MAD2L1MAD2MAD2L1FUNCTION Component of the spindle-assembly checkpoint that prevents the onset of anaphase until all chromosomes are properly aligned at the metaphase plate. Required for the execution of the mitotic checkpoint which monitors the process of kinetochore-spindle attachment and inhibits the activity of the anaphase promoting complex by sequestering CDC20 until all chromosomes are aligned at the metaphase plate.SUBUNIT Monomer and homodimer. Heterotetramer with MAD1L1. Formation of a heterotetrameric core complex containing two molecules each of MAD1L1 and of MAD2L1 promotes binding of another molecule of MAD2L1 to each MAD2L1, resulting in a heterohexamer. Interacts with CDC20, MAD2L1BP and with ADAM17/TACE. Dimeric MAD2L1 in the closed conformation interacts with CDC20. Monomeric MAD2L1 in the open conformation does not interact with CDC20. CDC20 competes with MAD1L1 for MAD2L1 binding. Interacts with TPR. Binds to UBD (via ubiquitin-like 1 domain) during mitosis. Interacts with isoform 1 and isoform 2 of NEK2. Interacts with HSF1; this interaction occurs in mitosis (PubMed:18794143).DOMAIN The protein has two highly different native conformations, an inactive open conformation that cannot bind CDC20 and that predominates in cytosolic monomers, and an active closed conformation. The protein in the closed conformation preferentially dimerizes with another molecule in the open conformation, but can also form a dimer with a molecule in the closed conformation. Formation of a heterotetrameric core complex containing two molecules of MAD1L1 and of MAD2L1 in the closed conformation promotes binding of another molecule of MAD2L1 in the open conformation and the conversion of the open to the closed form, and thereby promotes interaction with CDC20.PTM Phosphorylated on multiple serine residues. The level of phosphorylation varies during the cell cycle and is highest during mitosis. Phosphorylation abolishes interaction with MAD1L1 and reduces interaction with CDC20. Phosphorylated by NEK2.SIMILARITY Belongs to the MAD2 family.UniProtQ132572EQUAL205EQUALReactome DB_ID: 14141211EQUAL499EQUALReactome DB_ID: 1414081MAD2*CDC20 complex [cytosol]MAD2*CDC20 complexReactome DB_ID: 14144712EQUAL205EQUALReactome DB_ID: 14141211EQUAL499EQUALReactome Database ID Release 75141408Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=141408ReactomeR-HSA-1414081Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-141408.1Reactome Database ID Release 75141429Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=141429ReactomeR-HSA-1414293Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-141429.39637688Pubmed1998The checkpoint protein MAD2 and the mitotic regulator CDC20 form a ternary complex with the anaphase-promoting complex to control anaphase initiationFang, GYu, HKirschner, Marc WGenes Dev 12:1871-83Inactivation of APC/C via direct inhibition of the APC/C complexInactivation of APC/C via direct inhibition of the APC/C complexIn the direct inhibition model, the cytosolic Mitotic Checkpoint Complex, consisting of hBUBR1, hBUB3, Cdc20 and Mad2, directly inhibits APC/C by binding to it.Authored: Yen, T, 2004-05-05 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Formation of the MCC complexFormation of the MCC complexUpon 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.Authored: Yen, T, 2004-05-05 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Reactome DB_ID: 1414161UniProt:O43684 BUB3BUB3BUB3FUNCTION Has a dual function in spindle-assembly checkpoint signaling and in promoting the establishment of correct kinetochore-microtubule (K-MT) attachments. Promotes the formation of stable end-on bipolar attachments. Necessary for kinetochore localization of BUB1. Regulates chromosome segregation during oocyte meiosis. The BUB1/BUB3 complex plays a role in the inhibition of anaphase-promoting complex or cyclosome (APC/C) when spindle-assembly checkpoint is activated and inhibits the ubiquitin ligase activity of APC/C by phosphorylating its activator CDC20. This complex can also phosphorylate MAD1L1.SUBUNIT Interacts with BUB1 and BUBR1. The BUB1/BUB3 complex interacts with MAD1L1. Interacts with ZNF207/BuGZ; leading to promote stability and kinetochore loading of BUB3.PTM Poly-ADP-ribosylated by PARP1.SIMILARITY Belongs to the WD repeat BUB3 family.UniProtO436841EQUAL328EQUALReactome DB_ID: 14144712EQUAL205EQUALReactome DB_ID: 14141211EQUAL499EQUALReactome DB_ID: 1414361UniProt:O60566 BUB1BBUB1BSSK1MAD3LBUBR1BUB1BFUNCTION Essential component of the mitotic checkpoint. Required for normal mitosis progression. The mitotic checkpoint delays anaphase until all chromosomes are properly attached to the mitotic spindle. One of its checkpoint functions is to inhibit the activity of the anaphase-promoting complex/cyclosome (APC/C) by blocking the binding of CDC20 to APC/C, independently of its kinase activity. The other is to monitor kinetochore activities that depend on the kinetochore motor CENPE. Required for kinetochore localization of CENPE. Negatively regulates PLK1 activity in interphase cells and suppresses centrosome amplification. Also implicated in triggering apoptosis in polyploid cells that exit aberrantly from mitotic arrest. May play a role for tumor suppression.ACTIVITY REGULATION Kinase activity stimulated by CENPE.SUBUNIT Interacts with CENPE, CENPF, mitosin, PLK1 and BUB3. Part of a complex containing BUB3, CDC20 and BUB1B. Interacts with anaphase-promoting complex/cyclosome (APC/C). Interacts with KNL1. Interacts with RIPK3 (PubMed:29883609).TISSUE SPECIFICITY Highly expressed in thymus followed by spleen. Preferentially expressed in tissues with a high mitotic index.INDUCTION Induced during mitosis.DOMAIN The D-box targets the protein for rapid degradation by ubiquitin-dependent proteolysis during the transition from mitosis to interphase.DOMAIN The BUB1 N-terminal domain directs kinetochore localization and binding to BUB3.PTM Proteolytically cleaved by caspase-3 in a cell cycle specific manner. The cleavage might be involved in the durability of the cell cycle delay. Caspase-3 cleavage is associated with abrogation of the mitotic checkpoint. The major site of cleavage is at Asp-610.PTM Acetylation at Lys-250 regulates its degradation and timing in anaphase entry.PTM Ubiquitinated. Degraded by the proteasome.PTM Sumoylated with SUMO2 and SUMO3. The sumoylation mediates the association with CENPE at the kinetochore.PTM Autophosphorylated in vitro. Intramolecular autophosphorylation is stimulated by CENPE. Phosphorylated during mitosis and hyperphosphorylated in mitotically arrested cells. Phosphorylation at Ser-670 and Ser-1043 occurs at kinetochores upon mitotic entry with dephosphorylation at the onset of anaphase.DISEASE Defects in BUB1B are associated with tumor formation.SIMILARITY Belongs to the protein kinase superfamily. Ser/Thr protein kinase family. BUB1 subfamily.UniProtO605661EQUAL1050EQUALReactome DB_ID: 1414401hBUBR1:hBUB3:MAD2*:CDC20 complex [cytosol]hBUBR1:hBUB3:MAD2*:CDC20 complexReactome DB_ID: 14141611EQUAL328EQUALReactome DB_ID: 14144712EQUAL205EQUALReactome DB_ID: 14141211EQUAL499EQUALReactome DB_ID: 14143611EQUAL1050EQUALReactome Database ID Release 75141440Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=141440ReactomeR-HSA-1414401Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-141440.1Reactome Database ID Release 75141437Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=141437ReactomeR-HSA-1414372Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-141437.211535616Pubmed2001Checkpoint inhibition of the APC/C in HeLa cells is mediated by a complex of BUBR1, BUB3, CDC20, and MAD2Sudakin, VChan, GKYen, TimJ Cell Biol 154:925-36Binding of the MCC complex to the APC/C complexBinding of the MCC complex to the APC/C complexIn 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.Authored: Yen, T, 2004-05-05 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-03-07 23:46:51Reactome DB_ID: 1741911phosphorylated anaphase promoting complex (APC/C) [cytosol]phosphorylated anaphase promoting complex (APC/C)Reactome DB_ID: 17424412EQUAL179EQUALReactome DB_ID: 17418911EQUAL1944EQUALReactome DB_ID: 17421111EQUAL755EQUALReactome DB_ID: 17416811EQUAL808EQUALReactome DB_ID: 17413711EQUAL597EQUALReactome DB_ID: 94762211EQUAL222EQUALReactome DB_ID: 680514011EQUAL121EQUALReactome DB_ID: 17410012EQUAL193EQUALReactome DB_ID: 17407311EQUAL824EQUALReactome DB_ID: 17424211EQUAL599EQUALReactome DB_ID: 17412611EQUAL84EQUALReactome DB_ID: 17415611EQUAL620EQUALReactome DB_ID: 17405211EQUAL85EQUALReactome DB_ID: 17414211EQUAL185EQUALReactome DB_ID: 17422911EQUAL822EQUALReactome DB_ID: 680513812EQUAL110EQUALReactome DB_ID: 17423611EQUAL147EQUALReactome Database ID Release 75174191Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174191ReactomeR-HSA-1741913Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174191.3Reactome DB_ID: 1414401Reactome DB_ID: 1414101MCC:APC/C complex [cytosol]MCC:APC/C complexReactome DB_ID: 1741911Reactome DB_ID: 1414401Reactome Database ID Release 75141410Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=141410ReactomeR-HSA-1414101Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-141410.1Reactome Database ID Release 75141423Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=141423ReactomeR-HSA-1414232Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-141423.2Reactome Database ID Release 75141430Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=141430ReactomeR-HSA-1414302Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-141430.214593737Pubmed2003The mitotic checkpoint: a signaling pathway that allows a single unattached kinetochore to inhibit mitotic exitChan, GKYen, TimProg Cell Cycle Res 5:431-9Reactome Database ID Release 75141405Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=141405ReactomeR-HSA-1414054Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-141405.4Reactome Database ID Release 75176408Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176408ReactomeR-HSA-1764083Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176408.316508672Pubmed2006How APC/C orders destructionBuschhorn, BAPeters, JMNat Cell Biol 8:209-1112049731Pubmed2002The anaphase-promoting complex: proteolysis in mitosis and beyondPeters, JMMol Cell 9:931-4312208841Pubmed2002The anaphase-promoting complex: it's not just for mitosis any more.Harper, JWBurton, JLSolomon, MJGenes Dev 16:2179-20610465783Pubmed1999Whose end is destruction: cell division and the anaphase-promoting complex.Zachariae, WNasmyth, KGenes Dev 13:2039-5815678131Pubmed2005The anaphase-promoting complex: a key factor in the regulation of cell cycleCastro, ABernis, CVigneron, SLabbe, JCLorca, TOncogene 24:314-25Activation of APC/C and APC/C:Cdc20 mediated degradation of mitotic proteinsActivation of APC/C and APC/C:Cdc20 mediated degradation of mitotic proteinsAPC/C:Cdc20 is first activated at the prometaphase/metaphase transition through phosphorylation of core subunits of the APC/C by mitotic kinases as well as recruitment of the APC/C activator protein Cdc20. APC/C:Cdc20 promotes the multiubiquitination and ordered degradation of Cyclin A and Nek2 degradation in prometaphase followed by Cyclin B and securin in metaphase (Reviewed in Castro et al., 2005).Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Phosphorylation of the APC/CPhosphorylation of the APC/CPhosphorylation of APC subunits is required for Cdc20 mediated activation by of the APC/C at the metaphase anaphase transition (Kramer et al., 2000). While the kinases responsible for phosphorylation in vivo have not been determined with certainty, both Plk1 and Cyclin B:Cdc2 have been implicated in this process.Reviewed: Peters, JM, 2006-03-27 22:55:092.7.11Free APC/C phosphorylated by Plk1Free APC/C phosphorylated by Plk1Phosphorylation 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.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Reactome DB_ID: 1740911anaphase promoting complex (APC/C) [nucleoplasm]anaphase promoting complex (APC/C)Reactome DB_ID: 17415311EQUAL755EQUALReactome DB_ID: 17420411EQUAL599EQUALReactome DB_ID: 680513611EQUAL121EQUALReactome DB_ID: 17418812EQUAL179EQUALReactome DB_ID: 17411511EQUAL808EQUALReactome DB_ID: 17421611EQUAL85EQUALReactome DB_ID: 17416311EQUAL84EQUALReactome DB_ID: 17414111EQUAL822EQUALReactome DB_ID: 17417511EQUAL824EQUALReactome DB_ID: 17422811EQUAL597EQUALReactome DB_ID: 17406312EQUAL193EQUALReactome DB_ID: 17404711EQUAL185EQUALReactome DB_ID: 17404911EQUAL620EQUALReactome DB_ID: 17419711EQUAL147EQUALReactome DB_ID: 885205111EQUAL222EQUALReactome DB_ID: 17421711EQUAL1944EQUALReactome DB_ID: 680513712EQUAL110EQUALReactome Database ID Release 75174091Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174091ReactomeR-HSA-1740913Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174091.3Reactome DB_ID: 1741091PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 3002800O-phospho-L-threonine at 210210EQUAL1EQUAL603EQUALReactome Database ID Release 75174119Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174119ReactomeR-HSA-1741192Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174119.211859075Pubmed2002The cyclin-ubiquitin ligase activity of cyclosome/APC is jointly activated by protein kinases Cdk1-cyclin B and PlkGolan, AYudkovsky, YHershko, AJ Biol Chem 277:15552-714657031Pubmed2003Mitotic regulation of the human anaphase-promoting complex by phosphorylationKraft, CHerzog, FGieffers, CMechtler, KHagting, APines, JPeters, JMEMBO J 22:6598-6092.7.11.22Free APC/C phosphorylated by Cyclin B:Cdc2Free APC/C phosphorylated by Cyclin B:Cdc2Phosphorylation 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.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Reactome DB_ID: 1740911Reactome DB_ID: 1741091PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 170160Reactome Database ID Release 75174132Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174132ReactomeR-HSA-1741322Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174132.2Reactome Database ID Release 75176412Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176412ReactomeR-HSA-1764123Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176412.310793135Pubmed2000Mitotic regulation of the APC activator proteins CDC20 and CDH1Kramer, ERScheuringer, NPodtelejnikov, AVMann, MPeters, JMMol Biol Cell 11:1555-69APC/C:Cdc20 mediated degradation of mitotic proteinsAPC/C:Cdc20 mediated degradation of mitotic proteinsFollowing phosphorylation of the APC/C core subunits by mitotic kinases, the activating protein, Cdc20 is recruited to the APC and promotes the multiubiquitination and subsequent degradation of the mitotic cyclins (Cyclin A and Cyclin B) as well as the protein securin which functions in sister chromatid cohesion. Timely degradation of these proteins is essential for sister chromatid separation and the proper timing of exit from mitosis (See Zachariae and Nasmyth, 1999). Cdc20 is degraded late in mitosis (Reviewed in Owens and Hoyt, 2005)Reviewed: Peters, JM, 2006-03-27 22:55:09APC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpointAPC:Cdc20 mediated degradation of cell cycle proteins prior to satisfation of the cell cycle checkpointAPC:CDC20 mediates the degradation of a number of cell cycle proteins including Cyclin A and Nek2A.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Cdc20:Phospho-APC/C mediated degradation of Cyclin ACdc20:Phospho-APC/C mediated degradation of Cyclin ACyclin A, functions in mitosis as well as DNA replication and is degraded in the interim by the APC/C to permit normal chromosome segregation, cell division, and the onset of S phase (see Lukas and Bartek, 2004). Cyclin A is initially degraded early in mitosis by APC/C:Cdc20 when the spindle checkpoint is still active and degradation of securin and cyclin B is inhibited.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Association of Cyclin A with the APC/CAssociation of Cyclin A with the APC/CCyclin 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).Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-03-07 23:49:09Reactome DB_ID: 1742321Cyclin A:phospho-Cdc2(Thr 161) complex [cytosol]Cyclin A:phospho-Cdc2(Thr 161) complexConverted from EntitySet in ReactomeReactome DB_ID: 1700891CCNA [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityReactome DB_ID: 1574151O-phospho-L-threonine at 161161EQUAL1EQUAL297EQUALReactome Database ID Release 75174232Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174232ReactomeR-HSA-1742322Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174232.2Reactome DB_ID: 1414101Reactome DB_ID: 1741401Cdc2:Cyclin A:MCC:APC/C complex [cytosol]Cdc2:Cyclin A:MCC:APC/C complexReactome DB_ID: 1742321Reactome DB_ID: 1414101Reactome Database ID Release 75174140Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174140ReactomeR-HSA-1741401Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174140.1Reactome Database ID Release 75174171Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174171ReactomeR-HSA-1741713Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174171.310679238Pubmed2000Human p55(CDC)/Cdc20 associates with cyclin A and is phosphorylated by the cyclin A-Cdk2 complexOhtoshi, AMaeda, THigashi, HAshizawa, SHatakeyama, MBiochem Biophys Res Commun 268:530-411285280Pubmed2001Anaphase-promoting complex/cyclosome-dependent proteolysis of human cyclin A starts at the beginning of mitosis and is not subject to the spindle assembly checkpointGeley, SKramer, EGieffers, CGannon, JPeters, JMHunt, TJ Cell Biol 153:137-486.3.2.19Ubiquitination of Cyclin A by APC/C:Cdc20 complexUbiquitination of Cyclin A by APC/C:Cdc20 complexRape 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.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-02-17 05:46:22Reactome DB_ID: 1741401Converted from EntitySet in ReactomeReactome DB_ID: 1135954Reactome DB_ID: 1742221multiubiquitinated Cyclin A associated with MCC:APC/C complex [cytosol]multiubiquitinated Cyclin A associated with MCC:APC/C complexReactome DB_ID: 1741401Converted from EntitySet in ReactomeReactome DB_ID: 1135954Reactome Database ID Release 75174222Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174222ReactomeR-HSA-1742221Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174222.1PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 141410Reactome Database ID Release 75174219Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174219Reactome Database ID Release 75174104Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174104ReactomeR-HSA-1741042Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174104.216413484Pubmed2006The processivity of multiubiquitination by the APC determines the order of substrate degradationRape, MReddy, SKKirschner, Marc WCell 124:89-103GO0006511GO biological processDegradation multiubiquitinated Cyclin ADegradation multiubiquitinated Cyclin AFollowing multiubiquitination, Cyclin A is targeted for destruction by the 26S proteasome.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-03-07 23:53:31Reactome DB_ID: 1742221Reactome DB_ID: 1574151O-phospho-L-threonine at 161161EQUAL1EQUAL297EQUALConverted from EntitySet in ReactomeReactome DB_ID: 1135954Reactome DB_ID: 1414101PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 68819Reactome Database ID Release 75174255Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174255ReactomeR-HSA-1742552Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174255.2GO0043161GO biological processReactome Database ID Release 75174184Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174184ReactomeR-HSA-1741842Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174184.215577895Pubmed2004Cell division: the heart of the cycleLukas, JNature 432:564-7GO0031145GO biological processAPC-Cdc20 mediated degradation of Nek2AAPC-Cdc20 mediated degradation of Nek2ALike Cyclin A, NIMA-related kinase 2A (Nek2A) is degraded during pro-metaphase in a checkpoint-independent manner.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-07-11 10:28:00Association of Nek2A with MCC:APC/CAssociation of Nek2A with MCC:APC/CNek2A 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).Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-07-10 14:28:40Reactome DB_ID: 1773291UniProt:P51955 NEK2NEK2NLK1NEK2ANEK2FUNCTION Protein kinase which is involved in the control of centrosome separation and bipolar spindle formation in mitotic cells and chromatin condensation in meiotic cells. Regulates centrosome separation (essential for the formation of bipolar spindles and high-fidelity chromosome separation) by phosphorylating centrosomal proteins such as CROCC, CEP250 and NINL, resulting in their displacement from the centrosomes. Regulates kinetochore microtubule attachment stability in mitosis via phosphorylation of NDC80. Involved in regulation of mitotic checkpoint protein complex via phosphorylation of CDC20 and MAD2L1. Plays an active role in chromatin condensation during the first meiotic division through phosphorylation of HMGA2. Phosphorylates: PPP1CC; SGO1; NECAB3 and NPM1. Essential for localization of MAD2L1 to kinetochore and MAPK1 and NPM1 to the centrosome. Phosphorylates CEP68 and CNTLN directly or indirectly (PubMed:24554434). NEK2-mediated phosphorylation of CEP68 promotes CEP68 dissociation from the centrosome and its degradation at the onset of mitosis (PubMed:25704143). Involved in the regulation of centrosome disjunction (PubMed:26220856).ACTIVITY REGULATION Isoform 1 is inhibited by ionizing radiation in the presence of PPP1CA. Its catalytic activity is inhibited by the inhibitor CCT241950. In the presence of this inhibitor, displays an autoinhibited conformation: Tyr-70 side chain points into the active site, interacts with the activation loop, and blocks the alphaC helix.SUBUNIT Isoform 1, isoform 2 and isoform 4 form homo- and heterodimers. Interacts with NECAB3 and HMGA2 (By similarity). Isoform 1 interacts with CDC20, CTNB1, MAD1L1, MAPK, NEK11, NPM1, NDC80, PCNT and SGO1 (PubMed:14978040, PubMed:15358203, PubMed:15388344, PubMed:15161910, PubMed:17621308, PubMed:18086858, PubMed:18297113, PubMed:20599736, PubMed:20034488). Isoform 1 interacts with STK3/MST2 (via SARAH domain) and SAV1 (via SARAH domain) (PubMed:21076410). Isoform 1 and isoform 2 interact with MAD2L1 (PubMed:20034488). Isoform 1 and isoform 4 interact with PPP1CA and PPP1CC (PubMed:15659832, PubMed:17283141). Interacts with CEP68; the interaction leads to phosphorylation of CEP68. Interacts with CNTLN; the interaction leads to phosphorylation of CNTLN (PubMed:24554434). Isoform 1 interacts with CEP85 (PubMed:26220856).TISSUE SPECIFICITY Isoform 1 and isoform 2 are expressed in peripheral blood T-cells and a wide variety of transformed cell types. Isoform 1 and isoform 4 are expressed in the testis. Up-regulated in various cancer cell lines, as well as primary breast tumors.INDUCTION Expression and activity peak in the G2 phase of the mitotic cycle and decrease once the cells have entered mitosis due to degradation by the anaphase promoting complex APC/C-CDC20. In G1 phase, both isoform 1 and isoform 2 are almost undetectable. However, at the G1/S transition, there is an increase in expression of both isoforms which then remain at this increased level throughout S and G2. At the onset of mitosis, isoform 1 undergoes a rapid disappearance whereas isoform 2 continues to be present at about the same level as in G2. During the rest of mitosis, isoform 1 remains absent, while isoform 2 only begins to decline upon re-entry into the next G1 phase.DOMAIN The leucine-zipper domain is required for its dimerization and activation.PTM Activated by autophosphorylation. Protein phosphatase 1 represses autophosphorylation and activation of isoform 1 by dephosphorylation. Phosphorylation by STK3/MST2 is necessary for its localization to the centrosome.SIMILARITY Belongs to the protein kinase superfamily. NEK Ser/Thr protein kinase family. NIMA subfamily.UniProtP519551EQUAL445EQUALReactome DB_ID: 1414101Reactome DB_ID: 1794131Nek2A:MCC:APC/C complex [cytosol]Nek2A:MCC:APC/C complexReactome DB_ID: 17732911EQUAL445EQUALReactome DB_ID: 1414101Reactome Database ID Release 75179413Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=179413ReactomeR-HSA-1794131Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-179413.1Reactome Database ID Release 75179410Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=179410ReactomeR-HSA-1794102Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-179410.211742988Pubmed2001APC/C-mediated destruction of the centrosomal kinase Nek2A occurs in early mitosis and depends upon a cyclin A-type D-boxHames, RSWattam, SLYamano, HBacchieri, RFry, AMEMBO J 20:7117-2716648845Pubmed2006Early mitotic degradation of Nek2A depends on Cdc20-independent interaction with the APC/CHayes, MJKimata, YWattam, SLLindon, CMao, GYamano, HFry, AMNat Cell Biol 8:607-146.3.2.19Multiubiquitination of Nek2AMultiubiquitination of Nek2ANek2A is ubiquitinated by the APC/C-Cdc20 ubiquitin ligase.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-07-10 14:28:40Reactome DB_ID: 1794131Converted from EntitySet in ReactomeReactome DB_ID: 1135953Reactome DB_ID: 1794141Multiubiquitinated Nek2A [cytosol]Multiubiquitinated Nek2AReactome DB_ID: 1794131Converted from EntitySet in ReactomeReactome DB_ID: 1135953Reactome Database ID Release 75179414Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=179414ReactomeR-HSA-1794141Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-179414.1PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 179413Reactome Database ID Release 75179412Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=179412Reactome Database ID Release 75179417Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=179417ReactomeR-HSA-1794172Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-179417.2Degradation of multiubiquitinated Nek2ADegradation of multiubiquitinated Nek2ANek2A is degraded by the 26S proteasome following ubiquitylation by the E3 ubiquitin ligase APC/C: Cdc20.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-07-10 14:28:40Reactome DB_ID: 1794141Converted from EntitySet in ReactomeReactome DB_ID: 1135953Reactome DB_ID: 1414101Reactome Database ID Release 75179421Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=179421ReactomeR-HSA-1794212Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-179421.2Reactome Database ID Release 75179409Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=179409ReactomeR-HSA-1794093Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-179409.3GO0007096GO biological processReactome Database ID Release 75179419Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=179419ReactomeR-HSA-1794192Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-179419.2Activation of APC/C:Cdc20 by dissociation of Cdc20:phospho-APC/C from Cdc20:phospho-APC/C:Mad2:Bub3:BubR1Activation of APC/C:Cdc20 by dissociation of Cdc20:phospho-APC/C from Cdc20:phospho-APC/C:Mad2:Bub3:BubR1One 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.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2004-11-18 13:25:08Edited: Matthews, L, 2006-02-17 00:25:47Reactome DB_ID: 1414101Reactome DB_ID: 1741961hBUBR1:hBUB3:MAD2* complex [cytosol]hBUBR1:hBUB3:MAD2* complexReactome DB_ID: 14141611EQUAL328EQUALReactome DB_ID: 14144712EQUAL205EQUALReactome DB_ID: 14143611EQUAL1050EQUALReactome Database ID Release 75174196Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174196ReactomeR-HSA-1741961Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174196.1Reactome DB_ID: 1740811CDC20:p-APC/C [cytosol]CDC20:p-APC/CCDC20:Phospho-APC/CReactome DB_ID: 1741911Reactome DB_ID: 14141211EQUAL499EQUALReactome Database ID Release 75174081Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174081ReactomeR-HSA-1740811Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174081.1Reactome Database ID Release 75174238Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174238ReactomeR-HSA-1742383Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174238.3APC/C:Cdc20 mediated degradation of Cyclin BAPC/C:Cdc20 mediated degradation of Cyclin BThe degradation of cyclin B1, which appears to occur at the mitotic spindle, is delayed until the metaphase /anaphase transition by the spindle assembly checkpoint and is required in order for sister chromatids to separate (Geley et al. 2001;Hagting et al, 2002).Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Association of Cyclin B:Cdc2 with Cdc20:APC/C complexAssociation of Cyclin B:Cdc2 with Cdc20:APC/C complexCyclin B is believed to be recognized by the APC/C:Cdc20 complex through its D-box sequence.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Reactome DB_ID: 1574561CCNB1:p-T161-CDK1 [cytosol]CCNB1:p-T161-CDK1Cyclin B1:phospho-Cdc2(Thr 161)Reactome DB_ID: 15745111EQUAL433EQUALReactome DB_ID: 1574151O-phospho-L-threonine at 161161EQUAL1EQUAL297EQUALReactome Database ID Release 75157456Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157456ReactomeR-HSA-1574561Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157456.1Reactome DB_ID: 1740811Reactome DB_ID: 1740951Cdc20:phospho-APC/C:Cyclin B:Cdc2 complex [cytosol]Cdc20:phospho-APC/C:Cyclin B:Cdc2 complexReactome DB_ID: 1574561Reactome DB_ID: 1740811Reactome Database ID Release 75174095Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174095ReactomeR-HSA-1740951Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174095.1Reactome Database ID Release 75174120Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174120ReactomeR-HSA-1741203Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174120.36.3.2.19Ubiquitination of Cyclin B by phospho-APC/C:Cdc20 complexUbiquitination of Cyclin B by phospho-APC/C:Cdc20 complexAt 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.<br><br> This reaction takes place in the 'cytosol' and is mediated by the 'ubiquitin-protein ligase activity' of 'Cdc20:Phospho-APC/C'.<br>Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Reactome DB_ID: 1740951Converted from EntitySet in ReactomeReactome DB_ID: 1135954Reactome DB_ID: 1741311multiubiquitinated Cyclin B:Cdc2:Cdc20:phospho-APC/C complex [cytosol]multiubiquitinated Cyclin B:Cdc2:Cdc20:phospho-APC/C complexReactome DB_ID: 1740951Converted from EntitySet in ReactomeReactome DB_ID: 1135954Reactome Database ID Release 75174131Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174131ReactomeR-HSA-1741311Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174131.1PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 174081Reactome Database ID Release 75174076Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174076Reactome Database ID Release 75174227Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174227ReactomeR-HSA-1742272Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174227.2Degradation of multiubiquitinated Cyclin BDegradation of multiubiquitinated Cyclin BMulitubiquitinated Cyclin B is targeted for degradation by the 26S proteasome.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Reactome DB_ID: 1741311Reactome DB_ID: 1740811Reactome DB_ID: 1574151O-phospho-L-threonine at 161161EQUAL1EQUAL297EQUALConverted from EntitySet in ReactomeReactome DB_ID: 1135954Reactome Database ID Release 75174157Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174157ReactomeR-HSA-1741572Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174157.2Reactome Database ID Release 75174048Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174048ReactomeR-HSA-1740482Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174048.212070128Pubmed2002Human securin proteolysis is controlled by the spindle checkpoint and reveals when the APC/C switches from activation by Cdc20 to Cdh1Hagting, ADen Elzen, NVodermaier, HCWaizenegger, ICPeters, JMPines, JJ Cell Biol 157:1125-37APC/C:Cdc20 mediated degradation of SecurinAPC/C:Cdc20 mediated degradation of SecurinThe separation of sister chromatids in anaphase requires the destruction of the anaphase inhibitor, securin. Securin associates with and inactivates the protease, separase. Separase cleaves the cohesin subunit, Scc1 that is responsible for the cohesion of sister chromatids (reviewed in Nasmyth et al., 2000). Securin destruction begins at metaphase after the mitotic spindle checkpoint has been satisfied (Hagting et al., 2002).Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Association of Securin with Cdc20:APC/C complexAssociation of Securin with Cdc20:APC/C complexSecurin is thought to be recognized by the APC/C:Cdc20 complex through its conserved D-box sequence.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Reactome DB_ID: 1741901UniProt:O95997 PTTG1PTTG1PTTGPTTG1TUTR1EAP1FUNCTION Regulatory protein, which plays a central role in chromosome stability, in the p53/TP53 pathway, and DNA repair. Probably acts by blocking the action of key proteins. During the mitosis, it blocks Separase/ESPL1 function, preventing the proteolysis of the cohesin complex and the subsequent segregation of the chromosomes. At the onset of anaphase, it is ubiquitinated, conducting to its destruction and to the liberation of ESPL1. Its function is however not limited to a blocking activity, since it is required to activate ESPL1. Negatively regulates the transcriptional activity and related apoptosis activity of TP53. The negative regulation of TP53 may explain the strong transforming capability of the protein when it is overexpressed. May also play a role in DNA repair via its interaction with Ku, possibly by connecting DNA damage-response pathways with sister chromatid separation.SUBUNIT Interacts with RPS10 and DNAJA1 (By similarity). Interacts with the caspase-like ESPL1, and prevents its protease activity probably by covering its active site. Interacts with TP53 and blocks its activity probably by blocking its binding to DNA. Interacts with the Ku 70 kDa subunit of ds-DNA kinase. Interacts with PTTG1IP.TISSUE SPECIFICITY Expressed at low level in most tissues, except in adult testis, where it is highly expressed. Overexpressed in many patients suffering from pituitary adenomas, primary epithelial neoplasias, and esophageal cancer.DEVELOPMENTAL STAGE Low level during G1 and S phases. Peaks at M phase. During anaphase, it is degraded.DOMAIN The N-terminal destruction box (D-box) acts as a recognition signal for degradation via the ubiquitin-proteasome pathway.DOMAIN The TEK-boxes are required for 'Lys-11'-linked ubiquitination and facilitate the transfer of the first ubiquitin and ubiquitin chain nucleation. TEK-boxes may direct a catalytically competent orientation of the UBE2C/UBCH10-ubiquitin thioester with the acceptor lysine residue.PTM Phosphorylated at Ser-165 by CDK1 during mitosis.PTM Phosphorylated in vitro by ds-DNA kinase.PTM Ubiquitinated through 'Lys-11' linkage of ubiquitin moieties by the anaphase promoting complex (APC) at the onset of anaphase, conducting to its degradation. 'Lys-11'-linked ubiquitination is mediated by the E2 ligase UBE2C/UBCH10.SIMILARITY Belongs to the securin family.UniProtO959971EQUAL202EQUALReactome DB_ID: 1740811Reactome DB_ID: 1742121CDC20:p-APC/C:PTTG1 [cytosol]CDC20:p-APC/C:PTTG1Cdc20:phosph-APC/C:Securin complexReactome DB_ID: 17419011EQUAL202EQUALReactome DB_ID: 1740811Reactome Database ID Release 75174212Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174212ReactomeR-HSA-1742121Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174212.1Reactome Database ID Release 75174121Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174121ReactomeR-HSA-1741212Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174121.26.3.2.19Ubiquitination of Securin by phospho-APC/C:Cdc20 complexUbiquitination of Securin by phospho-APC/C:Cdc20 complexSecurin is ubiquitinated by APC/C:Cdc20 (Hagting et al., 2002; Jin et al. 2008).Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Reactome DB_ID: 1742121Converted from EntitySet in ReactomeReactome DB_ID: 1135953Reactome DB_ID: 30959441CDC20:pAPC/C:K11polyUb-PTTG1 [cytosol]CDC20:pAPC/C:K11polyUb-PTTG1CDC20:phospho-APC/C:K11polyUb-Securin complexReactome DB_ID: 1740811Reactome DB_ID: 30959431ubiquitinylated lysine (K11polyUb [cytosol]) at unknown positionubiquitinylated lysine [MOD:01148]1EQUAL202EQUALReactome Database ID Release 753095944Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=3095944ReactomeR-HSA-30959441Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-3095944.1PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 174081Reactome Database ID Release 75174144Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174144ReactomeR-HSA-1741442Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174144.218485873Pubmed2008Mechanism of ubiquitin-chain formation by the human anaphase-promoting complexJin, LWilliamson, ABanerjee, SPhilipp, IRape, MCell 133:653-65Degradation of multiubiquitinated SecurinDegradation of multiubiquitinated SecurinFollowing ubiquitination, securin is degraded by the 26S proteasome.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Reactome DB_ID: 30959441Reactome DB_ID: 1740811Converted from EntitySet in ReactomeReactome DB_ID: 1135954PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 68819Reactome Database ID Release 75174202Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174202ReactomeR-HSA-1742022Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174202.2Reactome Database ID Release 75174154Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174154ReactomeR-HSA-1741542Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174154.210827941Pubmed2000Splitting the chromosome: cutting the ties that bind sister chromatidsNasmyth, KPeters, JMUhlmann, FScience 288:1379-85Reactome Database ID Release 75176409Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176409ReactomeR-HSA-1764093Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176409.315949434Pubmed2005The D box asserts itselfOwens, TJHoyt, MAMol Cell 18:611-2Reactome Database ID Release 75176814Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176814ReactomeR-HSA-1768142Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176814.2Conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphaseConversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphaseThe activity of the APC/C must be appropriately regulated during the cell cycle to ensure the timely degradation of its substrates. Of particular importance is the conversion from APC/C:Cdc20 to APC/C:Cdh1 in late anaphase. Phosphorylation of both the APC/C complex and Cdh1 regulate this conversion. During mitosis, several APC/C subunits are phosphorylated increasing the activity of APC/C:Cdc20. However, phosphorylation of Cdh1 by mitotic Cyclin:Cdk complexes prevents it from activating the APC/C. Dephosphorylation of Cdh1 in late anaphase by Cdc14a results in the activation of APC/C:Cdh1 (reviewed in Castro et al, 2005).Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-02-17 00:35:213.1.3.16Dephosphorylation of phospho-Cdh1Dephosphorylation of phospho-Cdh1Phosphorylation 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.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-02-17 05:23:25Reactome DB_ID: 293561water [ChEBI:15377]waterChEBI15377Reactome DB_ID: 1741931phosphorylated residue at unknown position1EQUAL496EQUALReactome DB_ID: 17424911EQUAL496EQUALReactome DB_ID: 1112941diphosphoric acid [ChEBI:29888]diphosphoric acidChEBI29888PHYSIOL-LEFT-TO-RIGHTACTIVATIONConverted from EntitySet in ReactomeReactome DB_ID: 174146phospho-Cdh1 phosphatase [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityGO0004721GO molecular functionReactome Database ID Release 75174127Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174127Reactome Database ID Release 75174124Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174124ReactomeR-HSA-1741242Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174124.2Dissociation of Cdc20 from APC/C complexDissociation of Cdc20 from APC/C complexIn late mitosis, Cdc20 dissociates from the APC/C and is replaced by the activator Cdh1 (Ballabeni et al. 2011).Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Reactome DB_ID: 1740811Reactome DB_ID: 1741911Reactome DB_ID: 14141211EQUAL499EQUALReactome Database ID Release 75174224Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174224ReactomeR-HSA-1742243Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174224.322084091Pubmed2011Cell cycle adaptations of embryonic stem cellsBallabeni, AndreaPark, In-HyunZhao, RuiWang, WeipingLerou, Paul HDaley, George QKirschner, Marc WProc. Natl. Acad. Sci. U.S.A. 108:19252-7Association of Cdh1 with the APC/CAssociation of Cdh1 with the APC/CFollowing its dephosphorylation in late mitosis, Cdh1 replaces Cdc20 as the APC/C activator.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Reactome DB_ID: 17424911EQUAL496EQUALReactome DB_ID: 1741911Reactome DB_ID: 1741811phospho-APC/C:Cdh1 complex [cytosol]phospho-APC/C:Cdh1 complexReactome DB_ID: 17424911EQUAL496EQUALReactome DB_ID: 1741911Reactome Database ID Release 75174181Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174181ReactomeR-HSA-1741811Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174181.1Reactome Database ID Release 75174070Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174070ReactomeR-HSA-1740702Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174070.2Reactome Database ID Release 75176407Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=176407ReactomeR-HSA-1764073Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-176407.3APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1APC/C:Cdh1 mediated degradation of Cdc20 and other APC/C:Cdh1 targeted proteins in late mitosis/early G1From late mitosis through G1 phase APC/C:Cdh1 insures the continued degradation of the mitotic proteins and during mitotic exit and G1 its substrates include Cdc20, Plk1, Aurora A, Cdc6 and Geminin (see Castro et al., 2005). 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).Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Association of cell cycle proteins with the APC/C:Cdh1 complexAssociation of cell cycle proteins with the APC/C:Cdh1 complexThe 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).Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-02-17 00:25:47Reactome DB_ID: 1741811Converted from EntitySet in ReactomeReactome DB_ID: 1740561(APC/C:Cdh1)-targeted cell cycle proteins [cytosol]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUBE2C [cytosol]PTTG1 [cytosol]AURKB [cytosol]CDC20 [cytosol]PLK1 [cytosol]AURKA [cytosol]UniProtQ96GD4UniProtO14965Reactome DB_ID: 1741071cell cycle proteins:phospho-APC/C:Cdh1 complex [cytosol]cell cycle proteins:phospho-APC/C:Cdh1 complexReactome DB_ID: 1741811Converted from EntitySet in ReactomeReactome DB_ID: 1740561Reactome Database ID Release 75174107Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174107ReactomeR-HSA-1741071Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174107.1Reactome Database ID Release 75174088Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174088ReactomeR-HSA-1740883Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174088.312446569Pubmed2002The D-Box-activating domain (DAD) is a new proteolysis signal that stimulates the silent D-Box sequence of Aurora-ACastro, AVigneron, SBernis, CLabbe, JCPrigent, CLorca, TEMBO Rep 3:1209-1410733526Pubmed2000The KEN box: an APC recognition signal distinct from the D box targeted by Cdh1Pfleger, CMKirschner, Marc WGenes Dev 14:655-656.3.2.19Ubiquitination of cell cycle proteins targeted by the APC/C:Cdh1complexUbiquitination of cell cycle proteins targeted by the APC/C:Cdh1complexAt 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.<br><br> 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).<br>Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Reactome DB_ID: 1741071Converted from EntitySet in ReactomeReactome DB_ID: 1135954Reactome DB_ID: 1742481multiubiquitinated cell cycle protein:APC/C:Cdh1 complex [cytosol]multiubiquitinated cell cycle protein:APC/C:Cdh1 complexReactome DB_ID: 1741071Converted from EntitySet in ReactomeReactome DB_ID: 1135954Reactome Database ID Release 75174248Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174248ReactomeR-HSA-1742481Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174248.1PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 174107Reactome Database ID Release 75174158Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174158Reactome Database ID Release 75174195Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174195ReactomeR-HSA-1741953Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174195.3Degradation of multiubiquitinated cell cycle proteinsDegradation of multiubiquitinated cell cycle proteinsCell cycle proteins mulitubiquitinated by the APC/C are targeted for degradation by the 26S proteasome.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Reactome DB_ID: 1742481Reactome DB_ID: 1741811Converted from EntitySet in ReactomeReactome DB_ID: 1135954PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 68819Reactome Database ID Release 75174105Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174105ReactomeR-HSA-1741053Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174105.3RB1 recruits APC/C:Cdh1 complex to SKP2RB1 recruits APC/C:Cdh1 complex to SKP2The 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).Authored: Orlic-Milacic, Marija, 2020-05-07Reviewed: Dick, Frederick Andrew, 2020-05-17Edited: Orlic-Milacic, Marija, 2020-05-18Reactome DB_ID: 686421UniProt:P06400 RB1RB1RB1FUNCTION Key regulator of entry into cell division that acts as a tumor suppressor. Promotes G0-G1 transition when phosphorylated by CDK3/cyclin-C. Acts as a transcription repressor of E2F1 target genes. The underphosphorylated, active form of RB1 interacts with E2F1 and represses its transcription activity, leading to cell cycle arrest. Directly involved in heterochromatin formation by maintaining overall chromatin structure and, in particular, that of constitutive heterochromatin by stabilizing histone methylation. Recruits and targets histone methyltransferases SUV39H1, KMT5B and KMT5C, leading to epigenetic transcriptional repression. Controls histone H4 'Lys-20' trimethylation. Inhibits the intrinsic kinase activity of TAF1. Mediates transcriptional repression by SMARCA4/BRG1 by recruiting a histone deacetylase (HDAC) complex to the c-FOS promoter. In resting neurons, transcription of the c-FOS promoter is inhibited by BRG1-dependent recruitment of a phospho-RB1-HDAC1 repressor complex. Upon calcium influx, RB1 is dephosphorylated by calcineurin, which leads to release of the repressor complex (By similarity).FUNCTION (Microbial infection) In case of viral infections, interactions with SV40 large T antigen, HPV E7 protein or adenovirus E1A protein induce the disassembly of RB1-E2F1 complex thereby disrupting RB1's activity.SUBUNIT Interacts with ATAD5. Interacts with PRMT2, CDK1 and CDK2 (By similarity). The hypophosphorylated form interacts with and sequesters the E2F1 transcription factor (PubMed:8336704, PubMed:20940255). Interacts with heterodimeric E2F/DP transcription factor complexes containing TFDP1 and either E2F1, E2F3, E2F4 or E2F5, or TFDP2 and E2F4. The unphosphorylated form interacts with EID1, ARID3B, KDM5A, SUV39H1, MJD2A/JHDM3A and THOC1. Interacts with the N-terminal domain of TAF1. Interacts with SNW1, AATF, DNMT1, LIN9, LMNA, KMT5B, KMT5C, PELP1, UHRF2 and TMPO-alpha. May interact with NDC80. Interacts with GRIP1 and UBR4. Interacts with ARID4A and KDM5B. Interacts with E4F1 and LIMD1. Interacts with SMARCA4/BRG1 AND HDAC1 (By similarity). Interacts with PSMA3 and USP4. Interacts (when methylated at Lys-860) with L3MBTL1. Interacts with CHEK2; phosphorylates RB1. Interacts with CEBPA (PubMed:15107404). P-TEFB complex interacts with RB1; promotes phosphorylation of RB1 (PubMed:12037672). Interacts with RBBP9; the interaction disrupts RB1 binding to E2F1 (By similarity). Interacts with KAT2B/PCAF and EP300/P300 (By similarity).SUBUNIT (Microbial infection) Interacts with adenovirus E1A protein.SUBUNIT (Microbial infection) Interacts with HPV E7 protein.SUBUNIT (Microbial infection) Interacts with SV40 large T antigen.SUBUNIT (Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL123.SUBUNIT (Microbial infection) Interacts with molluscum contagiosum virus protein MC007.TISSUE SPECIFICITY Expressed in the retina. Expressed in foreskin keratinocytes (at protein level) (PubMed:20940255).DOMAIN The Pocket domain binds to the threonine-phosphorylated domain C, thereby preventing interaction with heterodimeric E2F/DP transcription factor complexes.PTM Phosphorylated by CDK6 and CDK4, and subsequently by CDK2 at Ser-567 in G1, thereby releasing E2F1 which is then able to activate cell growth. Dephosphorylated at the late M phase. SV40 large T antigen, HPV E7 and adenovirus E1A bind to the underphosphorylated, active form of pRb. Phosphorylation at Thr-821 and Thr-826 promotes interaction between the C-terminal domain C and the Pocket domain, and thereby inhibits interactions with heterodimeric E2F/DP transcription factor complexes. Dephosphorylated at Ser-795 by calcineruin upon calcium stimulation. CDK3/cyclin-C-mediated phosphorylation at Ser-807 and Ser-811 is required for G0-G1 transition. Phosphorylated by CDK1 and CDK2 upon TGFB1-mediated apoptosis (By similarity).PTM N-terminus is methylated by METTL11A/NTM1 (By similarity). Monomethylation at Lys-810 by SMYD2 enhances phosphorylation at Ser-807 and Ser-811, and promotes cell cycle progression. Monomethylation at Lys-860 by SMYD2 promotes interaction with L3MBTL1.PTM Acetylated during keratinocyte differentiation. Acetylation at Lys-873 and Lys-874 regulates subcellular localization. Can be deacetylated by SIRT1.SIMILARITY Belongs to the retinoblastoma protein (RB) family.UniProtP064002EQUAL928EQUALReactome DB_ID: 1742501Reactome DB_ID: 9755541UniProt:Q13309 SKP2SKP2FBXL1SKP2FUNCTION Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of target proteins involved in cell cycle progression, signal transduction and transcription. Specifically recognizes phosphorylated CDKN1B/p27kip and is involved in regulation of G1/S transition. Degradation of CDKN1B/p27kip also requires CKS1. Recognizes target proteins ORC1, CDT1, RBL2, KMT2A/MLL1, CDK9, RAG2, FOXO1, UBP43, and probably MYC, TOB1 and TAL1. Degradation of TAL1 also requires STUB1. Recognizes CDKN1A in association with CCNE1 or CCNE2 and CDK2. Promotes ubiquitination and destruction of CDH1 in a CK1-Dependent Manner, thereby regulating cell migration.FUNCTION Through the ubiquitin-mediated proteasomal degradation of hepatitis C virus non-structural protein 5A, has an antiviral activity towards that virus.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Part of a SCF(SKP2) complex consisting of CUL1, RBX1, SKP1 and SKP2. Component of a SCF(SKP2)-like complex containing CUL1, SKP1, TRIM21 and SKP2. Interacts directly with CUL1 and SKP1. Interacts with CKS1. Interacts with the cyclin-A-CDK2 complex. Interacts with ORC1, phosphorylated CDT1, phosphorylated RBL2, ELF4, phosphorylated RAG2, FOXO1, UBP43, MYC, TOB1, TAL1 and KMT2A/MLL1. Interacts with TRIM21. Interacts with IFI27; promotes the ubiquitin-mediated proteasomal degradation of NS5A (PubMed:27194766). Interacts with hepatitis C virus/HCV non-structural protein NS5A; promotes the ubiquitin-mediated proteasomal degradation of NS5A (PubMed:27194766).PTM Ubiquitinated by the APC/C complex, leading to its degradation by the proteasome. Deubiquitinated by USP13.PTM Acetylation at Lys-68 and Lys-71 increases stability through impairment of APC/C-mediated proteolysis and promotes cytoplasmic retention. Deacetylated by SIRT3.UniProtQ133091EQUAL424EQUALReactome DB_ID: 96869781RB1:SKP2:APC/C:Cdh1 [nucleoplasm]RB1:SKP2:APC/C:Cdh1RB1:SKP2:APC/C:FZR1Reactome DB_ID: 6864212EQUAL928EQUALReactome DB_ID: 1742501Reactome DB_ID: 97555411EQUAL424EQUALReactome Database ID Release 759686978Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9686978ReactomeR-HSA-96869781Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9686978.1Reactome Database ID Release 759686980Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9686980ReactomeR-HSA-96869801Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9686980.115469821Pubmed2004An Rb-Skp2-p27 pathway mediates acute cell cycle inhibition by Rb and is retained in a partial-penetrance Rb mutantJi, PengJiang, HongRekhtman, KatyaBloom, JoannaIchetovkin, MarinaPagano, MicheleZhu, LiangMol. Cell 16:47-5817187060Pubmed2007Retinoblastoma protein and anaphase-promoting complex physically interact and functionally cooperate during cell-cycle exitBinné, Ulrich KClasson, Marie KDick, Frederick AndrewWei, WenyiRape, MichaelKaelin, William GNäär, Anders MDyson, NJNat. Cell Biol. 9:225-32APC/C:Cdh1 polyubiquitinates SKP2APC/C:Cdh1 polyubiquitinates SKP2RB1-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).Authored: Orlic-Milacic, Marija, 2020-05-07Reviewed: Dick, Frederick Andrew, 2020-05-17Edited: Orlic-Milacic, Marija, 2020-05-18Reactome DB_ID: 96869781Converted from EntitySet in ReactomeReactome DB_ID: 685243Ub [nucleoplasm]Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntityUBA52(1-76) [nucleoplasm]UBB(1-76) [nucleoplasm]UBC(533-608) [nucleoplasm]UBC(153-228) [nucleoplasm]UBC(609-684) [nucleoplasm]UBB(77-152) [nucleoplasm]UBC(1-76) [nucleoplasm]RPS27A(1-76) [nucleoplasm]UBB(153-228) [nucleoplasm]UBC(381-456) [nucleoplasm]UBC(229-304) [nucleoplasm]UBC(77-152) [nucleoplasm]UBC(457-532) [nucleoplasm]UBC(305-380) [nucleoplasm]Reactome DB_ID: 1881921PolyUb-SKP2:RB1:phospho-APC/C:Cdh1 complex [nucleoplasm]PolyUb-SKP2:RB1:phospho-APC/C:Cdh1 complexReactome DB_ID: 6864212EQUAL928EQUALReactome DB_ID: 96870731ubiquitinylated lysine (K11polyUb [nucleoplasm]) at unknown position1EQUAL424EQUALReactome DB_ID: 1742501Reactome Database ID Release 75188192Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=188192ReactomeR-HSA-1881922Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-188192.2PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 9686978GO0061630GO molecular functionReactome Database ID Release 759687072Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9687072Reactome Database ID Release 759686969Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=9686969ReactomeR-HSA-96869691Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-9686969.1APC/C:Cdh1-mediated degradation of Skp2APC/C:Cdh1-mediated degradation of Skp2SKP2 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).Authored: Pagano, M, 2006-09-19 08:23:10Reviewed: Peters, JM, 2006-03-27 22:55:09Reviewed: Dick, Frederick Andrew, 2020-05-17Edited: Matthews, L, 2006-10-01 21:26:42Edited: Orlic-Milacic, Marija, 2020-05-18Reactome DB_ID: 1881921Reactome DB_ID: 6864212EQUAL928EQUALConverted from EntitySet in ReactomeReactome DB_ID: 685243Reactome DB_ID: 1742501PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 17775026S proteasome [nucleoplasm]26S proteasomeReactome DB_ID: 886666511EQUAL70EQUALReactome DB_ID: 174331144EQUAL277EQUALReactome DB_ID: 17433912EQUAL456EQUALReactome DB_ID: 174343146EQUAL264EQUALReactome DB_ID: 17434811EQUAL953EQUALReactome DB_ID: 174334121EQUAL219EQUALReactome DB_ID: 174342135EQUAL239EQUALReactome DB_ID: 17432811EQUAL534EQUALReactome DB_ID: 17432911EQUAL310EQUALReactome DB_ID: 17431012EQUAL254EQUALReactome DB_ID: 17433812EQUAL440EQUALReactome DB_ID: 17430811EQUAL271EQUALReactome DB_ID: 17432111EQUAL223EQUALReactome DB_ID: 17432011EQUAL249EQUALReactome DB_ID: 17431611EQUAL389EQUALReactome DB_ID: 17435111EQUAL248EQUALReactome DB_ID: 17431911EQUAL389EQUALReactome DB_ID: 17430911EQUAL324EQUALReactome DB_ID: 17433311EQUAL263EQUALReactome DB_ID: 17431411EQUAL246EQUALReactome DB_ID: 17432712EQUAL422EQUALReactome DB_ID: 17431111EQUAL908EQUALReactome DB_ID: 174336173EQUAL276EQUALReactome DB_ID: 17432611EQUAL376EQUALReactome DB_ID: 17431311EQUAL439EQUALReactome DB_ID: 174344160EQUAL263EQUALReactome DB_ID: 17431811EQUAL350EQUALReactome DB_ID: 17432211EQUAL226EQUALReactome DB_ID: 17434512EQUAL234EQUALReactome DB_ID: 17431511EQUAL418EQUALReactome DB_ID: 17433511EQUAL201EQUALReactome DB_ID: 17431212EQUAL406EQUALReactome DB_ID: 17432312EQUAL255EQUALReactome DB_ID: 17434612EQUAL504EQUALReactome DB_ID: 17433011EQUAL377EQUALReactome DB_ID: 17432411EQUAL261EQUALReactome DB_ID: 17434011EQUAL241EQUALReactome DB_ID: 174349140EQUAL273EQUALReactome DB_ID: 17434112EQUAL205EQUALReactome DB_ID: 17433212EQUAL433EQUALReactome DB_ID: 17435012EQUAL239EQUALReactome DB_ID: 174347129EQUAL241EQUALReactome Database ID Release 75177750Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=177750ReactomeR-HSA-1777502Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-177750.2Reactome Database ID Release 75174087Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174087Reactome Database ID Release 75188191Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=188191ReactomeR-HSA-1881913Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-188191.315014502Pubmed2004Control of the SCF(Skp2-Cks1) ubiquitin ligase by the APC/C(Cdh1) ubiquitin ligaseBashir, TDorrello, NVAmador, VGuardavaccaro, DPagano, MicheleNature 428:190-315014503Pubmed2004Degradation of the SCF component Skp2 in cell-cycle phase G1 by the anaphase-promoting complexWei, WAyad, NGWan, YZhang, GJKirschner, Marc WKaelin WG, JrNature 428:194-8Reactome Database ID Release 75174178Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174178ReactomeR-HSA-1741783Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174178.3Autodegradation of Cdh1 by Cdh1:APC/CAutodegradation of Cdh1 by Cdh1:APC/C Cdh1 is degraded by the APC/C during in G1 and G0. This auto-regulation may contribute to reducing the levels of Cdh1 levels during G1 and G0 (Listovsky et al., 2004).Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:006.3.2.19Multiubiquitination of APC/C-associated Cdh1Multiubiquitination of APC/C-associated Cdh1Cdh1 is multiubiquitinated by the APC/C:Cdh1 complex prior to degradation by the 26S proteasome.Authored: Lorca, T, Castro, A, 2006-01-26 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-02-17 05:21:42Reactome DB_ID: 1741671Converted from EntitySet in ReactomeReactome DB_ID: 685243Reactome DB_ID: 1740681multiubiquitinated Cdh1 associated with APC/C [nucleoplasm]multiubiquitinated Cdh1 associated with APC/CConverted from EntitySet in ReactomeReactome DB_ID: 685243Reactome DB_ID: 1742131phospho-Cdh1:phospho-APC/C [nucleoplasm]phospho-Cdh1:phospho-APC/CReactome DB_ID: 1742571phosphorylated residue at unknown position1EQUAL496EQUALReactome DB_ID: 1741091Reactome Database ID Release 75174213Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174213ReactomeR-HSA-1742131Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174213.1Reactome Database ID Release 75174068Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174068ReactomeR-HSA-1740681Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174068.1PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 174167Reactome Database ID Release 75174085Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174085Reactome Database ID Release 75174057Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174057ReactomeR-HSA-1740572Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174057.215029244Pubmed2004Mammalian Cdh1/Fzr mediates its own degradationListovsky, TOren, YSYudkovsky, YMahbubani, HMWeiss, AMLebendiker, MBrandeis, MEMBO J 23:1619-26Degradation of multiubiquitinated Cdh1Degradation of multiubiquitinated Cdh1At 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.<br><br> This reaction takes place in the 'nucleoplasm' and is mediated by the 'endopeptidase activity' of '26S proteasome'.<br>Authored: Matthews, L, 2006-01-30 00:00:00Reviewed: Peters, JM, 2006-03-27 22:55:09Edited: Matthews, L, 2006-01-30 00:00:00Reactome DB_ID: 1740681Converted from EntitySet in ReactomeReactome DB_ID: 685243Reactome DB_ID: 1741091PHYSIOL-LEFT-TO-RIGHTACTIVATIONReactome DB_ID: 177750Reactome Database ID Release 75174058Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174058ReactomeR-HSA-1740582Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174058.2Reactome Database ID Release 75174084Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174084ReactomeR-HSA-1740843Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174084.3Reactome Database ID Release 75174143Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=174143ReactomeR-HSA-1741431Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-174143.115840442Pubmed2005A roller coaster ride with the mitotic cyclinsFung, TKPoon, RYSemin Cell Dev Biol 16:335-4211336713Pubmed2001Three-dimensional structure of the anaphase-promoting complexGieffers, CDube, PHarris, JRStark, HPeters, JMMol Cell 7:907-1311562348Pubmed2001D box and KEN box motifs in budding yeast Hsl1p are required for APC-mediated degradation and direct binding to Cdc20p and Cdh1pBurton, JLSolomon, MJGenes Dev 15:2381-957985232Pubmed1994Proteasomes: protein degradation machines of the cellPeters, JMTrends Biochem Sci 19:377-82