BioPAX pathway converted from "Constitutive Signaling by NOTCH1 PEST Domain Mutants" in the Reactome database. Constitutive Signaling by NOTCH1 PEST Domain Mutants As NOTCH1 PEST domain is intracellular, NOTCH1 PEST domain mutants are expected to behave as the wild-type NOTCH1 with respect to ligand binding and proteolytic cleavage mediated activation of signaling. However, once the NICD1 fragment of NOTCH1 is released, PEST domain mutations prolong its half-life and transcriptional activity through interference with FBXW7 (FBW7)-mediated ubiquitination and degradation of NICD1 (Weng et al. 2004, Thompson et al. 2007, O'Neil et al. 2007). All NOTCH1 PEST domain mutants annotated here (NOTCH1 Q2395*, NOTCH1 Q2440*, NOTCH1 P2474Afs*4 and NOTCH1 P2514Rfs*4) either have a truncated PEST domain or lack the PEST domain completely. Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 LEFT-TO-RIGHT NOTCH1 PEST domain mutants bind DLL1 NOTCH1 PEST domain mutants are expected to bind to DLL1 ligand in an identical fashion to wild-type NOTCH1 (Jarriault et al. 1998, Yang et al. 2005, Cordle et al. 2008). Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 DLL1 Delta 1 ligand Reactome DB_ID: 157089 plasma membrane GENE ONTOLOGY GO:0005886 UniProt:O00548 DLL1 DLL1 UNQ146/PRO172 FUNCTION Transmembrane ligand protein of NOTCH1, NOTCH2 and NOTCH3 receptors that binds the extracellular domain (ECD) of Notch receptor in a cis and trans fashion manner (PubMed:11006133). Following transinteraction, ligand cells produce mechanical force that depends of a clathrin-mediated endocytosis, requiring ligand ubiquitination, EPN1 interaction, and actin polymerisation; these events promote Notch receptor extracellular domain (NECD) transendocytosis and triggers Notch signaling through induction of cleavage, hyperphosphorylation, and nuclear accumulation of the intracellular domain of Notch receptors (NICD) (By similarity). Is required for embryonic development and maintenance of adult stem cells in many different tissues and immune systeme; the DLL1-induced Notch signaling is mediated through an intercellular communication that regulates cell lineage, cell specification, cell patterning and morphogenesis through effects on differentiation and proliferation (PubMed:11581320). Plays a role in brain development at different level, namely by regulating neuronal differentiation of neural precursor cells via cell-cell interaction, most likely through the lateral inhibitory system in an endogenous level dependent-manner. During neocortex development, Dll1-Notch signaling transmission is mediated by dynamic interactions between intermediate neurogenic progenitors and radial glia; the cell-cell interactions are mediated via dynamic and transient elongation processes, likely to reactivate/maintain Notch activity in neighboring progenitors, and coordinate progenitor cell division and differentiation across radial and zonal boundaries. During cerebellar development, regulates Bergmann glial monolayer formation and its morphological maturation through a Notch signaling pathway. At the retina and spinal cord level, regulates neurogenesis by preventing the premature differentiation of neural progenitors and also by maintaining progenitors in spinal cord through Notch signaling pathway. Also controls neurogenesis of the neural tube in a progenitor domain-specific fashion along the dorsoventral axis. Maintains quiescence of neural stem cells and plays a role as a fate determinant that segregates asymmetrically to one daughter cell during neural stem cells mitosis, resulting in neuronal differentiation in Dll1-inheriting cell. Plays a role in immune systeme development, namely the development of all T-cells and marginal zone (MZ) B-cells (By similarity). Blocks the differentiation of progenitor cells into the B-cell lineage while promoting the emergence of a population of cells with the characteristics of a T-cell/NK-cell precursor (PubMed:11581320). Also plays a role during muscle development. During early development, inhibits myoblasts differentiation from the medial dermomyotomal lip and later regulates progenitor cell differentiation. Directly modulates cell adhesion and basal lamina formation in satellite cells through Notch signaling. Maintains myogenic progenitors pool by suppressing differentiation through down-regulation of MYOD1 and is required for satellite cell homing and PAX7 expression. During craniofacial and trunk myogenesis suppresses differentiation of cranial mesoderm-derived and somite-derived muscle via MYOD1 regulation but in cranial mesoderm-derived progenitors, is neither required for satellite cell homing nor for PAX7 expression. Also plays a role during pancreatic cell development. During type B pancreatic cell development, may be involved in the initiation of proximodistal patterning in the early pancreatic epithelium. Stimulates multipotent pancreatic progenitor cells proliferation and pancreatic growth by maintaining HES1 expression and PTF1A protein levels. During fetal stages of development, is required to maintain arterial identity and the responsiveness of arterial endothelial cells for VEGFA through regulation of KDR activation and NRP1 expression. Controls sprouting angiogenesis and subsequent vertical branch formation througth regulation on tip cell differentiation. Negatively regulates goblet cell differentiation in intestine and controls secretory fat commitment through lateral inhibition in small intestine. Plays a role during inner ear development; negatively regulates auditory hair cell differentiation. Plays a role during nephron development through Notch signaling pathway. Regulates growth, blood pressure and energy homeostasis (By similarity).SUBUNIT Homodimer. Interacts with TJP1. Interacts with MAGI1 (via PDZ domain); forms a complex with CTNNB1 and CDH2 and promotes recruitment to the adherens junction and stabilization on the cell surface. Interacts with PSEN1; undergoes a presenilin-dependent gamma-secretase cleavage that releases a Dll1-intracellular form. Interacts with MFAP5. Interacts with MIB1. Interacts with NEURL1B; leads to ubiquitination. Interacts with NEURL1 (By similarity). Interacts with SYNJ2BP; enhances DLL1 protein stability, and promotes Notch signaling in endothelial cells (PubMed:24025447). Interacts with MAGI1, MAGI2, MAGI3 and MPDZ (PubMed:15509766). Interacts (via ubiquitin) with EPN1 (via IUM domain); binding with NOTCH1 attached to neighboring cell, promotes ligand ubiquitination and EPN1 interaction, leading to NECD transendocytosis and Notch signaling. Interacts with NOTCH1 (By similarity) (PubMed:15509766, PubMed:24025447). Interacts with NOTCH2NLB; leading to promote Notch signaling pathway in a cell-autonomous manner through inhibition of cis DLL1-NOTCH2 interactions (PubMed:29856955).TISSUE SPECIFICITY Expressed in heart and pancreas, with lower expression in brain and muscle and almost no expression in placenta, lung, liver and kidney.PTM Ubiquitinated by MIB (MIB1 or MIB2), leading to its endocytosis and subsequent degradation (By similarity). Ubiquitinated; promotes recycling back to the plasma membrane and confers a strong affinity for NOTCH1. Multi-ubiquitination of LYS-613 by MIB1 promotes both cis and trans-interaction with NOTCH1, as well as activation of Notch signaling. Ubiquitinated by NEURL1B (By similarity).PTM Phosphorylated in a membrane association-dependent manner. Phosphorylation at Ser-697 requires the presence of Ser-694, whereas phosphorylation at Ser-694 occurs independently of the other site. Phosphorylation is required for full ligand activity in vitro and affects surface presentation, ectodomain shedding, and endocytosis.PTM O-fucosylated. Can be elongated to a disaccharide by MFNG. Homo sapiens NCBI Taxonomy 9606 UniProt O00548 18 EQUAL 723 EQUAL Reactome Database ID Release 81 157089 Database 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=157089 Reactome R-HSA-157089 1 Reactome 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-157089.1 Reactome http://www.reactome.org Converted from EntitySet in Reactome NOTCH1 PEST domain mutants Reactome DB_ID: 2220939 NOTCH1 P2514Rfs*4 Reactome DB_ID: 2768978 NOTCH1 P2514Rfs*4 Transmembrane Fragment NOTCH1 Pro2514Argfs*4 Transmembrane Fragment NOTCH1 PEST domain mutant P2514Rfs*4 transmembrane fragment Reactome DB_ID: 2768982 UniProt:P46531 NOTCH1 NOTCH1 TAN1 FUNCTION Functions as a receptor for membrane-bound ligands Jagged-1 (JAG1), Jagged-2 (JAG2) and Delta-1 (DLL1) to regulate cell-fate determination. Upon ligand activation through the released notch intracellular domain (NICD) it forms a transcriptional activator complex with RBPJ/RBPSUH and activates genes of the enhancer of split locus. Affects the implementation of differentiation, proliferation and apoptotic programs. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting. Involved in the maturation of both CD4(+) and CD8(+) cells in the thymus. Important for follicular differentiation and possibly cell fate selection within the follicle. During cerebellar development, functions as a receptor for neuronal DNER and is involved in the differentiation of Bergmann glia. Represses neuronal and myogenic differentiation. May play an essential role in postimplantation development, probably in some aspect of cell specification and/or differentiation. May be involved in mesoderm development, somite formation and neurogenesis. May enhance HIF1A function by sequestering HIF1AN away from HIF1A. Required for the THBS4 function in regulating protective astrogenesis from the subventricular zone (SVZ) niche after injury. Involved in determination of left/right symmetry by modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO).SUBUNIT Heterodimer of a C-terminal fragment N(TM) and an N-terminal fragment N(EC) which are probably linked by disulfide bonds. Interacts with DNER, DTX1, DTX2 and RBPJ/RBPSUH. Also interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH1 (PubMed:11101851, PubMed:12370315). The NOTCH1 intracellular domain interacts with SNW1; the interaction involves multimerized NOTCH1 NICD and is implicated in a formation of an intermediate preactivation complex which associates with DNA-bound CBF-1/RBPJ (PubMed:10713164). The activated membrane-bound form interacts with AAK1 which promotes NOTCH1 stabilization. Forms a trimeric complex with FBXW7 and SGK1. Interacts with HIF1AN. HIF1AN negatively regulates the function of notch intracellular domain (NICD), accelerating myogenic differentiation (PubMed:17573339). Interacts (via NICD) with SNAI1 (via zinc fingers); the interaction induces SNAI1 degradation via MDM2-mediated ubiquitination and inhibits SNAI1-induced cell invasion. Interacts (via NICD) with MDM2A. Interacts (via NICD) with BCL6; the interaction decreases MAML1 recruitment by NOTCH1 NICD on target genes DNA and inhibits NOTCH1 transcractivation activity. Interacts with THBS4 (By similarity). Interacts (via the EGF-like repeat region) with CCN3 (via CTCK domain) (PubMed:12050162). Interacts (via EGF-like domains) with DLL4 (via N-terminal DSL and MNNL domains) (By similarity). Interacts with ZMIZ1. Interacts (via NICD domain) with MEGF10 (via the cytoplasmic domain). Interacts with DLL1 and JAG1 (By similarity). Interacts (via NICD domain) with PRAG1 (By similarity). Forms a complex with PRAG1, N1ICD and MAML1, in a MAML1-dependent manner (By similarity). Interacts (via transmembrane region) with PSEN1; the interaction is direct (PubMed:30598546). Interacts with ZFP64 (By similarity).TISSUE SPECIFICITY In fetal tissues most abundant in spleen, brain stem and lung. Also present in most adult tissues where it is found mainly in lymphoid tissues.DOMAIN Interaction with PSEN1 causes partial unwinding of the transmembrane helix, facilitating access to the scissile peptide bond.PTM Synthesized in the endoplasmic reticulum as an inactive form which is proteolytically cleaved by a furin-like convertase in the trans-Golgi network before it reaches the plasma membrane to yield an active, ligand-accessible form (By similarity). Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by ADAM17 to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT) (PubMed:24226769). Following endocytosis, this fragment is then cleaved by one of the catalytic subunits of gamma-secretase (PSEN1 or PSEN2), to release a Notch-derived peptide containing the intracellular domain (NICD) from the membrane (PubMed:30598546).PTM Phosphorylated.PTM O-glycosylated on the EGF-like domains (PubMed:24226769). O-glucosylated at Ser-435 by KDELC1 and KDELC2 (PubMed:30127001). Contains both O-linked fucose and O-linked glucose in the EGF-like domains 11, 12 and 13, which are interacting with the residues on DLL4 (By similarity). O-linked glycosylation by GALNT11 is involved in determination of left/right symmetry: glycosylation promotes activation of NOTCH1, possibly by promoting cleavage by ADAM17, modulating the balance between motile and immotile (sensory) cilia at the left-right organiser (LRO) (PubMed:24226769). MFNG-, RFNG- and LFNG-mediated modification of O-fucose residues at specific EGF-like domains results in inhibition of its activation by JAG1 and enhancement of its activation by DLL1 via an increased binding to DLL1 (By similarity).PTM Ubiquitinated. Undergoes 'Lys-29'-linked polyubiquitination by ITCH; promotes the lysosomal degradation of non-activated internalized NOTCH1 (PubMed:18628966, PubMed:23886940). Monoubiquitination at Lys-1759 is required for activation by gamma-secretase cleavage, it promotes interaction with AAK1, which stabilizes it. Deubiquitination by EIF3F is necessary for nuclear import of activated Notch (PubMed:24226769).PTM Hydroxylated at Asn-1955 by HIF1AN. Hydroxylated at Asn-2022 by HIF1AN (By similarity). Hydroxylation reduces affinity for HI1AN and may thus indirectly modulate negative regulation of NICD (By similarity).SIMILARITY Belongs to the NOTCH family. UniProt P46531 2514 EQUAL L-arginine residue MOD MOD:00011 2515 EQUAL L-valine residue MOD MOD:00029 2516 EQUAL L-proline residue MOD MOD:00024 1665 EQUAL 2516 EQUAL Reactome Database ID Release 81 2768982 Database 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=2768982 Reactome R-HSA-2768982 1 Reactome 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-2768982.1 COSMIC COSV53024776 additional information MI MI:0361 COSMIC COSM33946 1 NOTCH1 Extracellular fragment (NECD1) 19xFucT-16xGlcS-2xFucS-NOTCH1(19-1664) Reactome DB_ID: 1983670 extracellular region GENE ONTOLOGY GO:0005576 73 EQUAL O-fucosyl-L-threonine MOD MOD:00813 116 EQUAL 194 EQUAL 232 EQUAL 311 EQUAL 349 EQUAL 466 EQUAL 617 EQUAL 692 EQUAL 767 EQUAL 805 EQUAL 883 EQUAL O-fucosyl-L-serine MOD MOD:00812 921 EQUAL 997 EQUAL 1035 EQUAL 1159 EQUAL 1197 EQUAL 1243 EQUAL 1321 EQUAL 1362 EQUAL 1402 EQUAL 65 EQUAL O-glucosyl-L-serine MOD MOD:00804 146 EQUAL 378 EQUAL 458 EQUAL 496 EQUAL 534 EQUAL 609 EQUAL 647 EQUAL 722 EQUAL 759 EQUAL 797 EQUAL 951 EQUAL 1027 EQUAL 1065 EQUAL 1189 EQUAL 1273 EQUAL 19 EQUAL 1664 EQUAL Reactome Database ID Release 81 1983670 Database 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=1983670 Reactome R-HSA-1983670 1 Reactome 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-1983670.1 1 Reactome Database ID Release 81 2768978 Database 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=2768978 Reactome R-HSA-2768978 1 Reactome 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-2768978.1 NOTCH1 Q2395* NOTCH1 Gln2395* Reactome DB_ID: 2902190 NOTCH1 Q2395* Transmembrane Fragment NOTCH1 Gln2395* Transmembrane Fragment Reactome DB_ID: 1485596 2395 EQUAL L-glutamine removal MOD MOD:01637 1665 EQUAL 2394 EQUAL Reactome Database ID Release 81 1485596 Database 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=1485596 Reactome R-HSA-1485596 1 Reactome 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-1485596.1 COSMIC COSV53056886 1 1 Reactome Database ID Release 81 2902190 Database 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=2902190 Reactome R-HSA-2902190 1 Reactome 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-2902190.1 NOTCH1 Q2440* NOTCH1 Gln2440* Reactome DB_ID: 2902189 1 NOTCH1 Q2440* Transmembrane Fragment NOTCH1 Gln2440* Transmembrane Fragment Reactome DB_ID: 1485602 2440 EQUAL 1665 EQUAL 2439 EQUAL Reactome Database ID Release 81 1485602 Database 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=1485602 Reactome R-HSA-1485602 1 Reactome 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-1485602.1 COSMIC COSV53024887 1 Reactome Database ID Release 81 2902189 Database 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=2902189 Reactome R-HSA-2902189 1 Reactome 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-2902189.1 NOTCH1 P2474Afs*4 Reactome DB_ID: 2902198 1 NOTCH1 P2474Afs*4 Transmembrane Fragment Reactome DB_ID: 2894873 2474 EQUAL L-alanine residue MOD MOD:00010 2475 EQUAL L-histidine residue MOD MOD:00018 2476 EQUAL 1665 EQUAL 2476 EQUAL Reactome Database ID Release 81 2894873 Database 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=2894873 Reactome R-HSA-2894873 1 Reactome 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-2894873.1 COSMIC COSV53084788 1 Reactome Database ID Release 81 2902198 Database 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=2902198 Reactome R-HSA-2902198 1 Reactome 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-2902198.1 Reactome Database ID Release 81 2220939 Database 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=2220939 Reactome R-HSA-2220939 1 Reactome 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-2220939.1 DLL1:NOTCH1 PEST Domain Mutants Reactome DB_ID: 2768988 1 1 Reactome Database ID Release 81 2768988 Database 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=2768988 Reactome R-HSA-2768988 1 Reactome 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-2768988.1 Reactome Database ID Release 81 2769008 Database 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=2769008 Reactome R-HSA-2769008 2 Reactome 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-2769008.2 15574878 Pubmed 2005 Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1 Yang, LT Nichols, JT Yao, C Manilay, JO Robey, EA Weinmaster, G Mol Biol Cell 16:927-42 18296446 Pubmed 2008 Localization of the delta-like-1-binding site in human Notch-1 and its modulation by calcium affinity Cordle, J Redfield, C Stacey, M van der Merwe, PA Willis, AC Champion, BR Hambleton, S Handford, Penny A J Biol Chem 283:11785-93 9819428 Pubmed 1998 Delta-1 activation of notch-1 signaling results in HES-1 transactivation Jarriault, S Le, Bail O Hirsinger, E Pourquie, O Logeat, F Strong, CF Brou, C Seidah, NG Isra, l A Mol Cell Biol 18:7423-31 LEFT-TO-RIGHT NOTCH1 PEST domain mutants bind DLL4 NOTCH1 PEST domain mutants are expected to bind to DLL4 ligand in an identical fashion to wild-type NOTCH1 (Koch et al. 2008, Hozumi et al. 2008, Benedito et al. 2009). Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 DLL4 Delta 4 ligand Reactome DB_ID: 158437 UniProt:Q9NR61 DLL4 DLL4 UNQ1895/PRO4341 FUNCTION Involved in the Notch signaling pathway as Notch ligand (PubMed:11134954). Activates NOTCH1 and NOTCH4. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting (PubMed:20616313). Essential for retinal progenitor proliferation. Required for suppressing rod fates in late retinal progenitors as well as for proper generation of other retinal cell types (By similarity). During spinal cord neurogenesis, inhibits V2a interneuron fate (PubMed:17728344).SUBUNIT Interacts with NOTCH4. Interacts (via N-terminal DSL and MNNL domains) with NOTCH1 (via EGF-like domains).TISSUE SPECIFICITY Expressed in vascular endothelium.DOMAIN The Delta-Serrate-Lag2 (DSL) domain is required for binding to the Notch receptor. UniProt Q9NR61 27 EQUAL 685 EQUAL Reactome Database ID Release 81 158437 Database 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=158437 Reactome R-HSA-158437 1 Reactome 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-158437.1 DLL4:NOTCH1 PEST Domain Mutants Reactome DB_ID: 2768992 1 1 Reactome Database ID Release 81 2768992 Database 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=2768992 Reactome R-HSA-2768992 1 Reactome 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-2768992.1 Reactome Database ID Release 81 2769000 Database 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=2769000 Reactome R-HSA-2769000 2 Reactome 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-2769000.2 18824585 Pubmed 2008 Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment Koch, U Fiorini, E Benedito, R Besseyrias, V Schuster-Gossler, K Pierres, M Manley, NR Duarte, A MacDonald, HR Radtke, F J Exp Med 205:2515-23 18824583 Pubmed 2008 Delta-like 4 is indispensable in thymic environment specific for T cell development Hozumi, K Mailhos, C Negishi, N Hirano, K Yahata, T Ando, K Zuklys, S Holländer, GA Shima, DT Habu, S J Exp Med 205:2507-13 19524514 Pubmed 2009 The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis Benedito, R Roca, C Sörensen, I Adams, S Gossler, A Fruttiger, M Adams, Ralf H Cell 137:1124-35 LEFT-TO-RIGHT NOTCH1 PEST domain mutants bind JAG1 NOTCH1 PEST domain mutants are expected to bind to JAG1 ligand in an identical fashion to wild-type NOTCH1 (Li et al. 1998, Benedito et al. 2009). Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 JAG1 Jagged 1 ligand Reactome DB_ID: 157098 UniProt:P78504 JAG1 JAG1 JAGL1 FUNCTION Ligand for multiple Notch receptors and involved in the mediation of Notch signaling (PubMed:18660822, PubMed:20437614). May be involved in cell-fate decisions during hematopoiesis (PubMed:9462510). Seems to be involved in early and late stages of mammalian cardiovascular development. Inhibits myoblast differentiation (By similarity). Enhances fibroblast growth factor-induced angiogenesis (in vitro).SUBUNIT Interacts with NOTCH2 and NOTCH3 (By similarity). Interacts with NOTCH1 (in the presence of calcium ions) (PubMed:18660822).TISSUE SPECIFICITY Widely expressed in adult and fetal tissues. In cervix epithelium expressed in undifferentiated subcolumnar reserve cells and squamous metaplasia. Expression is up-regulated in cervical squamous cell carcinoma. Expressed in bone marrow cell line HS-27a which supports the long-term maintenance of immature progenitor cells.DEVELOPMENTAL STAGE Expressed in 32-52 days embryos in the distal cardiac outflow tract and pulmonary artery, major arteries, portal vein, optic vesicle, otocyst, branchial arches, metanephros, pancreas, mesocardium, around the major bronchial branches, and in the neural tube.DOMAIN The second EGF-like domain is atypical. UniProt P78504 34 EQUAL 1218 EQUAL Reactome Database ID Release 81 157098 Database 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=157098 Reactome R-HSA-157098 1 Reactome 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-157098.1 JAG1:NOTCH1 PEST Domain Mutants Reactome DB_ID: 2769002 1 1 Reactome Database ID Release 81 2769002 Database 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=2769002 Reactome R-HSA-2769002 1 Reactome 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-2769002.1 Reactome Database ID Release 81 2768999 Database 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=2768999 Reactome R-HSA-2768999 3 Reactome 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-2768999.3 9462510 Pubmed 1998 The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1 Li, L Milner, LA Deng, Y Iwata, M Banta, AB Graf, L Marcovina, S Friedman, C Trask, BJ Hood, L Torok-Storb, B Immunity 8:43-55 LEFT-TO-RIGHT NOTCH1 PEST domain mutants bind JAG2 NOTCH1 PEST domain mutants are expected to bind to JAG2 ligand in an identical fashion to wild-type NOTCH1 (Luo et al. 1997, Shimizu et al. 2000). Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 JAG2 Jagged 2 ligand Reactome DB_ID: 157120 UniProt:Q9Y219 JAG2 JAG2 FUNCTION Putative Notch ligand involved in the mediation of Notch signaling. Involved in limb development (By similarity).TISSUE SPECIFICITY Expressed in heart, placenta and skeletal muscle and to a lesser extent in pancreas. Very low expression in brain, lung, liver and kidney. UniProt Q9Y219 24 EQUAL 1238 EQUAL Reactome Database ID Release 81 157120 Database 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=157120 Reactome R-HSA-157120 1 Reactome 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-157120.1 JAG2:NOTCH1 PEST Domain Mutants Reactome DB_ID: 2768998 1 1 Reactome Database ID Release 81 2768998 Database 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=2768998 Reactome R-HSA-2768998 1 Reactome 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-2768998.1 Reactome Database ID Release 81 2768993 Database 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=2768993 Reactome R-HSA-2768993 3 Reactome 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-2768993.3 11006133 Pubmed 2000 Physical interaction of Delta1, Jagged1, and Jagged2 with Notch1 and Notch3 receptors Shimizu, K Chiba, S Saito, T Kumano, K Hirai, H Biochem Biophys Res Commun 276:385-9 9315665 Pubmed 1997 Isolation and functional analysis of a cDNA for human Jagged2, a gene encoding a ligand for the Notch1 receptor Luo, B Aster, JC Hasserjian, RP Kuo, F Sklar, J Mol Cell Biol 17:6057-67 LEFT-TO-RIGHT 6.3.2.19 Ubiquitination of DLL/JAG ligands upon binding to NOTCH1 PEST domain mutants Ubiquitination of DLL/JAG ligands upon binding to NOTCH1 PEST domain mutants has not been investigated but is assumed to occur based on the behavior of the wild-type NOTCH1 (Lai et al. 2001, Itoh et al. 2003, Koo et al. 2005, Lai et al. 2005, Le Borgne et al. 2005, Pistouli et al. 2005, Song et al. 2006, Koo et al. 2007, Koutelou et al. 2008). Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 Converted from EntitySet in Reactome Ub ubiquitin Reactome DB_ID: 113595 RPS27A RPS27A(1-76) ubiquitin (RPS27A) Reactome DB_ID: 939205 cytosol GENE ONTOLOGY GO:0005829 UniProt:P62979 RPS27A RPS27A UBA80 UBCEP1 SUBUNIT Ribosomal protein S27a is part of the 40S ribosomal subunit.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eS31 family. UniProt P62979 1 EQUAL 76 EQUAL Reactome Database ID Release 81 939205 Database 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=939205 Reactome R-HSA-939205 1 Reactome 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-939205.1 UBA52 UBA52(1-76) ubiquitin (UBA52) Reactome DB_ID: 939203 UniProt:P62987 UBA52 UBA52 UBCEP2 SUBUNIT Ribosomal protein L40 is part of the 60S ribosomal subunit. Interacts with UBQLN1 (via UBA domain).MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY In the N-terminal section; belongs to the ubiquitin family.SIMILARITY In the C-terminal section; belongs to the eukaryotic ribosomal protein eL40 family. UniProt P62987 1 EQUAL 76 EQUAL Reactome Database ID Release 81 939203 Database 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=939203 Reactome R-HSA-939203 1 Reactome 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-939203.1 UBB UBB(1-76) ubiquitin (UBB 1) Reactome DB_ID: 939214 UniProt:P0CG47 UBB UBB SUBUNIT Interacts with SKP1-KMD2A and SKP1-KMD2B complexes.MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS The mRNA encoding variant UBB(+1) is produced by an unknown mechanism involving the deletion of a GT dinucleotide in the close proximity of a GAGAG motif (PubMed:9422699). This variant mRNA is found in normal brain, but the encoded protein accumulates only in brain neurofibrillary tangles and neuritic plaques in Alzheimer disease and other tauopathies, as well as polyglutaminopathies (PubMed:14597671). UBB(+1) variant cannot be used for polyubiquitination, is not effectively degraded by the proteasome when ubiquitinated and ubiquitinated UBB(+1) is refractory to disassembly by deubiquitinating enzymes (DUBs). In healthy brain, UBB(+1) C-terminus can be cleaved by UCHL3 (PubMed:21762696).MISCELLANEOUS For a better understanding, features related to ubiquitin are only indicated for the first chain.SIMILARITY Belongs to the ubiquitin family. UniProt P0CG47 1 EQUAL 76 EQUAL Reactome Database ID Release 81 939214 Database 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=939214 Reactome R-HSA-939214 1 Reactome 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-939214.1 UBB(77-152) ubiquitin (UBB 2) Reactome DB_ID: 939213 77 EQUAL 152 EQUAL Reactome Database ID Release 81 939213 Database 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=939213 Reactome R-HSA-939213 1 Reactome 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-939213.1 UBB(153-228) ubiquitin (UBB 3) Reactome DB_ID: 939230 153 EQUAL 228 EQUAL Reactome Database ID Release 81 939230 Database 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=939230 Reactome R-HSA-939230 1 Reactome 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-939230.1 UBC UBC(1-76) ubiquitin (UBC 1) Reactome DB_ID: 939188 UniProt:P0CG48 UBC UBC MISCELLANEOUS Ubiquitin is encoded by 4 different genes. UBA52 and RPS27A genes code for a single copy of ubiquitin fused to the ribosomal proteins L40 and S27a, respectively. UBB and UBC genes code for a polyubiquitin precursor with exact head to tail repeats, the number of repeats differ between species and strains.MISCELLANEOUS For the sake of clarity sequence features are annotated only for the first chain, and are not repeated for each of the following chains.SIMILARITY Belongs to the ubiquitin family. UniProt P0CG48 1 EQUAL 76 EQUAL Reactome Database ID Release 81 939188 Database 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=939188 Reactome R-HSA-939188 1 Reactome 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-939188.1 UBC(77-152) ubiquitin (UBC 2) Reactome DB_ID: 939164 77 EQUAL 152 EQUAL Reactome Database ID Release 81 939164 Database 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=939164 Reactome R-HSA-939164 1 Reactome 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-939164.1 UBC(153-228) ubiquitin (UBC 3) Reactome DB_ID: 939258 153 EQUAL 228 EQUAL Reactome Database ID Release 81 939258 Database 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=939258 Reactome R-HSA-939258 1 Reactome 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-939258.1 UBC(229-304) ubiquitin (UBC 4) Reactome DB_ID: 939192 229 EQUAL 304 EQUAL Reactome Database ID Release 81 939192 Database 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=939192 Reactome R-HSA-939192 1 Reactome 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-939192.1 UBC(305-380) ubiquitin (UBC 5) Reactome DB_ID: 939232 305 EQUAL 380 EQUAL Reactome Database ID Release 81 939232 Database 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=939232 Reactome R-HSA-939232 1 Reactome 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-939232.1 UBC(381-456) ubiquitin (UBC 6) Reactome DB_ID: 939191 381 EQUAL 456 EQUAL Reactome Database ID Release 81 939191 Database 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=939191 Reactome R-HSA-939191 1 Reactome 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-939191.1 UBC(457-532) ubiquitin (UBC 7) Reactome DB_ID: 939184 457 EQUAL 532 EQUAL Reactome Database ID Release 81 939184 Database 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=939184 Reactome R-HSA-939184 1 Reactome 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-939184.1 UBC(533-608) ubiquitin (UBC 8) Reactome DB_ID: 939239 533 EQUAL 608 EQUAL Reactome Database ID Release 81 939239 Database 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=939239 Reactome R-HSA-939239 1 Reactome 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-939239.1 UBC(609-684) ubiquitin (UBC 9) Reactome DB_ID: 939165 609 EQUAL 684 EQUAL Reactome Database ID Release 81 939165 Database 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=939165 Reactome R-HSA-939165 1 Reactome 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-939165.1 Reactome Database ID Release 81 113595 Database 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=113595 Reactome R-HSA-113595 1 Reactome 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-113595.1 Converted from EntitySet in Reactome DLL/JAG:NOTCH1 PEST Domain Mutants Reactome DB_ID: 2768995 Reactome Database ID Release 81 2768995 Database 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=2768995 Reactome R-HSA-2768995 1 Reactome 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-2768995.1 Ub-DLL/JAG:NOTCH1 PEST Domain Mutants Reactome DB_ID: 2769006 1 1 Reactome Database ID Release 81 2769006 Database 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=2769006 Reactome R-HSA-2769006 1 Reactome 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-2769006.1 ACTIVATION Converted from EntitySet in Reactome MIB/NEURL Mindbomb/Neuralized Reactome DB_ID: 1911464 MIB1 E3 ubiquitin-protein ligase MIB1 Mind bomb homolog 1 Reactome DB_ID: 1472877 UniProt:Q86YT6 MIB1 MIB1 DIP1 KIAA1323 ZZANK2 FUNCTION E3 ubiquitin-protein ligase that mediates ubiquitination of Delta receptors, which act as ligands of Notch proteins. Positively regulates the Delta-mediated Notch signaling by ubiquitinating the intracellular domain of Delta, leading to endocytosis of Delta receptors. Probably mediates ubiquitination and subsequent proteasomal degradation of DAPK1, thereby antagonizing anti-apoptotic effects of DAPK1 to promote TNF-induced apoptosis (By similarity). Involved in ubiquitination of centriolar satellite CEP131, CEP290 and PCM1 proteins and hence inhibits primary cilium formation in proliferating cells. Mediates 'Lys-63'-linked polyubiquitination of TBK1, which probably participates in kinase activation.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with CEP131 and PCM1.TISSUE SPECIFICITY Widely expressed at low level. Expressed at higher level in spinal cord, ovary, whole brain, and all specific brain regions examined.PTM Ubiquitinated; possibly via autoubiquitination (By similarity). Ubiquitinated; this modification is inhibited in response to cellular stress, such as ultraviolet light (UV) radiation or heat shock.MISCELLANEOUS In epilepsy brain tissue, levels of expression are increased in the cytoplasm and microsomal fractions (endoplasmic reticulum). UniProt Q86YT6 1 EQUAL 1006 EQUAL Reactome Database ID Release 81 1472877 Database 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=1472877 Reactome R-HSA-1472877 1 Reactome 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-1472877.1 MIB2 E3 ubiquitin-protein ligase MIB2 Mind bomb homolog 2 Reactome DB_ID: 1472879 UniProt:Q96AX9 MIB2 MIB2 SKD ZZANK1 FUNCTION E3 ubiquitin-protein ligase that mediates ubiquitination of Delta receptors, which act as ligands of Notch proteins. Positively regulates the Delta-mediated Notch signaling by ubiquitinating the intracellular domain of Delta, leading to endocytosis of Delta receptors.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with actin monomer.TISSUE SPECIFICITY Expressed in skeletal muscle, and to a lesser extent in heart, brain and kidney.INDUCTION Down-regulated in many primary skin melanomas. Treatment with a demethylating agent, 5'-aza-2-deoxycytidine, restores expression, suggesting that down-regulation is the result of methylation of the gene.PTM Ubiquitinated. Possibly via autoubiquitination (By similarity). UniProt Q96AX9 1 EQUAL 1013 EQUAL Reactome Database ID Release 81 1472879 Database 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=1472879 Reactome R-HSA-1472879 1 Reactome 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-1472879.1 NEURL Neuralized-like protein 1A NEURL1A NEURL1 RNF67 Reactome DB_ID: 1911454 UniProt:O76050 NEURL1 NEURL1 NEURL NEURL1A RNF67 FUNCTION Plays a role in hippocampal-dependent synaptic plasticity, learning and memory. Involved in the formation of spines and functional synaptic contacts by modulating the translational activity of the cytoplasmic polyadenylation element-binding protein CPEB3. Promotes ubiquitination of CPEB3, and hence induces CPEB3-dependent mRNA translation activation of glutamate receptor GRIA1 and GRIA2. Can function as an E3 ubiquitin-protein ligase to activate monoubiquitination of JAG1 (in vitro), thereby regulating the Notch pathway. Acts as a tumor suppressor; inhibits malignant cell transformation of medulloblastoma (MB) cells by inhibiting the Notch signaling pathway.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with CPEB3 (via N-terminal domain); the interaction increases CPEB3 ubiquitination. Interacts with DLL1.TISSUE SPECIFICITY Expressed in brain, testis, pituitary gland, pancreas and bone marrow. Also poorly expressed in malignant astrocytomas and several neuroectodermal tumor cell lines. Weakly expressed in medulloblastoma (MB) compared with normal cerebellar tissues.INDUCTION Down-regulated in medulloblastoma (MB).PTM Myristoylation is a determinant of membrane targeting. UniProt O76050 2 EQUAL 574 EQUAL Reactome Database ID Release 81 1911454 Database 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=1911454 Reactome R-HSA-1911454 1 Reactome 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-1911454.1 NEURL1B E3 ubiquitin-protein ligase NEURL1B Neuralized-like protein 1B Neuralized-like protein 3 Reactome DB_ID: 1911456 UniProt:A8MQ27 NEURL1B NEURL1B NEURL3 FUNCTION E3 ubiquitin-protein ligase involved in regulation of the Notch pathway through influencing the stability and activity of several Notch ligands.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Interacts with JAG1, DLL1 and DLL4.TISSUE SPECIFICITY Highest expression in brain, prostate and small intestine. In the brain the levels are higher in fetal than in adult stage. In the adult brain the highest levels are detected in the olfactory system, cerebellar cortex, optic nerve and the frontal lobe. UniProt A8MQ27 1 EQUAL 555 EQUAL Reactome Database ID Release 81 1911456 Database 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=1911456 Reactome R-HSA-1911456 1 Reactome 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-1911456.1 Reactome Database ID Release 81 1911464 Database 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=1911464 Reactome R-HSA-1911464 1 Reactome 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-1911464.1 GENE ONTOLOGY GO:0004842 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 81 1980072 Database 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=1980072 Reactome Database ID Release 81 2769007 Database 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=2769007 Reactome R-HSA-2769007 2 Reactome 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-2769007.2 11740940 Pubmed 2001 Drosophila neuralized is a ubiquitin ligase that promotes the internalization and degradation of delta Lai, EC Deblandre, GA Kintner, C Rubin, GM Dev Cell 1:783-94 15760269 Pubmed 2005 Two distinct E3 ubiquitin ligases have complementary functions in the regulation of delta and serrate signaling in Drosophila Le Borgne, R Remaud, S Hamel, S Schweisguth, F PLoS Biol 3:e96 18077452 Pubmed 2008 Neuralized-like 1 (Neurl1) targeted to the plasma membrane by N-myristoylation regulates the Notch ligand Jagged1 Koutelou, E Sato, S Tomomori-Sato, C Florens, Laurence A Swanson, SK Washburn, MP Kokkinaki, M Conaway, Ron C Conaway, Joan W Moschonas, NK J Biol Chem 283:3846-53 16093323 Pubmed 2005 The interplay between DSL proteins and ubiquitin ligases in Notch signaling Pitsouli, C Delidakis, C Development 132:4041-50 12530964 Pubmed 2003 Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta Itoh, M Kim, CH Palardy, G Oda, T Jiang, YJ Maust, D Yeo, SY Lorick, K Wright, GJ Ariza-McNaughton, L Weissman, AM Lewis, J Chandrasekharappa, SC Chitnis, AB Dev Cell 4:67-82 18043734 Pubmed 2007 An obligatory role of mind bomb-1 in notch signaling of mammalian development Koo, BK Yoon, MJ Yoon, KJ Im, SK Kim, YY Kim, CH Suh, PG Jan, YN Kong, YY PLoS One 2:e1221 15829515 Pubmed 2005 The ubiquitin ligase Drosophila Mind bomb promotes Notch signaling by regulating the localization and activity of Serrate and Delta Lai, EC Roegiers, F Qin, X Jan, YN Rubin, GM Development 132:2319-32 17003037 Pubmed 2006 Neuralized-2 regulates a Notch ligand in cooperation with Mind bomb-1 Song, R Koo, BK Yoon, KJ Yoon, MJ Yoo, KW Kim, HT Oh, HJ Kim, YY Han, JK Kim, CH Kong, YY J Biol Chem 281:36391-400 15824097 Pubmed 2005 Mind bomb-2 is an E3 ligase for Notch ligand Koo, BK Yoon, KJ Yoo, KW Lim, HS Song, R So, JH Kim, CH Kong, YY J Biol Chem 280:22335-42 LEFT-TO-RIGHT ADAM10/17 cleaves ligand-bound NOTCH1 PEST domain mutants to produce NEXT1 PEST domain mutants After NOTCH1 PEST domain mutants bind a DLL (DLL1 or DLL4) or JAG ligand (JAG1 or JAG2) in trans, they are expected to be cleaved by ADAM10 or ADAM17 metalloproteases, like the wild-type ligand-bound NOTCH1, to produce NEXT1 PEST domain mutant fragments (Pan and Rubin 1997, Brou et al. 2000, Hartmann et al. 2002, Gordon et al. 2007, van Tetering et al. 2009). Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 Converted from EntitySet in Reactome NEXT1 PEST domain mutants Reactome DB_ID: 2289143 NEXT1 P2514Rfs*4 NEXT1 Pro2514Argfs*4 NEXT1 PEST domain mutant P2514Rfs*4 Reactome DB_ID: 2768989 1721 EQUAL 2516 EQUAL Reactome Database ID Release 81 2768989 Database 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=2768989 Reactome R-HSA-2768989 1 Reactome 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-2768989.1 COSMIC COSV53024776 COSMIC COSM33946 NEXT1 Q2395* NEXT1 Gln2395* Reactome DB_ID: 2902192 1721 EQUAL 2394 EQUAL Reactome Database ID Release 81 2902192 Database 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=2902192 Reactome R-HSA-2902192 1 Reactome 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-2902192.1 COSMIC COSV53056886 NEXT1 Q2440* NEXT1 Gln2440* Reactome DB_ID: 2902196 1721 EQUAL 2439 EQUAL Reactome Database ID Release 81 2902196 Database 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=2902196 Reactome R-HSA-2902196 1 Reactome 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-2902196.1 COSMIC COSV53024887 NEXT1 P2474Afs*4 Reactome DB_ID: 2902194 1721 EQUAL 2476 EQUAL Reactome Database ID Release 81 2902194 Database 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=2902194 Reactome R-HSA-2902194 1 Reactome 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-2902194.1 COSMIC COSV53084788 Reactome Database ID Release 81 2289143 Database 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=2289143 Reactome R-HSA-2289143 1 Reactome 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-2289143.1 NOTCH1 fragment:Ub-DSL Ub-DLL/JAG:NOTCH1 fragment Reactome DB_ID: 1911540 NOTCH1 fragment:DSL NOTCH1 fragment:DLL/JAG Reactome DB_ID: 157658 NOTCH1 fragment Reactome DB_ID: 2193050 NOTCH1(1665-1720) NOTCH1 S2 cleavage fragment Reactome DB_ID: 157654 1665 EQUAL 1720 EQUAL Reactome Database ID Release 81 157654 Database 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=157654 Reactome R-HSA-157654 1 Reactome 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-157654.1 1 1 Reactome Database ID Release 81 2193050 Database 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=2193050 Reactome R-HSA-2193050 1 Reactome 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-2193050.1 1 Converted from EntitySet in Reactome DSL DLL/JAG NOTCH Ligand Reactome DB_ID: 157643 Reactome Database ID Release 81 157643 Database 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=157643 Reactome R-HSA-157643 1 Reactome 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-157643.1 1 Reactome Database ID Release 81 157658 Database 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=157658 Reactome R-HSA-157658 1 Reactome 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-157658.1 1 1 Reactome Database ID Release 81 1911540 Database 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=1911540 Reactome R-HSA-1911540 1 Reactome 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-1911540.1 ACTIVATION ADAM10/17:Zn2+ Reactome DB_ID: 1852620 Converted from EntitySet in Reactome ADAM10/17 Reactome DB_ID: 1852617 KUZ ADAM10 ADAM 10 metalloprotease Reactome DB_ID: 157237 UniProt:O14672 ADAM10 ADAM10 KUZ MADM FUNCTION Cleaves the membrane-bound precursor of TNF-alpha at '76-Ala-|-Val-77' to its mature soluble form. Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface (PubMed:20592283). Responsible for the proteolytic release of several other cell-surface proteins, including heparin-binding epidermal growth-like factor, ephrin-A2, CD44, CDH2 and for constitutive and regulated alpha-secretase cleavage of amyloid precursor protein (APP) (PubMed:26686862, PubMed:11786905, PubMed:29224781). Contributes to the normal cleavage of the cellular prion protein (PubMed:11477090). Involved in the cleavage of the adhesion molecule L1 at the cell surface and in released membrane vesicles, suggesting a vesicle-based protease activity (PubMed:12475894). Controls also the proteolytic processing of Notch and mediates lateral inhibition during neurogenesis (By similarity). Responsible for the FasL ectodomain shedding and for the generation of the remnant ADAM10-processed FasL (FasL APL) transmembrane form (PubMed:17557115). Also cleaves the ectodomain of the integral membrane proteins CORIN and ITM2B (PubMed:19114711, PubMed:21288900). Mediates the proteolytic cleavage of LAG3, leading to release the secreted form of LAG3 (By similarity). Mediates the proteolytic cleavage of IL6R and IL11RA, leading to the release of secreted forms of IL6R and IL11RA (PubMed:26876177). Enhances the cleavage of CHL1 by BACE1 (By similarity). Cleaves NRCAM (By similarity). Cleaves TREM2, resulting in shedding of the TREM2 ectodomain (PubMed:24990881). Involved in the development and maturation of glomerular and coronary vasculature (By similarity). During development of the cochlear organ of Corti, promotes pillar cell separation by forming a ternary complex with CADH1 and EPHA4 and cleaving CADH1 at adherens junctions (By similarity). May regulate the EFNA5-EPHA3 signaling (PubMed:16239146).FUNCTION (Microbial infection) Promotes the cytotoxic activity of S.aureus hly by binding to the toxin at zonula adherens and promoting formation of toxin pores.ACTIVITY REGULATION Catalytically inactive when the propeptide is intact and associated with the mature enzyme (By similarity). The disintegrin and cysteine-rich regions modulate access of substrates to exerts an inhibitory effect on the cleavage of ADAM10 substrates (PubMed:29224781).SUBUNIT Forms a ternary EFNA5-EPHA3-ADAM10 complex mediating EFNA5 extracellular domain shedding by ADAM10 which regulates the EFNA5-EPHA3 complex internalization and function, the cleavage occurs in trans, with ADAM10 and its substrate being on the membranes of opposing cells (PubMed:16239146). Interacts with the clathrin adapter AP2 complex subunits AP2A1, AP2A2, AP2B1, and AP2M1; this interaction facilitates ADAM10 endocytosis from the plasma membrane during long-term potentiation in hippocampal neurons (PubMed:23676497). Interacts (via extracellular domain) with TSPAN33 (via extracellular domain) and (via cytoplasmic domain) with AFDN; interaction with TSPAN33 allows the docking of ADAM10 to zonula adherens through a PDZ11-dependent interaction between TSPAN33 and PLEKHA7 while interaction with AFDN locks ADAM10 at zonula adherens (PubMed:30463011). Forms a ternary complex composed of ADAM10, EPHA4 and CADH1; within the complex, ADAM10 cleaves CADH1 which disrupts adherens junctions (By similarity). Interacts with EPHA2 (By similarity). Interacts with NGF in a divalent cation-dependent manner (PubMed:20164177). Interacts with TSPAN14; the interaction promotes ADAM10 maturation and cell surface expression (PubMed:26686862, PubMed:26668317). Interacts with TSPAN5, TSPAN10, TSPAN15, TSPAN17 and TSPAN33; these interactions regulate ADAM10 substrate specificity (PubMed:26686862). Interacts with DLG1; this interaction recruits ADAM10 to the cell membrane during long-term depression in hippocampal neurons (PubMed:23676497). Interacts (via extracellular domain) with BACE1 (via extracellular domain) (By similarity). Interacts with FAM171A1 (PubMed:30312582).SUBUNIT (Microbial infection) Interacts with S.aureus hly; this interaction is necessary for toxin pore formation, disruption of focal adhesions and S.aureus hly-mediated cytotoxicity.TISSUE SPECIFICITY Expressed in the brain (at protein level) (PubMed:23676497). Expressed in spleen, lymph node, thymus, peripheral blood leukocyte, bone marrow, cartilage, chondrocytes and fetal liver (PubMed:11511685, PubMed:9016778).INDUCTION In osteoarthritis affected-cartilage.DOMAIN The propeptide keeps the metalloprotease in a latent form via a cysteine switch mechanism. This mechanism may be mediated by a highly conserved cysteine (Cys-173) in the propeptide, which interacts and neutralizes the zinc-coordinating HEXGHXXGXXHD catalytic core of the metalloprotease domain. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme.DOMAIN The Cys-rich region C-terminal to the disintegrin domain functions as a substrate-recognition module, it recognizes the EFNA5-EPHA3 complex but not the individual proteins (By similarity). Both Cys-rich and stalk region are necessary for interaction with TSPAN5, TSPAN10, TSPAN14, TSPAN17, TSPAN33 (PubMed:26668317). Stalk region is sufficient for interaction with TSPAN15 (By similarity).PTM The precursor is cleaved by furin and PCSK7. UniProt O14672 214 EQUAL 748 EQUAL Reactome Database ID Release 81 157237 Database 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=157237 Reactome R-HSA-157237 1 Reactome 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-157237.1 TACE ADAM17 ADAM 17 metalloprotease ADAM 17 sheddase Reactome DB_ID: 179878 UniProt:P78536 ADAM17 ADAM17 CSVP TACE FUNCTION Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form (PubMed:9034191). Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface (PubMed:20592283). Responsible for the proteolytic release of several other cell-surface proteins, including p75 TNF-receptor, interleukin 1 receptor type II, p55 TNF-receptor, transforming growth factor-alpha, L-selectin, growth hormone receptor, MUC1 and the amyloid precursor protein (PubMed:12441351). Acts as an activator of Notch pathway by mediating cleavage of Notch, generating the membrane-associated intermediate fragment called Notch extracellular truncation (NEXT) (PubMed:24226769). Plays a role in the proteolytic processing of ACE2 (PubMed:24227843). Plays a role in hemostasis through shedding of GP1BA, the platelet glycoprotein Ib alpha chain (By similarity). Mediates the proteolytic cleavage of LAG3, leading to release the secreted form of LAG3 (By similarity). Mediates the proteolytic cleavage of IL6R, leading to the release of secreted form of IL6R (PubMed:26876177, PubMed:28060820). Mediates the proteolytic cleavage and shedding of FCGR3A upon NK cell stimulation, a mechanism that allows for increased NK cell motility and detachment from opsonized target cells.SUBUNIT Interacts with MAD2L1, MAPK14 and MUC1 (PubMed:12441351, PubMed:20188673). Interacts with iRhom1/RHBDF1 and iRhom2/RHBDF2 (PubMed:29897333). Interacts with FRMD8 via its interaction with iRhom1/RHBDF1 and iRhom2/RHBDF2 (PubMed:29897333).TISSUE SPECIFICITY Ubiquitously expressed. Expressed at highest levels in adult heart, placenta, skeletal muscle, pancreas, spleen, thymus, prostate, testes, ovary and small intestine, and in fetal brain, lung, liver and kidney. Expressed in natural killer cells (at protein level) (PubMed:24337742).INDUCTION In arthritis-affected cartilage.DOMAIN Must be membrane anchored to cleave the different substrates. The cytoplasmic domain is not required for the this activity. Only the catalytic domain is essential to shed TNF and p75 TNFR (By similarity).DOMAIN The conserved cysteine present in the cysteine-switch motif binds the catalytic zinc ion, thus inhibiting the enzyme. The dissociation of the cysteine from the zinc ion upon the activation-peptide release activates the enzyme.PTM The precursor is cleaved by a furin endopeptidase.PTM Phosphorylated. Stimulation by growth factor or phorbol 12-myristate 13-acetate induces phosphorylation of Ser-819 but decreases phosphorylation of Ser-791. Phosphorylation at THR-735 by MAPK14 is required for ADAM17-mediated ectodomain shedding. UniProt P78536 215 EQUAL 824 EQUAL Reactome Database ID Release 81 179878 Database 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=179878 Reactome R-HSA-179878 1 Reactome 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-179878.1 Reactome Database ID Release 81 1852617 Database 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=1852617 Reactome R-HSA-1852617 1 Reactome 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-1852617.1 1 Zn2+ Zn++ zinc(2+) zinc Zn(II) Reactome DB_ID: 109265 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI CHEBI:29105 Reactome Database ID Release 81 109265 Database 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=109265 Reactome R-ALL-109265 3 Reactome 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-ALL-109265.3 COMPOUND C00038 1 Reactome Database ID Release 81 1852620 Database 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=1852620 Reactome R-HSA-1852620 1 Reactome 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-1852620.1 GENE ONTOLOGY GO:0008237 Reactome Database ID Release 81 1852619 Database 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=1852619 Reactome Database ID Release 81 2220944 Database 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=2220944 Reactome R-HSA-2220944 2 Reactome 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-2220944.2 10882063 Pubmed 2000 A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE Brou, C Logeat, F Gupta, N Bessia, C LeBail, O Doedens, JR Cumano, A Roux, P Black, RA Israel, A Mol Cell 5:207-16 9244301 Pubmed 1997 Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis Pan, D Rubin, GM Cell 90:271-80 19726682 Pubmed 2009 Metalloprotease ADAM10 is required for Notch1 site 2 cleavage van Tetering, G van Diest, P Verlaan, I van der Wall, E Kopan, R Vooijs, M J Biol Chem 284:31018-27 12354787 Pubmed 2002 The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts Hartmann, D De Strooper, B Serneels, L Craessaerts, K Herreman, A Annaert, W Umans, L Lübke, T Lena Illert, A von Figura, K Saftig, P Hum Mol Genet 11:2615-24 17401372 Pubmed 2007 Structural basis for autoinhibition of Notch Gordon, WR Vardar-Ulu, D Histen, G Sanchez-Irizarry, C Aster, JC Blacklow, SC Nat Struct Mol Biol 14:295-300 LEFT-TO-RIGHT 3.4.23.32 3.4.23.43 3.4.23.20 3.4.23.25 3.4.23.36 3.4.23.35 3.4.23.34 3.4.23.4 3.4.23.5 3.4.23.1 3.4.23.15 NEXT1 PEST domain mutants are cleaved to produce NICD1 PEST domain mutants NEXT1 PEST domain mutant fragments are expected to be cleaved by the gamma-secretase complex at the S3 site in a similar manner to wild-type NEXT1 (Schroeter et al. 1998, De Strooper et al. 1999, Huppert et al. 2000, Fortini 2002, Rustighi et al. 2009). Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 Converted from EntitySet in Reactome NICD1 PEST Domain Mutants Reactome DB_ID: 2220987 NICD1 P2514Rfs*4 NICD1 Pro2514Argfs*4 NICD1 PEST domain mutant P2514Rfs*4 Reactome DB_ID: 2768996 1754 EQUAL 2516 EQUAL Reactome Database ID Release 81 2768996 Database 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=2768996 Reactome R-HSA-2768996 1 Reactome 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-2768996.1 COSMIC COSV53024776 COSMIC COSM33946 NICD1 Q2395* NICD1 Gln2395* Reactome DB_ID: 2902195 1754 EQUAL 2394 EQUAL Reactome Database ID Release 81 2902195 Database 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=2902195 Reactome R-HSA-2902195 1 Reactome 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-2902195.1 COSMIC COSV53056886 NICD1 Q2440* NICD1 Gln2440* Reactome DB_ID: 2902191 1754 EQUAL 2439 EQUAL Reactome Database ID Release 81 2902191 Database 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=2902191 Reactome R-HSA-2902191 1 Reactome 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-2902191.1 COSMIC COSV53024887 NICD1 P2474Afs*4 Reactome DB_ID: 2902193 1754 EQUAL 2476 EQUAL Reactome Database ID Release 81 2902193 Database 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=2902193 Reactome R-HSA-2902193 1 Reactome 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-2902193.1 COSMIC COSV53084788 Reactome Database ID Release 81 2220987 Database 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=2220987 Reactome R-HSA-2220987 1 Reactome 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-2220987.1 TM1 NOTCH1(1721-1753) NOTCH1 Transmembrane remnant 1 Reactome DB_ID: 157656 1721 EQUAL 1753 EQUAL Reactome Database ID Release 81 157656 Database 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=157656 Reactome R-HSA-157656 1 Reactome 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-157656.1 ACTIVATION activeUnit: #Complex17 gamma-secretase complex Reactome DB_ID: 157343 NCSTN Nicastrin NICA_HUMAN Reactome DB_ID: 2534241 UniProt:Q92542 NCSTN NCSTN KIAA0253 UNQ1874/PRO4317 FUNCTION Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:10993067, PubMed:12679784, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels.SUBUNIT Component of the gamma-secretase complex (PubMed:10993067, PubMed:30598546, PubMed:30630874). The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PSENEN/PEN2 (PubMed:12740439, PubMed:25043039, PubMed:26623517, PubMed:26280335, PubMed:25918421, PubMed:30598546, PubMed:30630874). Binds to proteolytic processed C-terminal fragments C83 and C99 of the amyloid precursor protein (APP) (PubMed:10993067, PubMed:30630874). Interacts with PSEN1 and PSEN2 (PubMed:10993067).TISSUE SPECIFICITY Detected in brain (at protein level) (PubMed:10993067). Widely expressed (PubMed:11396676).INDUCTION Constitutively expressed in neural cells.PTM N-glycosylated.SIMILARITY Belongs to the nicastrin family. UniProt Q92542 34 EQUAL 709 EQUAL Reactome Database ID Release 81 2534241 Database 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=2534241 Reactome R-HSA-2534241 1 Reactome 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-2534241.1 1 PEN-2 PSENEN Reactome DB_ID: 157331 UniProt:Q9NZ42 PSENEN PSENEN PEN2 MDS033 FUNCTION Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:12522139, PubMed:12763021, PubMed:12740439, PubMed:12679784, PubMed:24941111, PubMed:30598546, PubMed:30630874). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (Probable). PSENEN modulates both endoproteolysis of presenilin and gamma-secretase activity (PubMed:12522139, PubMed:12763021, PubMed:12740439, PubMed:12679784, PubMed:24941111).SUBUNIT The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PSENEN.TISSUE SPECIFICITY Widely expressed. Expressed in leukocytes, lung, placenta, small intestine, liver, kidney, spleen thymus, skeletal muscle, heart and brain.SIMILARITY Belongs to the PEN-2 family.CAUTION The high-resolution electron microscopy structures indicate that the N-terminus is cytoplasmic, followed by two short helices that dip into the membrane, but do not cross it (PubMed:26280335). In contrast, results based on mutagenesis to create N-glycosylation sites indicate that the N-terminus is lumenal (PubMed:12639958, PubMed:30598546, PubMed:30630874). Both studies indicate that the C-terminus is lumenal (PubMed:12639958, PubMed:26280335). UniProt Q9NZ42 1 EQUAL 101 EQUAL Reactome Database ID Release 81 157331 Database 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=157331 Reactome R-HSA-157331 1 Reactome 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-157331.1 1 Converted from EntitySet in Reactome APH-1 Reactome DB_ID: 157341 APH1B APH-1B Reactome DB_ID: 157340 UniProt:Q8WW43 APH1B APH1B PSFL UNQ688/PRO1328 FUNCTION Probable subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral proteins such as Notch receptors and APP (amyloid-beta precursor protein). It probably represents a stabilizing cofactor for the presenilin homodimer that promotes the formation of a stable complex. Probably present in a minority of gamma-secretase complexes compared to APH1A.SUBUNIT Probable component of the gamma-secretase complex, a complex composed of a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PEN2. Such minimal complex is sufficient for secretase activity, although other components may exist (By similarity). Interacts with PSEN1 and PSEN2.TISSUE SPECIFICITY Weakly or not expressed in leukocytes, lung, placenta, small intestine, liver, kidney, spleen thymus, colon, skeletal muscle, heart and brain.SIMILARITY Belongs to the APH-1 family. UniProt Q8WW43 1 EQUAL 257 EQUAL Reactome Database ID Release 81 157340 Database 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=157340 Reactome R-HSA-157340 1 Reactome 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-157340.1 APH1A Gamma-secretase subunit APH-1A APH1A_HUMAN Reactome DB_ID: 3211581 UniProt:Q96BI3 APH1A APH1A PSF CGI-78 UNQ579/PRO1141 FUNCTION Non-catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:12297508, PubMed:12522139, PubMed:12763021, PubMed:12679784, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). Required for normal gamma-secretase assembly (PubMed:12522139, PubMed:12471034, PubMed:12763021, PubMed:19369254). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (Probable).SUBUNIT The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PSENEN/PEN2 (PubMed:12297508, PubMed:12740439, PubMed:19369254, PubMed:25043039, PubMed:26623517, PubMed:26280335, PubMed:30598546, PubMed:30630874).TISSUE SPECIFICITY Widely expressed. Expressed in leukocytes, lung, placenta, small intestine, liver, kidney, spleen thymus, skeletal muscle, heart and brain. Isoform 1 and isoform 2 are nearly expressed at the same level.SIMILARITY Belongs to the APH-1 family. UniProt Q96BI3 1 EQUAL 265 EQUAL Reactome Database ID Release 81 3211581 Database 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=3211581 Reactome R-HSA-3211581 1 Reactome 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-3211581.1 Reactome Database ID Release 81 157341 Database 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=157341 Reactome R-HSA-157341 1 Reactome 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-157341.1 1 Converted from EntitySet in Reactome PSEN Presenilin Reactome DB_ID: 9013333 PSEN2 PSEN2 dimer Presenilin-2 Reactome DB_ID: 157352 PSEN2(298-448) PSEN2 C-terminal fragment Presenilin-2 CTF subunit Reactome DB_ID: 9013329 UniProt:P49810 PSEN2 PSEN2 AD4 PS2 PSNL2 STM2 FUNCTION Probable catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein). Requires the other members of the gamma-secretase complex to have a protease activity. May play a role in intracellular signaling and gene expression or in linking chromatin to the nuclear membrane. May function in the cytoplasmic partitioning of proteins. The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is involved in calcium homeostasis (PubMed:16959576). Is a regulator of mitochondrion-endoplasmic reticulum membrane tethering and modulates calcium ions shuttling between ER and mitochondria (PubMed:21285369).SUBUNIT Interacts with DOCK3 (By similarity). Homodimer. Component of the gamma-secretase complex, a complex composed of a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PEN2. Such minimal complex is sufficient for secretase activity, although other components may exist. Interacts with HERPUD1, FLNA, FLNB and PARL.TISSUE SPECIFICITY Isoform 1 is seen in the placenta, skeletal muscle and heart while isoform 2 is seen in the heart, brain, placenta, liver, skeletal muscle and kidney.DOMAIN The PAL motif is required for normal active site conformation.PTM Heterogeneous proteolytic processing generates N-terminal and C-terminal fragments.PTM Phosphorylated on serine residues.SIMILARITY Belongs to the peptidase A22A family. UniProt P49810 298 EQUAL 448 EQUAL Reactome Database ID Release 81 9013329 Database 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=9013329 Reactome R-HSA-9013329 1 Reactome 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-9013329.1 1 PSEN2(1-297) PSEN2 N-terminal fragment Presenilin-2 NTF subunit Reactome DB_ID: 201599 1 EQUAL 297 EQUAL Reactome Database ID Release 81 201599 Database 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=201599 Reactome R-HSA-201599 2 Reactome 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-201599.2 1 Reactome Database ID Release 81 157352 Database 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=157352 Reactome R-HSA-157352 2 Reactome 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-157352.2 PS1 PSEN1 Presenillin-1 PSEN1 dimer Reactome DB_ID: 2534316 PSEN1(299-467) Presenilin-1 C-terminal fragment Presenilin-1 CTF subunit Reactome DB_ID: 2534245 UniProt:P49768 PSEN1 PSEN1 AD3 PS1 PSNL1 FUNCTION Catalytic subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:15274632, PubMed:10545183, PubMed:10593990, PubMed:10206644, PubMed:10899933, PubMed:10811883, PubMed:12679784, PubMed:12740439, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874, PubMed:28269784, PubMed:20460383). Requires the presence of the other members of the gamma-secretase complex for protease activity (PubMed:15274632, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). Plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (PubMed:9738936, PubMed:10593990, PubMed:10899933, PubMed:10811883). Stimulates cell-cell adhesion via its interaction with CDH1; this stabilizes the complexes between CDH1 (E-cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1 and JUP (gamma-catenin) (PubMed:11953314). Under conditions of apoptosis or calcium influx, cleaves CDH1 (PubMed:11953314). This promotes the disassembly of the complexes between CDH1 and CTNND1, JUP and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby negatively regulates Wnt signaling (PubMed:9738936, PubMed:11953314). Required for normal embryonic brain and skeleton development, and for normal angiogenesis (By similarity). Mediates the proteolytic cleavage of EphB2/CTF1 into EphB2/CTF2 (PubMed:17428795, PubMed:28269784). The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is therefore involved in calcium homeostasis (PubMed:25394380, PubMed:16959576). Involved in the regulation of neurite outgrowth (PubMed:15004326, PubMed:20460383). Is a regulator of presynaptic facilitation, spike transmission and synaptic vesicles replenishment in a process that depends on gamma-secretase activity. It acts through the control of SYT7 presynaptic expression (By similarity).SUBUNIT Homodimer. The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A/APH1B) and PEN2 (PubMed:15274632, PubMed:12679784, PubMed:12740439, PubMed:25043039, PubMed:26280335, PubMed:25394380, PubMed:30598546, PubMed:30630874). Such minimal complex is sufficient for secretase activity (PubMed:15274632, PubMed:12679784, PubMed:12740439, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). Other components which are associated with the complex include SLC25A64, SLC5A7, PHB and PSEN1 isoform 3. As part of the gamma-secretase complex, interacts with CRB2 (via transmembrane domain) (PubMed:20299451). Predominantly heterodimer of a N-terminal (NTF) and a C-terminal (CTF) endoproteolytical fragment (PubMed:15274632). Associates with proteolytic processed C-terminal fragments C83 and C99 of the amyloid precursor protein (APP) (via transmembrane domain) (PubMed:30630874). Associates with NOTCH1 (via transmembrane domain) (PubMed:10593990, PubMed:30598546). Associates with cadherin/catenin adhesion complexes through direct binding to CDH1 or CDH2 (PubMed:11953314, PubMed:14515347, PubMed:16126725). Interaction with CDH1 stabilizes the complex and stimulates cell-cell aggregation (PubMed:11953314). Interaction with CDH2 is essential for trafficking of CDH2 from the endoplasmic reticulum to the plasma membrane (PubMed:14515347). Interacts with CTNND2, CTNNB1, CTNND1, JUP, HERPUD1, FLNA, FLNB, MTCH1, PKP4 and PARL (PubMed:9738936, PubMed:9437013, PubMed:10551805, PubMed:10037471, PubMed:11953314, PubMed:11799129, PubMed:16126725). Interacts through its N-terminus with GFAP (isoform 2) (PubMed:12058025). Interacts with DOCK3 (By similarity). Interacts with isoform 1 and isoform 3 of UBQLN1 (PubMed:21143716).TISSUE SPECIFICITY Detected in azurophile granules in neutrophils and in platelet cytoplasmic granules (at protein level) (PubMed:11987239). Expressed in a wide range of tissues including various regions of the brain, liver, spleen and lymph nodes (PubMed:7596406, PubMed:8641442, PubMed:8574969).DOMAIN The PAL motif is required for normal active site conformation.DOMAIN Substrates, such as NOTCH1 and APP peptides, are bound between PSEN1 transmembrane domains and via the first lumenal loop and the cytoplasmic loop between the sixth and seventh transmembrane domains. Substrate binding causes a conformation change and formation of an intermolecular antiparallel beta-sheet between PSEN1 and its substrates.PTM Heterogeneous proteolytic processing generates N-terminal (NTF) and C-terminal (CTF) fragments of approximately 35 and 20 kDa, respectively. During apoptosis, the C-terminal fragment (CTF) is further cleaved by caspase-3 to produce the fragment, PS1-CTF12.PTM After endoproteolysis, the C-terminal fragment (CTF) is phosphorylated on serine residues by PKA and/or PKC. Phosphorylation on Ser-346 inhibits endoproteolysis.SIMILARITY Belongs to the peptidase A22A family. UniProt P49768 299 EQUAL 467 EQUAL Reactome Database ID Release 81 2534245 Database 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=2534245 Reactome R-HSA-2534245 2 Reactome 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-2534245.2 1 PSEN1(1-298) Presenilin-1 N-terminal fragment presenilin-1 NTF subunit Reactome DB_ID: 2534298 1 EQUAL 298 EQUAL Reactome Database ID Release 81 2534298 Database 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=2534298 Reactome R-HSA-2534298 2 Reactome 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-2534298.2 1 Reactome Database ID Release 81 2534316 Database 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=2534316 Reactome R-HSA-2534316 2 Reactome 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-2534316.2 Reactome Database ID Release 81 9013333 Database 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=9013333 Reactome R-HSA-9013333 1 Reactome 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-9013333.1 1 Reactome Database ID Release 81 157343 Database 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=157343 Reactome R-HSA-157343 2 Reactome 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-157343.2 GENE ONTOLOGY GO:0004190 Reactome Database ID Release 81 157355 Database 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=157355 Reactome Database ID Release 81 2220988 Database 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=2220988 Reactome R-HSA-2220988 2 Reactome 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-2220988.2 12209127 Pubmed 2002 Gamma-secretase-mediated proteolysis in cell-surface-receptor signalling Fortini, ME Nat Rev Mol Cell Biol 3:673-84 19151708 Pubmed 2009 The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer Rustighi, A Tiberi, L Soldano, A Napoli, M Nuciforo, P Rosato, A Kaplan, F Capobianco, A Pece, S Di Fiore, PP Del Sal, G Nat Cell Biol 11:133-42 10206645 Pubmed 1999 A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain De Strooper, B Annaert, W Cupers, P Saftig, P Craessaerts, K Mumm, JS Schroeter, EH Schrijvers, V Wolfe, MS Ray, WJ Goate, A Kopan, R Nature 398:518-22 9620803 Pubmed 1998 Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain Schroeter, EH Kisslinger, JA Kopan, R Nature 393:382-6 10879540 Pubmed 2000 Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1 Huppert, SS Le, A Schroeter, EH Mumm, JS Saxena, MT Milner, LA Kopan, R Nature 405:966-70 LEFT-TO-RIGHT NICD1 PEST domain mutants translocate from cytosol to nucleus Cytosolic NICD1 PEST domain mutants are expected to translocate to the nucleus in an identical manner to wild-type NICD1. Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 Converted from EntitySet in Reactome NICD1 PEST Domain Mutants Reactome DB_ID: 2769016 NICD1 P2514Rfs*4 NICD1 Pro2514Argfs*4 NICD1 PEST domain mutant P2514Rfs*4 Reactome DB_ID: 2769013 nucleoplasm GENE ONTOLOGY GO:0005654 1754 EQUAL 2516 EQUAL Reactome Database ID Release 81 2769013 Database 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=2769013 Reactome R-HSA-2769013 1 Reactome 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-2769013.1 COSMIC COSV53024776 COSMIC COSM33946 NICD1 Q2440* NICD1 Gln2440* Reactome DB_ID: 2902200 2403 EQUAL 1754 EQUAL 2439 EQUAL Reactome Database ID Release 81 2902200 Database 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=2902200 Reactome R-HSA-2902200 1 Reactome 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-2902200.1 COSMIC COSV53024887 NICD1 Q2395* NICD1 Gln2395* Reactome DB_ID: 2902201 1754 EQUAL 2394 EQUAL Reactome Database ID Release 81 2902201 Database 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=2902201 Reactome R-HSA-2902201 1 Reactome 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-2902201.1 COSMIC COSV53056886 NICD1 P2474Afs*4 Reactome DB_ID: 2902208 1754 EQUAL 2476 EQUAL Reactome Database ID Release 81 2902208 Database 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=2902208 Reactome R-HSA-2902208 1 Reactome 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-2902208.1 COSMIC COSV53084788 Reactome Database ID Release 81 2769016 Database 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=2769016 Reactome R-HSA-2769016 1 Reactome 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-2769016.1 Reactome Database ID Release 81 2769015 Database 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=2769015 Reactome R-HSA-2769015 2 Reactome 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-2769015.2 9604939 Pubmed 1998 Nuclear access and action of notch in vivo Struhl, G Adachi, A Cell 93:649-60 9651681 Pubmed 1998 Indirect evidence for Delta-dependent intracellular processing of notch in Drosophila embryos Lecourtois, M Schweisguth, F Curr Biol 8:771-4 LEFT-TO-RIGHT NICD1 PEST domain mutants displace co-repressor complex from RBPJ (CSL) In the nucleus, NICD1 PEST domain mutants are expected to displace the NCOR co-repressor and form a complex with RBPJ and SNW1, like wild-type NICD1 (Oka et al. 1995, Kao et al. 1998, Zhou et al. 2000, Perissi et al. 2004, Perissi et al. 2008). Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 CSL NCOR corepressor complex RBPJ:NCOR corepressor complex Reactome DB_ID: 350052 SNW1 SKIP SNW domain-containing protein SNW1_HUMAN Reactome DB_ID: 351663 UniProt:Q13573 SNW1 SNW1 SKIIP SKIP FUNCTION Involved in pre-mRNA splicing as component of the spliceosome (PubMed:11991638, PubMed:28502770, PubMed:28076346). Is required in the specific splicing of CDKN1A pre-mRNA; the function probably involves the recruitment of U2AF2 to the mRNA. Is proposed to recruit PPIL1 to the spliceosome. May be involved in cyclin-D1/CCND1 mRNA stability through the SNARP complex which associates with both the 3'end of the CCND1 gene and its mRNA. Involved in transcriptional regulation. Modulates TGF-beta-mediated transcription via association with SMAD proteins, MYOD1-mediated transcription via association with PABPN1, RB1-mediated transcriptional repression, and retinoid-X receptor (RXR)- and vitamin D receptor (VDR)-dependent gene transcription in a cell line-specific manner probably involving coactivators NCOA1 and GRIP1. Is involved in NOTCH1-mediated transcriptional activation. Binds to multimerized forms of Notch intracellular domain (NICD) and is proposed to recruit transcriptional coactivators such as MAML1 to form an intermediate preactivation complex which associates with DNA-bound CBF-1/RBPJ to form a transcriptional activation complex by releasing SNW1 and redundant NOTCH1 NICD.FUNCTION (Microbial infection) Is recruited by HIV-1 Tat to Tat:P-TEFb:TAR RNA complexes and is involved in Tat transcription by recruitment of MYC, MEN1 and TRRAP to the HIV promoter.FUNCTION (Microbial infection) Proposed to be involved in transcriptional activation by EBV EBNA2 of CBF-1/RBPJ-repressed promoters.SUBUNIT Identified in the spliceosome C complex (PubMed:11991638, PubMed:28502770, PubMed:28076346). Associates with U4/U6-U5 tri-small nuclear ribonucleoproteins (U4/U6-U5 tri-snRNPs). Interacts with SKI, SMAD2,SMAD3, RBPJ, RB1, PABPN1, MAGEA1, SIRT1, FOXN3, U2AF2, DAXX and ATP1B4. Interacts with PPIL1 (PubMed:16595688, PubMed:20007319, PubMed:20368803, PubMed:33220177). Interacts with VDR and RXRA; preferentially associates with VDR:RXRA heterodimers (PubMed:9632709, PubMed:12529369). Interacts with NCOR2 (PubMed:10644367). Interacts with MAML1 (PubMed:21245387). Interacts with NOTCH1 NICD; the interaction involves multimerized NOTCH1 NICD (PubMed:21245387). Forms a complex with NOTCH1 NICD and MAML1; the association is dissociated by RBPJ (PubMed:21245387). Associates with positive transcription elongation factor b (P-TEFb) (PubMed:15905409). Component of the SNARP complex which consists at least of SNIP1, SNW1, THRAP3, BCLAF1 and PNN (PubMed:18794151).SUBUNIT (Microbial infection) Interacts with human papillomavirus type-16 (HPV16) E7 protein.SUBUNIT (Microbial infection) Interacts with EBV EBNA2; EBNA2 competes with NCOR2 for interaction with SNW1.SIMILARITY Belongs to the SNW family. UniProt Q13573 2 EQUAL 536 EQUAL Reactome Database ID Release 81 351663 Database 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=351663 Reactome R-HSA-351663 1 Reactome 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-351663.1 1 Converted from EntitySet in Reactome TBL1 Reactome DB_ID: 350064 TBL1 TBL1X TBL1X_HUMAN Reactome DB_ID: 351644 UniProt:O60907 TBL1X TBL1X TBL1 FUNCTION F-box-like protein involved in the recruitment of the ubiquitin/19S proteasome complex to nuclear receptor-regulated transcription units (PubMed:14980219). Plays an essential role in transcription activation mediated by nuclear receptors. Probably acts as integral component of corepressor complexes that mediates the recruitment of the 19S proteasome complex, leading to the subsequent proteasomal degradation of transcription repressor complexes, thereby allowing cofactor exchange (PubMed:21240272).SUBUNIT Homotetramer; dimer of dimers (PubMed:21240272). Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1R, CORO2A and GPS2 (PubMed:10809664, PubMed:21240272). Interacts with GPS2 (when sumoylated); leading to protect GPS2 against degradation by the proteasome (PubMed:24943844). Component of a E3 ubiquitin ligase complex containing UBE2D1, SIAH1, CACYBP/SIP, SKP1, APC and TBL1X (PubMed:11389839). Probably part of other corepressor complexes, that do not contain NCOR1 and NCOR2. Interacts with histones H2B, H3a and H4. Interacts with MECP2; recruits TBL1X to the heterochromatin foci (By similarity).TISSUE SPECIFICITY Ubiquitous.DOMAIN The F-box-like domain is related to the F-box domain, and apparently displays the same function as component of ubiquitin E3 ligase complexes.SIMILARITY Belongs to the WD repeat EBI family. UniProt O60907 1 EQUAL 577 EQUAL Reactome Database ID Release 81 351644 Database 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=351644 Reactome R-HSA-351644 1 Reactome 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-351644.1 TBL1R TBL1XR1 TBL1R_HUMAN F-box-like/WD repeat-containing protein Reactome DB_ID: 351643 UniProt:Q9BZK7 TBL1XR1 TBL1XR1 IRA1 TBLR1 FUNCTION F-box-like protein involved in the recruitment of the ubiquitin/19S proteasome complex to nuclear receptor-regulated transcription units. Plays an essential role in transcription activation mediated by nuclear receptors. Probably acts as integral component of the N-Cor corepressor complex that mediates the recruitment of the 19S proteasome complex, leading to the subsequent proteasomal degradation of N-Cor complex, thereby allowing cofactor exchange, and transcription activation.SUBUNIT Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1XR1, CORO2A and GPS2 (PubMed:11931768). Probable component of some E3 ubiquitin ligase complex. Interacts with histones H2B and H4 (PubMed:12628926). Interacts with MECP2; bridges interaction between MECP2 and NCOR1 (By similarity).TISSUE SPECIFICITY Widely expressed including the pituitary, hypothalamus, white and brown adipose tissue, muscle and liver.DOMAIN The F-box-like domain is related to the F-box domain, and apparently displays the same function as component of ubiquitin E3 ligase complexes.SIMILARITY Belongs to the WD repeat EBI family. UniProt Q9BZK7 1 EQUAL 514 EQUAL Reactome Database ID Release 81 351643 Database 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=351643 Reactome R-HSA-351643 1 Reactome 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-351643.1 Reactome Database ID Release 81 350064 Database 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=350064 Reactome R-HSA-350064 1 Reactome 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-350064.1 1 Converted from EntitySet in Reactome NCOR1, NCOR2 NCOR corepressor protein Reactome DB_ID: 349716 NCOR1 Nuclear receptor corepressor 1 NCOR1_HUMAN Reactome DB_ID: 442501 UniProt:O75376 NCOR1 NCOR1 KIAA1047 FUNCTION Mediates transcriptional repression by certain nuclear receptors (PubMed:20812024). Part of a complex which promotes histone deacetylation and the formation of repressive chromatin structures which may impede the access of basal transcription factors. Participates in the transcriptional repressor activity produced by BCL6. Recruited by ZBTB7A to the androgen response elements/ARE on target genes, negatively regulates androgen receptor signaling and androgen-induced cell proliferation (PubMed:20812024). Mediates the NR1D1-dependent repression and circadian regulation of TSHB expression (By similarity). The NCOR1-HDAC3 complex regulates the circadian expression of the core clock gene ARTNL/BMAL1 and the genes involved in lipid metabolism in the liver (By similarity).SUBUNIT Forms a large corepressor complex that contains SIN3A/B and histone deacetylases HDAC1 and HDAC2. This complex associates with the thyroid receptor (TR) and the retinoid acid receptor (RAR) in the absence of ligand. Interacts directly with RARA; the interaction is facilitated with RARA trimethylation. Component of the N-Cor repressor complex, at least composed of CBFA2T3, HEXIM1, NCOR1, NCOR2, HDAC3, TBL1X, TBL1XR1, CORO2A and GPS2. Interacts with ZBTB33; the interaction serves to recruit the N-CoR complex to promoter regions containing methylated CpG dinucleotides. Interacts with TRIM28 and KDM3A. Interacts (via the RD1 domain) with BAZ1A (via its N-terminal); the interaction corepresses a number of NCOR1-regulated genes. Interacts with BCL6, C1D, DACH1, HEXIM1, HDAC7, RORA, RORC, SAP30, SIAH2, SIN3A and SIN3B. May interact with DEAF1. Interacts with RXRA. Interacts with SETD5 (By similarity). Interacts with VDR (PubMed:28698609). Interacts with ZBTB7A (PubMed:20812024). Interacts with AR (PubMed:20812024). Interacts with HDAC3 (By similarity).DOMAIN The N-terminal region contains three independent domains that are capable of mediating transcriptional repression (RD1, RD2 and RD3).DOMAIN The C-terminal region contains two separate nuclear receptor-interacting domains (ID1 and ID2), each of which contains a conserved sequence referred to as the CORNR box. This motif is necessary and sufficient for binding to unligated nuclear hormone receptors, while sequences flanking the CORNR box determine the precise nuclear hormone receptor specificity (By similarity).PTM Ubiquitinated; mediated by SIAH2 and leading to its subsequent proteasomal degradation.SIMILARITY Belongs to the N-CoR nuclear receptor corepressors family. UniProt O75376 1 EQUAL 2440 EQUAL Reactome Database ID Release 81 442501 Database 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=442501 Reactome R-HSA-442501 1 Reactome 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-442501.1 Smrt NCOR2 Nuclear receptor corepressor 2 NCOR2_HUMAN Reactome DB_ID: 442469 UniProt:Q9Y618 NCOR2 NCOR2 CTG26 FUNCTION Transcriptional corepressor (PubMed:20812024). Mediates the transcriptional repression activity of some nuclear receptors by promoting chromatin condensation, thus preventing access of the basal transcription. Isoform 1 and isoform 4 have different affinities for different nuclear receptors. Involved in the regulation BCL6-dependent of the germinal center (GC) reactions, mainly through the control of the GC B-cells proliferation and survival. Recruited by ZBTB7A to the androgen response elements/ARE on target genes, negatively regulates androgen receptor signaling and androgen-induced cell proliferation (PubMed:20812024).SUBUNIT Forms a large corepressor complex that contains SIN3A/B and histone deacetylases HDAC1 and HDAC2. This complex associates with the thyroid (TR) and the retinoid acid receptors (RAR) in the absence of ligand, and may stabilize their interaction with TFIIB. Interacts directly with RARA in the absence of ligand; the interaction represses RARA activity. Interacts (isoform SMRT) with HDAC10. Interacts with MINT. Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1R, CORO2A and GPS2 (PubMed:10809664, PubMed:10944117, PubMed:11931768, PubMed:19858209, PubMed:21240272). Interacts with CBFA2T3 and ATXN1L. Interacts with RARB; the interaction is weak and does not repress RARB transactivational activity. Interacts with HDAC7 and C1D. Interacts with NR4A2; this interaction increases in the absence of PITX3. Interacts with BCL6 (via the BTB domain), required for BCL6 transcriptional repressor activity on a subset of target genes. Forms ternary complexes with BCOR and BCL6 on target gene promoters but, on enhancer elements, interacts with BCL6 and HDAC3 to repress proximal gene expression. May interact with DEAF1. Interacts with RXRA. Interacts with MECP2 (By similarity). Interacts with ZBTB7A (PubMed:20812024). Interacts with AR (PubMed:20812024). Interacts with TBL1Y (PubMed:30341416).TISSUE SPECIFICITY Ubiquitous. High levels of expression are detected in lung, spleen and brain.INDUCTION Regulated during cell cycle progression.DOMAIN The N-terminal region contains repression functions that are divided into three independent repression domains (RD1, RD2 and RD3). The C-terminal region contains the nuclear receptor-interacting domains that are divided in two separate interaction domains (ID1 and ID2).DOMAIN The two interaction domains (ID) contain a conserved sequence referred to as the CORNR box. This motif is required and sufficient to permit binding to unligated TR and RARS. Sequences flanking the CORNR box determine nuclear hormone receptor specificity.SIMILARITY Belongs to the N-CoR nuclear receptor corepressors family. UniProt Q9Y618 1 EQUAL 2525 EQUAL Reactome Database ID Release 81 442469 Database 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=442469 Reactome R-HSA-442469 1 Reactome 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-442469.1 Reactome Database ID Release 81 349716 Database 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=349716 Reactome R-HSA-349716 1 Reactome 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-349716.1 1 Converted from EntitySet in Reactome HDAC Reactome DB_ID: 350066 HDAC1 HDA1_HUMAN Histone deacetylase 1 Reactome DB_ID: 205021 UniProt:Q13547 HDAC1 HDAC1 RPD3L1 FUNCTION Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) (PubMed:16762839, PubMed:17704056, PubMed:28497810). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (PubMed:16762839, PubMed:17704056). Histone deacetylases act via the formation of large multiprotein complexes (PubMed:16762839, PubMed:17704056). Also functions as deacetylase for non-histone targets, such as NR1D2, RELA, SP1, SP3 and TSHZ3 (PubMed:12837748, PubMed:16478997, PubMed:17996965, PubMed:19343227). Deacetylates SP proteins, SP1 and SP3, and regulates their function (PubMed:12837748, PubMed:16478997). Component of the BRG1-RB1-HDAC1 complex, which negatively regulates the CREST-mediated transcription in resting neurons (PubMed:19081374). Upon calcium stimulation, HDAC1 is released from the complex and CREBBP is recruited, which facilitates transcriptional activation (PubMed:19081374). Deacetylates TSHZ3 and regulates its transcriptional repressor activity (PubMed:19343227). Deacetylates 'Lys-310' in RELA and thereby inhibits the transcriptional activity of NF-kappa-B (PubMed:17000776). Deacetylates NR1D2 and abrogates the effect of KAT5-mediated relieving of NR1D2 transcription repression activity (PubMed:17996965). Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development (By similarity). Involved in CIART-mediated transcriptional repression of the circadian transcriptional activator: CLOCK-ARNTL/BMAL1 heterodimer (By similarity). Required for the transcriptional repression of circadian target genes, such as PER1, mediated by the large PER complex or CRY1 through histone deacetylation (By similarity). In addition to protein deacetylase activity, also has protein-lysine deacylase activity: acts as a protein decrotonylase by mediating decrotonylation ((2E)-butenoyl) of histones (PubMed:28497810).SUBUNIT Part of the core histone deacetylase (HDAC) complex composed of HDAC1, HDAC2, RBBP4 and RBBP7 (PubMed:12493763, PubMed:12724404, PubMed:19061646). The core complex associates with MTA2, MBD2, MBD3, MTA1L1, CHD3 and CHD4 to form the nucleosome remodeling and histone deacetylation (NuRD) complex, or with SIN3, SAP18 and SAP30 to form the SIN3 HDAC complex (PubMed:11102443). Component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B/BRAF35, KDM1A, RCOR1/CoREST and PHF21A/BHC80 (PubMed:12493763). The BHC complex may also contain ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I (PubMed:12493763). Component of a mSin3A corepressor complex that contains SIN3A, SAP130, SUDS3/SAP45, ARID4B/SAP180, HDAC1 and HDAC2 (PubMed:12724404). Found in a trimeric complex with APBB1 and TSHZ3; the interaction between HDAC1 and APBB1 is mediated by TSHZ3 (PubMed:19343227). Interacts with TSHZ3 (via N-terminus); the interaction is direct (PubMed:19343227). Component of a RCOR/GFI/KDM1A/HDAC complex (By similarity). Part of a complex composed of TRIM28, HDAC1, HDAC2 and EHMT2 (PubMed:17704056). Part of a complex containing at least CDYL, MIER1, MIER2, HDAC1 and HDAC2 (PubMed:19061646). The large PER complex involved in the histone deacetylation is composed of at least HDAC1, PER2, SFPQ and SIN3A (By similarity). Associates with the 9-1-1 complex; interacts with HUS1 (PubMed:10846170). Found in a complex with DNMT3A and HDAC7 (By similarity). Interacts with the non-histone region of MACROH2A1 (By similarity). Interacts with TRIM28; the interaction recruits HDAC1 to E2F1 and inhibits its acetylation (PubMed:17704056). Interacts with SP1; the interaction deacetylates SP1 and regulates its transcriptional activity (PubMed:16478997). Interacts with SP3; the interaction deacetylates SP3 and regulates its transcriptional activity (PubMed:12837748, PubMed:17548428). In vitro, C(18) ceramides increase this interaction and the subsequent SP3 deacetylation and SP3-mediated repression of the TERT promoter (PubMed:12837748, PubMed:17548428). Interacts with APEX1; the interaction is not dependent on the acetylated status of APEX1 (PubMed:14633989). Interacts with C10orf90/FATS (via its N-terminal); the interaction prevents binding of HDAC1 to CDKN1A/p21 and facilitates the acetylation and stabilization of CDKN1A/p21 (By similarity). Interacts with CDKN1A/p21 (By similarity). Interacts with CDK5 complexed to CDK5R1 (p25) (By similarity). Interacts directly with GFI1 and GFI1B (By similarity). Interacts with NR1D2 (via C-terminus) (PubMed:17996965). Interacts with TSC22D3 isoform 1; this interaction affects HDAC1 activity on MYOG promoter and thus inhibits MYOD1 transcriptional activity (By similarity). Interacts with BAZ2A/TIP5, BANP, BCL6, BCOR, BHLHE40/DEC1, BRMS1, BRMS1L, CBFA2T3, CHFR, CIART, CRY1, DAXX, DDIT3/CHOP, DDX5, DNMT1, E4F1, EP300, HCFC1, HDAC9, INSM1, NFE4, NR4A2/NURR1, MIER1, KDM4A, KDM5B, KLF1, MINT, NRIP1, PCAF, PHB2, PRDM6, PRDM16, RB1, RERE, SAMSN1, SAP30L, SETDB1, SMAD3, SMARCAD1, SMARCA4/BRG1, SMYD2, SUV39H1, TGIF, TGIF2, TRAF6, UHRF1, UHRF2, ZMYND15, ZNF431 and ZNF541 (PubMed:10669754, PubMed:17369852, PubMed:19081374, PubMed:19182791, PubMed:21549307, PubMed:11331609, PubMed:11006275, PubMed:10846170, PubMed:12730668, PubMed:18093978, PubMed:11533236, PubMed:10898795, PubMed:10655483, PubMed:16569215, PubMed:16820529, PubMed:17872950, PubMed:12670868, PubMed:21829689, PubMed:10487760, PubMed:11427533, PubMed:19049980, PubMed:15273251, PubMed:15361834, PubMed:17373667, PubMed:16166625, PubMed:15454082, PubMed:17000776, PubMed:15927959, PubMed:15451426, PubMed:12482978). Interacts with KDM5A; this interaction impairs histone deacetylation (By similarity). Interacts with DNTTIP1 (PubMed:25653165). Identified in a histone deacetylase complex that contains DNTTIP1, HDAC1 and MIDEAS; this complex assembles into a tetramer that contains four copies of each protein chain (PubMed:25653165). Interacts with CCAR2 (PubMed:21030595). Interacts with PPHLN1 (PubMed:17963697). Found in a complex with YY1, SIN3A and GON4L (By similarity). Interacts with CHD4 (PubMed:27616479). Found in a complex composed of at least SINHCAF, SIN3A, HDAC1, SAP30, RBBP4, OGT and TET1 (By similarity). Interacts with SIN3A (By similarity). Interacts with DHX36; this interaction occurs in a RNA-dependent manner (PubMed:18279852). Interacts with ZBTB7A (PubMed:25514493). Interacts with SMAD4; positively regulated by ZBTB7A (PubMed:25514493). Interacts with PACS2 (PubMed:29656858). Forms a complex comprising APPL1, RUVBL2, APPL2, CTNNB1 and HDAC2 (PubMed:19433865). Interacts with ZNF638 (PubMed:30487602). Interacts with SPHK2 (PubMed:19729656). Interacts with ERCC6 (PubMed:26030138). Interacts with NSD2 (By similarity). Interacts with SMYD4 (via MYND-type zinc finger) (PubMed:30110327). Interacts with PWWP2A in a MTA1-dependent manner (By similarity). Interacts with PWWP2B (By similarity). Interacts with ZNF516 and BRCC3; these interactions are enhanced in the presence of PWWP2B (By similarity).SUBUNIT (Microbial infection) Interacts with SV40 large T antigen.TISSUE SPECIFICITY Ubiquitous, with higher levels in heart, pancreas and testis, and lower levels in kidney and brain.PTM Sumoylated on Lys-444 and Lys-476; which promotes enzymatic activity. Desumoylated by SENP1.PTM Phosphorylation on Ser-421 and Ser-423 promotes enzymatic activity and interactions with NuRD and SIN3 complexes. Phosphorylated by CDK5.PTM Ubiquitinated by CHFR, leading to its degradation by the proteasome. Ubiquitinated by KCTD11, leading to proteasomal degradation.SIMILARITY Belongs to the histone deacetylase family. HD type 1 subfamily. UniProt Q13547 1 EQUAL 482 EQUAL Reactome Database ID Release 81 205021 Database 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=205021 Reactome R-HSA-205021 1 Reactome 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-205021.1 HDAC10 HDA10_HUMAN Reactome DB_ID: 351579 UniProt:Q969S8 HDAC10 HDAC10 FUNCTION Polyamine deacetylase (PDAC), which acts preferentially on N(8)-acetylspermidine, and also on acetylcadaverine and acetylputrescine (PubMed:28516954). Exhibits attenuated catalytic activity toward N(1),N(8)-diacetylspermidine and very low activity, if any, toward N(1)-acetylspermidine (PubMed:28516954). Histone deacetylase activity has been observed in vitro (PubMed:11861901, PubMed:11726666, PubMed:11677242, PubMed:11739383). Has also been shown to be involved in MSH2 deacetylation (PubMed:26221039). The physiological relevance of protein/histone deacetylase activity is unclear and could be very weak (PubMed:28516954). May play a role in the promotion of late stages of autophagy, possibly autophagosome-lysosome fusion and/or lysosomal exocytosis in neuroblastoma cells (PubMed:23801752, PubMed:29968769). May play a role in homologous recombination (PubMed:21247901). May promote DNA mismatch repair (PubMed:26221039).SUBUNIT Interacts with HDAC3 (PubMed:11861901). Interacts with HDAC2 and NCOR2/SMRT (PubMed:11739383). Interacts with HSPA8/HSC70 (PubMed:23801752). Interacts with MSH2 (PubMed:26221039).TISSUE SPECIFICITY Widely expressed with high levels in liver and kidney.DISEASE In neuroblastoma cells, may promote autophagy in response to chemotherapy-induced DNA damage and efflux of chemotherapeutics via lysosomal exocytosis, hence protecting cells from cytotoxic agents (PubMed:23801752, PubMed:29968769). Expression levels may correlate with survival in neuroblastoma patients, with low levels in the tumor correlating with long-term patient survival and high expression with poor prognosis (PubMed:23801752). Therefore has been proposed as a biomarker to predict neuroblastoma chemoresistance and treatment outcome (PubMed:23801752).MISCELLANEOUS Like some other members of the HD type 2 subfamily, such as HDAC4, inhibited by the antitumor drug trichostatin A (TSA).SIMILARITY Belongs to the histone deacetylase family. HD type 2 subfamily.CAUTION Protein/histone deacetylase activity in vivo is uncertain. The 3D structure analysis of the zebrafish ortholog shows that a glutamate gatekeeper and a sterically constricted active site confer specificity for N(8)-acetylspermidine hydrolysis and disfavour acetyllysine hydrolysis. Supporting this observation, has been shown to exhibit only very low activity, if any, towards acetyl-lysine peptide substrates (PubMed:28516954). However, histone deacetylase activity has been observed in vitro (PubMed:28516954, PubMed:11861901, PubMed:11726666, PubMed:11677242, PubMed:11739383). Has also been shown to be involved in MSH2 deacetylation (PubMed:26221039). UniProt Q969S8 1 EQUAL 669 EQUAL Reactome Database ID Release 81 351579 Database 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=351579 Reactome R-HSA-351579 1 Reactome 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-351579.1 HDAC3 Histone deacetylase 3 HDAC3_HUMAN Reactome DB_ID: 442464 UniProt:O15379 HDAC3 HDAC3 FUNCTION Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4), and some other non-histone substrates (PubMed:23911289, PubMed:21030595, PubMed:21444723, PubMed:25301942, PubMed:28497810, PubMed:28167758). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (PubMed:23911289). Histone deacetylases act via the formation of large multiprotein complexes (PubMed:23911289). Participates in the BCL6 transcriptional repressor activity by deacetylating the H3 'Lys-27' (H3K27) on enhancer elements, antagonizing EP300 acetyltransferase activity and repressing proximal gene expression (PubMed:23911289). Acts as a molecular chaperone for shuttling phosphorylated NR2C1 to PML bodies for sumoylation (By similarity). Contributes, together with XBP1 isoform 1, to the activation of NFE2L2-mediated HMOX1 transcription factor gene expression in a PI(3)K/mTORC2/Akt-dependent signaling pathway leading to endothelial cell (EC) survival under disturbed flow/oxidative stress (PubMed:25190803). Regulates both the transcriptional activation and repression phases of the circadian clock in a deacetylase activity-independent manner (By similarity). During the activation phase, promotes the accumulation of ubiquitinated ARNTL/BMAL1 at the E-boxes and during the repression phase, blocks FBXL3-mediated CRY1/2 ubiquitination and promotes the interaction of CRY1 and ARNTL/BMAL1 (By similarity). The NCOR1-HDAC3 complex regulates the circadian expression of the core clock gene ARTNL/BMAL1 and the genes involved in lipid metabolism in the liver (By similarity). Also functions as deacetylase for non-histone targets, such as KAT5, MEF2D, MAPK14 and RARA (PubMed:21030595, PubMed:21444723, PubMed:25301942, PubMed:28167758). Serves as a corepressor of RARA, mediating its deacetylation and repression, leading to inhibition of RARE DNA element binding (PubMed:28167758). In association with RARA, plays a role in the repression of microRNA-10a and thereby in the inflammatory response (PubMed:28167758). In addition to protein deacetylase activity, also acts as protein-lysine deacylase by recognizing other acyl groups: catalyzes removal of (2E)-butenoyl (crotonyl) and 2-hydroxyisobutanoyl (2-hydroxyisobutyryl) acyl groups from lysine residues, leading to protein decrotonylation and de-2-hydroxyisobutyrylation, respectively (PubMed:28497810, PubMed:29192674, PubMed:34608293). Catalyzes decrotonylation of MAPRE1/EB1 (PubMed:34608293).SUBUNIT Interacts with HDAC7 and HDAC9 (PubMed:11466315, PubMed:10655483). Interacts with DAXX, KDM4A, HDAC10 and DACH1 (PubMed:10669754, PubMed:11861901, PubMed:14525983, PubMed:15927959). Found in a complex with NCOR1 and NCOR2 (PubMed:10860984). Component of the N-Cor repressor complex, at least composed of NCOR1, NCOR2, HDAC3, TBL1X, TBL1R, CORO2A and GPS2 (PubMed:11931768). Interacts with BCOR, MJD2A/JHDM3A, NRIP1, PRDM6 and SRY (PubMed:10898795, PubMed:11006275, PubMed:15297880). Interacts with BTBD14B (By similarity). Interacts with GLIS2 (By similarity). Interacts (via the DNA-binding domain) with NR2C1; the interaction recruits phosphorylated NR2C1 to PML bodies for sumoylation (By similarity). Component of the Notch corepressor complex (PubMed:19409814). Interacts with CBFA2T3 and NKAP (PubMed:11533236, PubMed:19409814). Interacts with APEX1; the interaction is not dependent on the acetylated status of APEX1 (PubMed:14633989). Interacts with ZMYND15 (By similarity). Interacts with SMRT/NCOR2 and BCL6 on DNA enhancer elements (PubMed:23911289). Interacts with INSM1 (PubMed:16569215, PubMed:18417529). Interacts with XBP1 isoform 1; the interaction occurs in endothelial cell (EC) under disturbed flow (PubMed:25190803). Interacts (via C-terminus) with CCAR2 (via N-terminus) (PubMed:21030595). Interacts with and deacetylates MEF2D (PubMed:21030595). Interacts with BEND3 (PubMed:21914818). Interacts with NKAPL (By similarity). Interacts with DHX36; this interaction occurs in a RNA-dependent manner (PubMed:18279852). Interacts weakly with CRY1; this interaction is enhanced in the presence of FBXL3 (By similarity). Interacts with FBXL3 and ARNTL/BMAL1 (By similarity). Interacts with NCOR1 (By similarity). Interacts with RARA (PubMed:28167758). Interacts with SETD5 (By similarity).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus (HHV-5) immediate early protein IE1; this interaction decreases histone acetylation and allows transcriptional activation by the virus.TISSUE SPECIFICITY Widely expressed.INDUCTION Up-regulated by disturbed flow in umbilical vein endothelial cells in vitro (PubMed:25190803).PTM Sumoylated in vitro.SIMILARITY Belongs to the histone deacetylase family. HD type 1 subfamily. UniProt O15379 1 EQUAL 428 EQUAL Reactome Database ID Release 81 442464 Database 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=442464 Reactome R-HSA-442464 1 Reactome 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-442464.1 HDAC5 Histone deacetylase 5 HDAC5_HUMAN Reactome DB_ID: 3004533 UniProt:Q9UQL6 HDAC5 HDAC5 KIAA0600 FUNCTION Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation by repressing transcription of myocyte enhancer MEF2C. During muscle differentiation, it shuttles into the cytoplasm, allowing the expression of myocyte enhancer factors. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. Serves as a corepressor of RARA and causes its deacetylation (PubMed:28167758). In association with RARA, plays a role in the repression of microRNA-10a and thereby in the inflammatory response (PubMed:28167758).SUBUNIT Interacts with AHRR, BAHD1, BCOR, HDAC7, HDAC9, CTBP1, MEF2C, NCOR2, NRIP1, PHB2 and a 14-3-3 chaperone protein. Interacts with BCL6, DDIT3/CHOP, GRK5, KDM5B and MYOCD. Interacts with EP300 in the presence of TFAP2C. Interacts with ANKRA2. Interacts with CUL7 (as part of the 3M complex); negatively regulated by ANKRA2. Interacts with ZBTB7B; the interaction allows the recruitment of HDAC4 on CD8 loci for deacetylation and possible inhibition of CD8 genes expression (By similarity). Interacts with RARA (PubMed:28167758).TISSUE SPECIFICITY Ubiquitous.DOMAIN The nuclear export sequence mediates the shuttling between the nucleus and the cytoplasm.PTM Phosphorylated by AMPK, CaMK1, SIK1 and PRKD1 at Ser-259 and Ser-498. The phosphorylation is required for the export to the cytoplasm and inhibition. Phosphorylated by the PKC kinases PKN1 and PKN2, impairing nuclear import. Phosphorylated by GRK5, leading to nuclear export of HDAC5 and allowing MEF2-mediated transcription (By similarity).PTM Ubiquitinated. Polyubiquitination however does not lead to its degradation.SIMILARITY Belongs to the histone deacetylase family. HD type 2 subfamily. UniProt Q9UQL6 1 EQUAL 1122 EQUAL Reactome Database ID Release 81 3004533 Database 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=3004533 Reactome R-HSA-3004533 1 Reactome 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-3004533.1 HDAC7 Histone deacetylase 7 HDAC7_HUMAN Reactome DB_ID: 3004534 UniProt:Q8WUI4 HDAC7 HDAC7 HDAC7A FUNCTION Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation by repressing transcription of myocyte enhancer factors such as MEF2A, MEF2B and MEF2C. During muscle differentiation, it shuttles into the cytoplasm, allowing the expression of myocyte enhancer factors (By similarity). May be involved in Epstein-Barr virus (EBV) latency, possibly by repressing the viral BZLF1 gene. Positively regulates the transcriptional repressor activity of FOXP3 (PubMed:17360565). Serves as a corepressor of RARA, causing its deacetylation and inhibition of RARE DNA element binding (PubMed:28167758). In association with RARA, plays a role in the repression of microRNA-10a and thereby in the inflammatory response (PubMed:28167758).SUBUNIT Interacts with HDAC1, HDAC2, HDAC3, HDAC4, HDAC5, NCOR1, NCOR2, SIN3A, SIN3B, RBBP4, RBBP7, MTA1L1, SAP30 and MBD3. Interacts with the 14-3-3 protein YWHAE, MEF2A, MEF2B and MEF2C (By similarity). Interacts with KAT5 and EDNRA. Interacts with KDM5B. Interacts with ZMYND15 (By similarity). Interacts with PML (isoform PML-4). Interacts with FOXP3. Interacts with RARA (PubMed:28167758).DOMAIN The nuclear export sequence mediates the shuttling between the nucleus and the cytoplasm.PTM May be phosphorylated by CaMK1. Phosphorylated by the PKC kinases PKN1 and PKN2, impairing nuclear import. Phosphorylation at Ser-155 by MARK2, MARK3 and PRKD1 promotes interaction with 14-3-3 proteins and export from the nucleus. Phosphorylation at Ser-155 is a prerequisite for phosphorylation at Ser-181.MISCELLANEOUS Its activity is inhibited by Trichostatin A (TSA), a known histone deacetylase inhibitor.SIMILARITY Belongs to the histone deacetylase family. HD type 2 subfamily. UniProt Q8WUI4 1 EQUAL 952 EQUAL Reactome Database ID Release 81 3004534 Database 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=3004534 Reactome R-HSA-3004534 1 Reactome 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-3004534.1 HDAC9 Histone deacetylase 9 HDAC9_HUMAN Reactome DB_ID: 3004554 UniProt:Q9UKV0 HDAC9 HDAC9 HDAC7 HDAC7B HDRP KIAA0744 MITR FUNCTION Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Represses MEF2-dependent transcription.FUNCTION Isoform 3 lacks active site residues and therefore is catalytically inactive. Represses MEF2-dependent transcription by recruiting HDAC1 and/or HDAC3. Seems to inhibit skeletal myogenesis and to be involved in heart development. Protects neurons from apoptosis, both by inhibiting JUN phosphorylation by MAPK10 and by repressing JUN transcription via HDAC1 recruitment to JUN promoter.ACTIVITY REGULATION Inhibited by Trichostatin A (TSA) and suberoylanilide hydroxamic acid.SUBUNIT Homodimer. Interacts with CTBP1. The phosphorylated form interacts with 14-3-3 (By similarity). Interacts with HDAC1 and HDAC3, and probably with HDAC4 and HDAC5. Interacts with MEF2, MAPK10, ETV6, NCOR1 and BCL6. Interacts with FOXP3 in the absence of T-cell stimulation.TISSUE SPECIFICITY Broadly expressed, with highest levels in brain, heart, muscle and testis. Isoform 3 is present in human bladder carcinoma cells (at protein level).PTM Phosphorylated on Ser-220 and Ser-450; which promotes 14-3-3-binding, impairs interaction with MEF2, and antagonizes antimyogenic activity. Phosphorylated on Ser-240; which impairs nuclear accumulation (By similarity). Isoform 7 is phosphorylated on Tyr-1010. Phosphorylated by the PKC kinases PKN1 and PKN2, impairing nuclear import.PTM Sumoylated.DISEASE A chromosomal aberration involving HDAC9 is found in a family with Peters anomaly. Translocation t(1;7)(q41;p21) with TGFB2 resulting in lack of HDAC9 protein.SIMILARITY Belongs to the histone deacetylase family. HD type 2 subfamily. UniProt Q9UKV0 1 EQUAL 1011 EQUAL Reactome Database ID Release 81 3004554 Database 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=3004554 Reactome R-HSA-3004554 1 Reactome 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-3004554.1 HDAC11 HDA11_HUMAN Histone deacetylase 11 Reactome DB_ID: 351590 UniProt:Q96DB2 HDAC11 HDAC11 FUNCTION Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes.SUBUNIT Interacts with HDAC6.TISSUE SPECIFICITY Weakly expressed in most tissues. Strongly expressed in brain, heart, skeletal muscle, kidney and testis.MISCELLANEOUS Its activity is inhibited by trapoxin, a known histone deacetylase inhibitor.SIMILARITY Belongs to the histone deacetylase family. UniProt Q96DB2 1 EQUAL 347 EQUAL Reactome Database ID Release 81 351590 Database 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=351590 Reactome R-HSA-351590 1 Reactome 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-351590.1 HDAC2 HDA2_HUMAN Histone deacetylase 2 Reactome DB_ID: 205135 UniProt:Q92769 HDAC2 HDAC2 FUNCTION Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) (PubMed:28497810). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (By similarity). Histone deacetylases act via the formation of large multiprotein complexes (By similarity). Forms transcriptional repressor complexes by associating with MAD, SIN3, YY1 and N-COR (PubMed:12724404). Component of a RCOR/GFI/KDM1A/HDAC complex that suppresses, via histone deacetylase (HDAC) recruitment, a number of genes implicated in multilineage blood cell development (By similarity). Also deacetylates non-histone targets: deacetylates TSHZ3, thereby regulating its transcriptional repressor activity (PubMed:19343227). May be involved in the transcriptional repression of circadian target genes, such as PER1, mediated by CRY1 through histone deacetylation (By similarity). Involved in MTA1-mediated transcriptional corepression of TFF1 and CDKN1A (PubMed:21965678). In addition to protein deacetylase activity, also acts as protein-lysine deacylase by recognizing other acyl groups: catalyzes removal of (2E)-butenoyl (crotonyl) and 2-hydroxyisobutanoyl (2-hydroxyisobutyryl) acyl groups from lysine residues, leading to protein decrotonylation and de-2-hydroxyisobutyrylation, respectively (PubMed:28497810, PubMed:29192674).SUBUNIT Part of the core histone deacetylase (HDAC) complex composed of HDAC1, HDAC2, RBBP4 and RBBP7 (PubMed:10904264). The core complex associates with MTA2, MBD3, MTA1L1, CHD3 and CHD4 to form the nucleosome remodeling and histone deacetylation (NuRD) complex, or with SIN3, SAP18 and SAP30 to form the SIN3 HDAC complex (PubMed:10904264). Component of a RCOR/GFI/KDM1A/HDAC complex (By similarity). Component of a BHC histone deacetylase complex that contains HDAC1, HDAC2, HMG20B, KDM1A, RCOR1 and PHF21A (PubMed:12493763). The BHC complex may also contain ZMYM2, ZNF217, ZMYM3, GSE1 and GTF2I (PubMed:12493763). Part of a complex containing the core histones H2A, H2B, H3 and H4, DEK and unphosphorylated DAXX (PubMed:12140263). Part of a complex containing ATR and CHD4 (PubMed:10545197). Forms a heterologous complex at least with YY1 (PubMed:8917507). Interacts in the late S-phase of DNA-replication with DNMT1 in the other transcriptional repressor complex composed of DNMT1, DMAP1, PCNA, CAF1 (PubMed:10888872). Component of a mSin3A corepressor complex that contains SIN3A, SAP130, SUDS3, ARID4B, HDAC1 and HDAC2 (PubMed:12724404). Part of a complex composed of TRIM28, HDAC1, HDAC2 and EHMT2 (PubMed:10904264). Part of a complex containing at least CDYL, MIER1, MIER2, HDAC1 and HDAC2 (PubMed:19061646). Component of a histone deacetylase complex containing DNTTIP1, ZNF541, HDAC1 and HDAC2 (PubMed:21573134). Forms a complex comprising APPL1, RUVBL2, APPL2, CTNNB1 and HDAC1 (PubMed:19433865). Interacts with SPHK2 (PubMed:19729656). Interacts directly with GFI1 and GFI1B (By similarity). Interacts with SNW1, HDAC7, PRDM6, SAP30, SETDB1 and SUV39H1 (PubMed:10644367). Interacts with the MACROH2A1 (via the non-histone region) (By similarity). Interacts with ATR, CBFA2T3, DNMT1, SMARCAD1, MINT, HDAC10, HCFC1, NRIP1, KDM4A and PELP1 (PubMed:15927959, PubMed:15456770, PubMed:15060175, PubMed:11331609, PubMed:21549307, PubMed:12670868, PubMed:11533236, PubMed:11739383, PubMed:10888872). Interacts with CHFR and SAP30L (PubMed:19182791, PubMed:16820529). Interacts (CK2 phosphorylated form) with SP3 (PubMed:12176973). Interacts with TSHZ3 (via its N-terminus) (PubMed:19343227). Interacts with APEX1; the interaction is not dependent on the acetylated status of APEX1 (PubMed:14633989). Interacts with PIMREG (PubMed:18757745). Interacts with BCL6 (non-acetylated form) (PubMed:18212045, PubMed:12402037). Interacts with CRY1, INSM1 and ZNF431 (By similarity). Interacts with NACC2 (PubMed:22926524). Interacts with MTA1, with a preference for sumoylated MTA1 (PubMed:21965678, PubMed:24970816). Interacts with SIX3 (By similarity). Interacts with BEND3 (PubMed:21914818). Interacts with ZNF263; recruited to the SIX3 promoter along with other proteins involved in chromatin modification and transcriptional corepression where it contributes to transcriptional repression (PubMed:32051553). Interacts with PWWP2B (By similarity).TISSUE SPECIFICITY Widely expressed; lower levels in brain and lung.PTM S-nitrosylated by GAPDH. In neurons, S-nitrosylation at Cys-262 and Cys-274 does not affect enzyme activity, but induces HDAC2 release from chromatin. This in turn increases acetylation of histones surrounding neurotrophin-dependent gene promoters and promotes their transcription. In embryonic cortical neurons, S-Nitrosylation regulates dendritic growth and branching.SIMILARITY Belongs to the histone deacetylase family. HD type 1 subfamily. UniProt Q92769 1 EQUAL 488 EQUAL Reactome Database ID Release 81 205135 Database 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=205135 Reactome R-HSA-205135 1 Reactome 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-205135.1 HDAC4 HDAC4_HUMAN Histone deacetylase 4 Reactome DB_ID: 351581 UniProt:P56524 HDAC4 HDAC4 KIAA0288 FUNCTION Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events. Histone deacetylases act via the formation of large multiprotein complexes. Involved in muscle maturation via its interaction with the myocyte enhancer factors such as MEF2A, MEF2C and MEF2D. Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer. Deacetylates HSPA1A and HSPA1B at 'Lys-77' leading to their preferential binding to co-chaperone STUB1 (PubMed:27708256).SUBUNIT Homodimer. Homodimerization via its N-terminal domain (PubMed:12032081). Interacts with MEF2A (PubMed:10487761). Interacts with MEF2C and MEF2D (PubMed:10523670). Interacts with AHRR (By similarity). Interacts with NR2C1 (PubMed:11463856). Interacts with HDAC7 (By similarity). Interacts with a 14-3-3 chaperone protein in a phosphorylation dependent manner (PubMed:10958686). Interacts with BTBD14B (By similarity). Interacts with KDM5B (PubMed:17373667). Interacts with MYOCD (By similarity). Interacts with MORC2 (PubMed:20110259). Interacts (via PxLPxI/L motif) with ANKRA2 (via ankyrin repeats). Interacts with CUL7 (as part of the 3M complex); negatively regulated by ANKRA2 (PubMed:25752541). Interacts with EP300 in the presence of TFAP2C (PubMed:24413532). Interacts with HSPA1A and HSPA1B leading to their deacetylation at 'Lys-77' (PubMed:27708256). Interacts with ZBTB7B; the interaction allows the recruitment of HDAC4 on CD8 loci for deacetylation and possible inhibition of CD8 genes expression (By similarity). Interacts with DHX36 (By similarity). Interacts with SIK3; this interaction leads to HDAC4 retention in the cytoplasm (By similarity). Interacts with ZNF638 (PubMed:30487602).TISSUE SPECIFICITY Ubiquitous.DOMAIN The nuclear export sequence mediates the shuttling between the nucleus and the cytoplasm.DOMAIN The PxLPxI/L motif mediates interaction with ankyrin repeats of ANKRA2.PTM Phosphorylated by CaMK4 at Ser-246, Ser-467 and Ser-632. Phosphorylation at other residues by CaMK2D is required for the interaction with 14-3-3. Phosphorylation at Ser-350, within the PxLPxI/L motif, impairs the binding of ANKRA2 but generates a high-affinity docking site for 14-3-3.PTM Sumoylation on Lys-559 is promoted by the E3 SUMO-protein ligase RANBP2, and prevented by phosphorylation by CaMK4.SIMILARITY Belongs to the histone deacetylase family. HD type 2 subfamily. UniProt P56524 1 EQUAL 1084 EQUAL Reactome Database ID Release 81 351581 Database 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=351581 Reactome R-HSA-351581 1 Reactome 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-351581.1 HDAC6 HDAC6_HUMAN Reactome DB_ID: 351589 UniProt:Q9UBN7 HDAC6 HDAC6 KIAA0901 JM21 FUNCTION Responsible for the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) (PubMed:10220385). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (PubMed:10220385). Histone deacetylases act via the formation of large multiprotein complexes (PubMed:10220385). In addition to histones, deacetylates other proteins: plays a central role in microtubule-dependent cell motility by mediating deacetylation of tubulin (PubMed:12024216, PubMed:20308065). Promotes deacetylation of CTTN, leading to actin polymerization, promotion of autophagosome-lysosome fusion and completion of autophagy (PubMed:30538141). Involved in the MTA1-mediated epigenetic regulation of ESR1 expression in breast cancer (PubMed:24413532). In addition to its protein deacetylase activity, plays a key role in the degradation of misfolded proteins: when misfolded proteins are too abundant to be degraded by the chaperone refolding system and the ubiquitin-proteasome, mediates the transport of misfolded proteins to a cytoplasmic juxtanuclear structure called aggresome (PubMed:17846173). Probably acts as an adapter that recognizes polyubiquitinated misfolded proteins and target them to the aggresome, facilitating their clearance by autophagy (PubMed:17846173).SUBUNIT Interacts with SIRT2 (via both phosphorylated, unphosphorylated, active or inactive forms); the interaction is necessary for the complex to interact with alpha-tubulin (PubMed:12620231, PubMed:17516032). Under proteasome impairment conditions, interacts with UBD via its histone deacetylase 1 and UBP-type zinc-finger regions (PubMed:19033385, PubMed:25422469). Interacts with BBIP1, CBFA2T3, CYLD, DDIT3/CHOP, ZMYND15, F-actin and HDAC11 (PubMed:19893491, PubMed:11533236, PubMed:11948178, PubMed:19081074, PubMed:17872950). Interacts with RIPOR2; this interaction occurs during early myogenic differentiation and prevents HDAC6 to deacetylate tubulin (PubMed:24687993). Interacts with DYSF; this interaction occurs during early myogenic differentiation (PubMed:24687993). Interacts with TPPP; inhibiting the tubulin deacetylase activity of HDAC6 (PubMed:20308065, PubMed:23093407). Interacts with DYNLL1 (PubMed:31505170). Interacts with ATP13A2; the interaction results in recruitment of HDAC6 to lysosomes to promote CTTN deacetylation (PubMed:30538141).PTM Phosphorylated by AURKA.PTM Ubiquitinated. Its polyubiquitination however does not lead to its degradation.PTM Sumoylated in vitro.SIMILARITY Belongs to the histone deacetylase family. HD type 2 subfamily. UniProt Q9UBN7 1 EQUAL 1215 EQUAL Reactome Database ID Release 81 351589 Database 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=351589 Reactome R-HSA-351589 1 Reactome 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-351589.1 HDAC8 Histone deacetylase 8 HDAC8_HUMAN Reactome DB_ID: 3004556 UniProt:Q9BY41 HDAC8 HDAC8 HDACL1 CDA07 FUNCTION Histone deacetylase that catalyzes the deacetylation of lysine residues on the N-terminal part of the core histones (H2A, H2B, H3 and H4) (PubMed:10748112, PubMed:10922473, PubMed:10926844, PubMed:14701748, PubMed:28497810). Histone deacetylation gives a tag for epigenetic repression and plays an important role in transcriptional regulation, cell cycle progression and developmental events (PubMed:10748112, PubMed:10922473, PubMed:10926844, PubMed:14701748). Histone deacetylases act via the formation of large multiprotein complexes (PubMed:10748112, PubMed:10922473, PubMed:10926844, PubMed:14701748). Also involved in the deacetylation of cohesin complex protein SMC3 regulating release of cohesin complexes from chromatin (PubMed:22885700). May play a role in smooth muscle cell contractility (PubMed:15772115). In addition to protein deacetylase activity, also has protein-lysine deacylase activity: acts as a protein decrotonylase by mediating decrotonylation ((2E)-butenoyl) of histones (PubMed:28497810).ACTIVITY REGULATION Its activity is inhibited by trichostatin A (TSA), suberoylanilide hydroxamic acid (SAHA), 3-(1-methyl-4-phenylacetyl-1H-2-pyrrolyl)-N-hydroxy-2-propenamide (APHA), 4-dimethylamino-N-(6-hydroxycarbamoyethyl)benzamide-N-hydroxy-7-(4-dimethylaminobenzoyl)aminoheptanamide (MS-344), 5-(4-methyl-benzoylamino)-biphenyl-3,4'-dicarboxylic acid 3-dimethylamide 4'-hydroxyamide (CRA-A) and butyrate.SUBUNIT Interacts with PEPB2-MYH11, a fusion protein consisting of the 165 N-terminal residues of CBF-beta (PEPB2) with the tail region of MYH11 produced by the inversion Inv(16)(p13q22), a translocation associated with acute myeloid leukemia of M4EO subtype (PubMed:12509458). The PEPB2-MYH1 fusion protein also interacts with RUNX1, a well known transcriptional regulator, suggesting that the interaction with HDAC8 may participate in the conversion of RUNX1 into a constitutive transcriptional repressor (PubMed:12509458). Interacts with CBFA2T3 (PubMed:11533236). Interacts with phosphorylated SMG5/EST1B; this interaction protects SMG5 from ubiquitin-mediated degradation (PubMed:16809764). Associates with alpha-SMA (smooth muscle alpha-actin) (PubMed:15772115).TISSUE SPECIFICITY Weakly expressed in most tissues. Expressed at higher level in heart, brain, kidney and pancreas and also in liver, lung, placenta, prostate and kidney.PTM Phosphorylated by PKA on serine 39. Phosphorylation reduces deacetylase activity observed preferentially on histones H3 and H4.SIMILARITY Belongs to the histone deacetylase family. HD type 1 subfamily. UniProt Q9BY41 1 EQUAL 377 EQUAL Reactome Database ID Release 81 3004556 Database 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=3004556 Reactome R-HSA-3004556 1 Reactome 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-3004556.1 Reactome Database ID Release 81 350066 Database 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=350066 Reactome R-HSA-350066 1 Reactome 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-350066.1 1 RBPJ Recombining binding protein suppressor of hairless SUH_HUMAN CBF1 Reactome DB_ID: 3008668 UniProt:Q06330 RBPJ RBPJ IGKJRB IGKJRB1 RBPJK RBPSUH FUNCTION Transcriptional regulator that plays a central role in Notch signaling, a signaling pathway involved in cell-cell communication that regulates a broad spectrum of cell-fate determinations. Acts as a transcriptional repressor when it is not associated with Notch proteins. When associated with some NICD product of Notch proteins (Notch intracellular domain), it acts as a transcriptional activator that activates transcription of Notch target genes. Probably represses or activates transcription via the recruitment of chromatin remodeling complexes containing histone deacetylase or histone acetylase proteins, respectively. Specifically binds to the immunoglobulin kappa-type J segment recombination signal sequence. Binds specifically to methylated DNA (PubMed:21991380). Binds to the oxygen responsive element of COX4I2 and activates its transcription under hypoxia conditions (4% oxygen) (PubMed:23303788). Negatively regulates the phagocyte oxidative burst in response to bacterial infection by repressing transcription of NADPH oxidase subunits (By similarity).SUBUNIT Interacts with activated NOTCH1, NOTCH2 or NOTCH3. Interacts with MINT/SHARP. This interaction may mediate the recruitment of large corepressor complexes containing proteins such as HDAC1, HDAC2, NCOR2, SAP30, FHL1/KYOT2 and CIR1. Interacts with EP300, MAML1 and PTF1A. Interacts with Epstein-Barr virus EBNA2, EBNA3, EBNA4 and EBNA6. Interacts with RITA1/C12orf52, leading to nuclear export, prevent the interaction between RBPJ and NICD product and subsequent down-regulation of the Notch signaling pathway. Interacts with SNW1. Interacts with CHCHD2 and CXXC5 (PubMed:23303788). Interacts with BEND6 (via BEN domain). Interacts with NKAPL (By similarity). Interacts with ZMIZ1. Interacts with RBM15 (By similarity).SIMILARITY Belongs to the Su(H) family.CAUTION Despite some similarity with the 'phage' integrase family, it has no recombinase activity. UniProt Q06330 1 EQUAL 500 EQUAL Reactome Database ID Release 81 3008668 Database 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=3008668 Reactome R-HSA-3008668 1 Reactome 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-3008668.1 1 Reactome Database ID Release 81 350052 Database 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=350052 Reactome R-HSA-350052 2 Reactome 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-350052.2 NICD1 PEST domain mutants:RBPJ:SNW1 Reactome DB_ID: 2220969 1 1 1 Reactome Database ID Release 81 2220969 Database 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=2220969 Reactome R-HSA-2220969 1 Reactome 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-2220969.1 NCOR:HDAC:TBL1 Reactome DB_ID: 1911465 1 1 1 Reactome Database ID Release 81 1911465 Database 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=1911465 Reactome R-HSA-1911465 1 Reactome 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-1911465.1 Reactome Database ID Release 81 2220982 Database 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=2220982 Reactome R-HSA-2220982 2 Reactome 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-2220982.2 10713164 Pubmed 2000 SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function Zhou, S Fujimuro, M Hsieh, JJ Chen, L Miyamoto, A Weinmaster, G Hayward, SD Mol Cell Biol 20:2400-10 18374649 Pubmed 2008 TBL1 and TBLR1 phosphorylation on regulated gene promoters overcomes dual CtBP and NCoR/SMRT transcriptional repression checkpoints Perissi, V Scafoglio, C Zhang, J Ohgi, KA Rose, DW Glass, CK Rosenfeld, MG Mol Cell 29:755-66 14980219 Pubmed 2004 A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors Perissi, V Aggarwal, A Glass, CK Rose, DW Rosenfeld, MG Cell 116:511-26 9694793 Pubmed 1998 A histone deacetylase corepressor complex regulates the Notch signal transduction pathway Kao, HY Ordentlich, P Koyano-Nakagawa, N Tang, Z Downes, M Kintner, CR Evans, RM Kadesch, T Genes Dev 12:2269-77 7588063 Pubmed 1995 Disruption of the mouse RBP-J kappa gene results in early embryonic death Oka, C Nakano, T Wakeham, A de la Pompa, JL Mori, C Sakai, T Okazaki, S Kawaichi, M Shiota, K Mak, TW Honjo, Tasuku Development 121:3291-301 LEFT-TO-RIGHT NICD1 PEST domain mutants in complex with RBPJ (CSL) bind MAML NICD1 PEST domain mutants in complex with RBPJ and SNW1 are expected, similar to the wild-type NICD1:RBPJ:SNW1 complex, to recruit MAML and histone acetylatransferases to form the NOTCH1 PEST domain mutants coactivator complex (Fryer et al. 2002, Wallberg et al. 2002, Nam et al. 2006). Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 KAT3A CREBBP CREB-binding protein CBP_HUMAN Reactome DB_ID: 193545 UniProt:Q92793 CREBBP CREBBP CBP FUNCTION Acetylates histones, giving a specific tag for transcriptional activation (PubMed:24616510). Also acetylates non-histone proteins, like DDX21, FBL, IRF2, MAFG, NCOA3, POLR1E/PAF53 and FOXO1 (PubMed:10490106, PubMed:11154691, PubMed:12738767, PubMed:12929931, PubMed:9707565, PubMed:24207024, PubMed:28790157, PubMed:30540930). Binds specifically to phosphorylated CREB and enhances its transcriptional activity toward cAMP-responsive genes. Acts as a coactivator of ALX1. Acts as a circadian transcriptional coactivator which enhances the activity of the circadian transcriptional activators: NPAS2-ARNTL/BMAL1 and CLOCK-ARNTL/BMAL1 heterodimers (PubMed:14645221). Acetylates PCNA; acetylation promotes removal of chromatin-bound PCNA and its degradation during nucleotide excision repair (NER) (PubMed:24939902). Acetylates POLR1E/PAF53, leading to decreased association of RNA polymerase I with the rDNA promoter region and coding region (PubMed:24207024). Acetylates DDX21, thereby inhibiting DDX21 helicase activity (PubMed:28790157). Acetylates FBL, preventing methylation of 'Gln-105' of histone H2A (H2AQ104me) (PubMed:30540930). Functions as a transcriptional coactivator for SMAD4 in the TGF-beta signaling pathway (PubMed:25514493).SUBUNIT Found in a complex containing NCOA2; NCOA3; IKKA; IKKB and IKBKG. Probably part of a complex with HIF1A and EP300. Interacts with GATA1; the interaction results in acetylation and enhancement of transcriptional activity of GATA1. Interacts with MAF AND ZCCHC12. Interacts with DAXX; the interaction is dependent on CBP sumoylation and results in suppression of the transcriptional activity via recruitment of HDAC2 to DAXX (By similarity). Interacts with phosphorylated CREB1. Interacts with CITED4 (C-terminal region). Interacts (via the TAZ-type 1 domain) with HIF1A. Interacts with SRCAP, CARM1, ELF3, MLLT7/FOXO4, N4BP2, NCOA1, NCOA3, NCOA6, PCAF, DDX5, DDX17, PELP1, PML, SMAD1, SMAD2, SMAD3, SPIB and TRERF1. Interacts with KLF1; the interaction results in acetylation of KLF1 and enhancement of its transcriptional activity. Interacts with MTDH. Interacts with NFATC4. Interacts with MAFG; the interaction acetylates MAFG in the basic region and stimulates NFE2 transcriptional activity through increasing its DNA-binding activity. Interacts with IRF2; the interaction acetylates IRF2 and regulates its activity on the H4 promoter. Interacts with IRF3 (when phosphorylated); forming the dsRNA-activated factor 1 (DRAF1), a complex which activates the transcription of the type I interferon genes (PubMed:27302953). Interacts (via N-terminus) with SS18L1/CREST (via C-terminus). Interacts with MECOM. Interacts with CITED1 (via C-terminus). Interacts with FOXO1; the interaction acetylates FOXO1 and inhibits its transcriptional activity. Interacts with NPAS2, CLOCK and ARNTL/BMAL1. Interacts with ASF1A and ASF1B; this promotes histone acetylation. Interacts with acetylated TP53/p53 and with the acetylated histones H3 and H4. Interacts (via transactivation domain and C-terminus) with PCNA; the interaction occurs on chromatin in UV-irradiated damaged cells (PubMed:24939902). Interacts with DHX9 (via N-terminus); this interaction mediates association with RNA polymerase II holoenzyme and stimulates CREB-dependent transcriptional activation (PubMed:9323138). Interacts with SMAD4; negatively regulated by ZBTB7A (PubMed:25514493). Interacts with DUX4 (via C-terminus) (PubMed:26951377). Forms a complex with KMT2A and CREB1 (PubMed:23651431). Interacts with DDX3X; this interaction may facilitate HNF4A acetylation (PubMed:28128295).SUBUNIT (Microbial infection) Interacts with HTLV-1 Tax, p30II and HBZ.SUBUNIT (Microbial infection) Interacts with human herpes virus 8/HHV-8 protein vIRF-1; this interaction inhibits CREBBP binding to IRF3.SUBUNIT (Microbial infection) Interacts with HIV-1 Tat.DOMAIN The KIX domain mediates binding to HIV-1 Tat.PTM Methylation of the KIX domain by CARM1 blocks association with CREB. This results in the blockade of CREB signaling, and in activation of apoptotic response (By similarity).PTM Phosphorylated by CHUK/IKKA at Ser-1382 and Ser-1386; these phosphorylations promote cell growth by switching the binding preference of CREBBP from TP53 to NF-kappa-B.PTM Sumoylation negatively regulates transcriptional activity via the recruitment of DAAX.PTM Autoacetylation is required for binding to protein substrates, such as acetylated histones and acetylated TP53/p53.DISEASE Chromosomal aberrations involving CREBBP may be a cause of acute myeloid leukemias. Translocation t(8;16)(p11;p13) with KAT6A; translocation t(11;16)(q23;p13.3) with KMT2A/MLL1; translocation t(10;16)(q22;p13) with KAT6B. KAT6A-CREBBP may induce leukemia by inhibiting RUNX1-mediated transcription. UniProt Q92793 1 EQUAL 2442 EQUAL Reactome Database ID Release 81 193545 Database 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=193545 Reactome R-HSA-193545 1 Reactome 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-193545.1 Converted from EntitySet in Reactome MAML Reactome DB_ID: 212357 MAML1 Reactome DB_ID: 212416 UniProt:Q92585 MAML1 MAML1 KIAA0200 FUNCTION Acts as a transcriptional coactivator for NOTCH proteins. Has been shown to amplify NOTCH-induced transcription of HES1. Enhances phosphorylation and proteolytic turnover of the NOTCH intracellular domain in the nucleus through interaction with CDK8. Binds to CREBBP/CBP which promotes nucleosome acetylation at NOTCH enhancers and activates transcription. Induces phosphorylation and localization of CREBBP to nuclear foci. Plays a role in hematopoietic development by regulating NOTCH-mediated lymphoid cell fate decisions.SUBUNIT Interacts (via N-terminus) with NOTCH1, NOTCH2, NOTCH3 and NOTCH4 (via ankyrin repeat region). Interacts (via N-terminus) with p53 (via DNA-binding region). Forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa/CBF1. Also binds CREBBP/CBP and CDK8.Forms a complex with PRAG1, NOTCH1 and MAML1, in a MAML1-dependent manner (By similarity).TISSUE SPECIFICITY Widely expressed with highest levels in heart, pancreas, peripheral blood leukocytes and spleen.DOMAIN The C-terminal region is required for transcriptional activation.SIMILARITY Belongs to the mastermind family. UniProt Q92585 1 EQUAL 1016 EQUAL Reactome Database ID Release 81 212416 Database 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=212416 Reactome R-HSA-212416 1 Reactome 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-212416.1 MAML2 Reactome DB_ID: 212353 UniProt:Q8IZL2 MAML2 MAML2 KIAA1819 FUNCTION Acts as a transcriptional coactivator for NOTCH proteins. Has been shown to amplify NOTCH-induced transcription of HES1. Potentiates activation by NOTCH3 and NOTCH4 more efficiently than MAML1 or MAML3.SUBUNIT Interacts through its N-terminal region with the ankyrin repeat region of the Notch proteins NOTCH1, NOTCH2, NOTCH3 and NOTCH4. Forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa.TISSUE SPECIFICITY Widely expressed with high levels detected in placenta, salivary gland and skeletal muscle.DOMAIN The C-terminal domain is required for transcriptional activation.DISEASE A chromosomal aberration involving MAML2 is found in mucoepidermoid carcinomas, benign Warthin tumors and clear cell hidradenomas. Translocation t(11;19)(q21;p13) with CRTC1. The fusion protein consists of the N-terminus of CRTC1 joined to the C-terminus of MAML2. The reciprocal fusion protein consisting of the N-terminus of MAML2 joined to the C-terminus of CRTC1 has been detected in a small number of mucoepidermoid carcinomas.SIMILARITY Belongs to the mastermind family. UniProt Q8IZL2 1 EQUAL 1156 EQUAL Reactome Database ID Release 81 212353 Database 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=212353 Reactome R-HSA-212353 1 Reactome 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-212353.1 MAML3 MAML3_HUMAN Reactome DB_ID: 349689 UniProt:Q96JK9 MAML3 MAML3 KIAA1816 FUNCTION Acts as a transcriptional coactivator for NOTCH proteins. Has been shown to amplify NOTCH-induced transcription of HES1.SUBUNIT Interacts through its N-terminal region with the ankyrin repeat region of the Notch proteins NOTCH1, NOTCH2, NOTCH3 and NOTCH4. Forms a DNA-binding complex with Notch proteins and RBPSUH/RBP-J kappa.DOMAIN The C-terminal domain is required for transcriptional activation.SIMILARITY Belongs to the mastermind family. UniProt Q96JK9 1 EQUAL 1134 EQUAL Reactome Database ID Release 81 349689 Database 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=349689 Reactome R-HSA-349689 1 Reactome 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-349689.1 MAMLD1 MAMD1_HUMAN Reactome DB_ID: 349692 UniProt:Q13495 MAMLD1 MAMLD1 CG1 CXorf6 FUNCTION Transactivates the HES3 promoter independently of NOTCH proteins. HES3 is a non-canonical NOTCH target gene which lacks binding sites for RBPJ.TISSUE SPECIFICITY Expressed in fetal brain, fetal ovary and fetal testis. Expressed in adult brain, ovary, skin, testis, uterus. Highly expressed in skeletal muscle.INDUCTION By NR5A1.SIMILARITY Belongs to the mastermind family. UniProt Q13495 1 EQUAL 774 EQUAL Reactome Database ID Release 81 349692 Database 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=349692 Reactome R-HSA-349692 1 Reactome 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-349692.1 Reactome Database ID Release 81 212357 Database 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=212357 Reactome R-HSA-212357 2 Reactome 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-212357.2 Converted from EntitySet in Reactome PCAF Reactome DB_ID: 350078 PCAF KAT2B PCAF_HUMAN Histone acetyltransferase PCAF Reactome DB_ID: 352430 UniProt:Q92831 KAT2B KAT2B PCAF FUNCTION Functions as a histone acetyltransferase (HAT) to promote transcriptional activation (PubMed:8945521). Has significant histone acetyltransferase activity with core histones (H3 and H4), and also with nucleosome core particles (PubMed:8945521). Also acetylates non-histone proteins, such as ACLY, MAPRE1/EB1, PLK4, RRP9/U3-55K and TBX5 (PubMed:9707565, PubMed:10675335, PubMed:23001180, PubMed:27796307, PubMed:23932781, PubMed:26867678, PubMed:29174768). Inhibits cell-cycle progression and counteracts the mitogenic activity of the adenoviral oncoprotein E1A (PubMed:8684459). Acts as a circadian transcriptional coactivator which enhances the activity of the circadian transcriptional activators: NPAS2-ARNTL/BMAL1 and CLOCK-ARNTL/BMAL1 heterodimers (PubMed:14645221). Involved in heart and limb development by mediating acetylation of TBX5, acetylation regulating nucleocytoplasmic shuttling of TBX5 (PubMed:29174768). Acts as a negative regulator of centrosome amplification by mediating acetylation of PLK4 (PubMed:27796307). Acetylates RRP9/U3-55K, a core subunit of the U3 snoRNP complex, impairing pre-rRNA processing (PubMed:26867678). Acetylates MAPRE1/EB1, promoting dynamic kinetochore-microtubule interactions in early mitosis (PubMed:23001180). Also acetylates spermidine (PubMed:27389534).FUNCTION (Microbial infection) In case of HIV-1 infection, it is recruited by the viral protein Tat. Regulates Tat's transactivating activity and may help inducing chromatin remodeling of proviral genes.ACTIVITY REGULATION Activated in vitro by very low concentrations of spermidine, but inhibited at spermidine concentrations higher than 4 uM. The activating effect of low spermidine concentrations may be mediated by N(8)-acetylspermidine produced by KAT2B/P/CAF itself acting as a positive feedback loop.SUBUNIT Interacts with SIRT1. Interacts (unsumoylated form) with NR2C1; the interaction promotes transactivation activity (By similarity). Interacts with EP300, CREBBP and DDX17. Interacts with NCOA1 and NCOA3. Component of a large chromatin remodeling complex, at least composed of MYSM1, KAT2B/PCAF, RBM10 and KIF11/TRIP5. Interacts with NR2C2 (hypophosphorylated and unsumoylated form); the interaction promotes the transactivation activity of NR2C2. Interacts with KLF1; the interaction does not acetylate KLF1 and there is no enhancement of its transactivational activity. Interacts with NFE4. Interacts with MECOM. Interacts with E2F1; the interaction acetylates E2F1 augmenting its DNA-binding and transcriptional activity. Interacts with NPAS2, ARNTL/BMAL1 and CLOCK. Interacts with BCAS3. Interacts with CEBPB (PubMed:17301242). Interacts with NR4A3 (By similarity). Interacts with NFATC2 (By similarity). Interacts with TBX5 (PubMed:29174768). Interacts with PLK4 (PubMed:27796307). Interacts with RB1; this interaction leads to RB1 acetylation (By similarity).SUBUNIT (Microbial infection) Interacts with and acetylates HIV-1 Tat.SUBUNIT (Microbial infection) Interacts with HTLV-1 Tax.TISSUE SPECIFICITY Ubiquitously expressed but most abundant in heart and skeletal muscle. Also expressed in the skin, in keratinocytes (at protein level) (PubMed:20940255).DEVELOPMENTAL STAGE Up-regulated during keratinocyte differentiation (at protein level).DOMAIN (Microbial infection) The bromodomain mediates binding to HIV-1 Tat.DISEASE Defects in KAT2B has been found in a patient with isolated coloboma, a defect of the eye characterized by the absence of ocular structures due to abnormal morphogenesis of the optic cup and stalk, and the fusion of the fetal fissure (optic fissure). Isolated colobomas may be associated with an abnormally small eye (microphthalmia) or small cornea.SIMILARITY Belongs to the acetyltransferase family. GCN5 subfamily. UniProt Q92831 1 EQUAL 832 EQUAL Reactome Database ID Release 81 352430 Database 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=352430 Reactome R-HSA-352430 1 Reactome 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-352430.1 GCN5 KAT2A Histone acetyltransferase KAT2A KAT2A_HUMAN Reactome DB_ID: 3006516 UniProt:Q92830 KAT2A KAT2A GCN5 GCN5L2 FUNCTION Protein lysine acyltransferase that can act as a acetyltransferase, glutaryltransferase or succinyltransferase, depending on the context (PubMed:29211711). Acts as a histone lysine succinyltransferase: catalyzes succinylation of histone H3 on 'Lys-79' (H3K79succ), with a maximum frequency around the transcription start sites of genes (PubMed:29211711). Succinylation of histones gives a specific tag for epigenetic transcription activation (PubMed:29211711). Association with the 2-oxoglutarate dehydrogenase complex, which provides succinyl-CoA, is required for histone succinylation (PubMed:29211711). In different complexes, functions either as an acetyltransferase (HAT) or as a succinyltransferase: in the SAGA and ATAC complexes, acts as a histone acetyltransferase (PubMed:17301242, PubMed:19103755, PubMed:29211711). Has significant histone acetyltransferase activity with core histones, but not with nucleosome core particles (PubMed:17301242, PubMed:19103755). Acetylation of histones gives a specific tag for epigenetic transcription activation (PubMed:17301242, PubMed:19103755, PubMed:29211711). Recruited by the XPC complex at promoters, where it specifically mediates acetylation of histone variant H2A.Z.1/H2A.Z, thereby promoting expression of target genes (PubMed:29973595, PubMed:31527837). Involved in long-term memory consolidation and synaptic plasticity: acts by promoting expression of a hippocampal gene expression network linked to neuroactive receptor signaling (By similarity). Acts as a positive regulator of T-cell activation: upon TCR stimulation, recruited to the IL2 promoter following interaction with NFATC2 and catalyzes acetylation of histone H3 at 'Lys-9' (H3K9ac), leading to promote IL2 expression (By similarity). Required for growth and differentiation of craniofacial cartilage and bone by regulating acetylation of histone H3 at 'Lys-9' (H3K9ac) (By similarity). Regulates embryonic stem cell (ESC) pluripotency and differentiation (By similarity). Also acetylates non-histone proteins, such as CEBPB, PLK4 and TBX5 (PubMed:17301242, PubMed:27796307, PubMed:29174768). Involved in heart and limb development by mediating acetylation of TBX5, acetylation regulating nucleocytoplasmic shuttling of TBX5 (PubMed:29174768). Acts as a negative regulator of centrosome amplification by mediating acetylation of PLK4 (PubMed:27796307). Also acts as a histone glutaryltransferase: catalyzes glutarylation of histone H4 on 'Lys-91' (H4K91glu), a mark that destabilizes nucleosomes by promoting dissociation of the H2A-H2B dimers from nucleosomes (PubMed:31542297).FUNCTION (Microbial infection) In case of HIV-1 infection, it is recruited by the viral protein Tat. Regulates Tat's transactivating activity and may help inducing chromatin remodeling of proviral genes.SUBUNIT Homooligomer; may form a tetramer of homodimers (PubMed:30109122). Interacts with EP300, CREBBP and ADA2. Component of the TFTC-HAT complex, at least composed of TAF5L, TAF6L, TAF3, TADA3L, SUPT3H/SPT3, TAF2/TAFII150, TAF4/TAFII135, TAF5/TAFII100, KAT2A/GCN5L2, TAF10 and TRRAP (PubMed:10373431, PubMed:10611234, PubMed:11438666). Component of the STAGA transcription coactivator-HAT complex, at least composed of SUPT3H, KAT2A, SUPT7L, TAF5L, TAF6L, TADA3L, TAD1L, TAF10, TAF12, TRRAP and TAF9 (PubMed:18206972). The STAGA core complex is associated with a subcomplex required for histone deubiquitination composed of ATXN7L3, ENY2 and USP22 (PubMed:18206972). Component of the ADA2A-containing complex (ATAC), composed of KAT14, KAT2A, TADA2L, TADA3L, ZZ3, MBIP, WDR5, YEATS2, CCDC101 and DR1 (PubMed:19103755). In the complex, it probably interacts directly with KAT14, MBIP and WDR5 (PubMed:19103755). Interacts with PML (By similarity). Interacts with CEBPB (PubMed:17301242). Interacts with TACC1, TACC2 and TACC3 (PubMed:14767476). Interacts with RELA (By similarity). Interacts with NFATC2 (By similarity). Interacts with TBX5 (PubMed:29174768). Interacts with PLK4 (PubMed:27796307). Associates with the 2-oxoglutarate dehydrogenase complex (PubMed:29211711). Interacts with XPC; leading to KAT2A recruitment to promoters and subsequent acetylation of histones (PubMed:29973595, PubMed:31527837). Interacts with ERCC3/XPB; leading to KAT2A recruitment to promoters and subsequent acetylation of histones (PubMed:30894545).SUBUNIT (Microbial infection) Interacts with and acetylates HIV-1 Tat.TISSUE SPECIFICITY Expressed in all tissues tested, with most abundant expression in ovary.DOMAIN Loop3 is required for substrate specificity and adopts different structural conformations in succinyl-CoA-bound and acetyl-CoA-bound forms. Tyr-645 has an important role in the selective binding of succinyl-CoA over acetyl-CoA.SIMILARITY Belongs to the acetyltransferase family. GCN5 subfamily.CAUTION According to a report, has weak protein acyltransferase activity compared to protein acetyltransferase activity (PubMed:27377381). These conclusions are however not supported by subsequent studies (PubMed:29211711, PubMed:31542297). UniProt Q92830 1 EQUAL 837 EQUAL Reactome Database ID Release 81 3006516 Database 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=3006516 Reactome R-HSA-3006516 1 Reactome 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-3006516.1 Reactome Database ID Release 81 350078 Database 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=350078 Reactome R-HSA-350078 1 Reactome 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-350078.1 p300 EP300 Histone acetyltransferase p300 EP300_HUMAN KAT3B Reactome DB_ID: 381325 UniProt:Q09472 EP300 EP300 P300 FUNCTION Functions as histone acetyltransferase and regulates transcription via chromatin remodeling (PubMed:23415232, PubMed:23934153, PubMed:8945521). Acetylates all four core histones in nucleosomes. Histone acetylation gives an epigenetic tag for transcriptional activation (PubMed:23415232, PubMed:23934153, PubMed:8945521). Mediates cAMP-gene regulation by binding specifically to phosphorylated CREB protein. Mediates acetylation of histone H3 at 'Lys-122' (H3K122ac), a modification that localizes at the surface of the histone octamer and stimulates transcription, possibly by promoting nucleosome instability. Mediates acetylation of histone H3 at 'Lys-27' (H3K27ac) (PubMed:23911289). Also functions as acetyltransferase for non-histone targets, such as ALX1, HDAC1, PRMT1 or SIRT2 (PubMed:12929931, PubMed:16762839, PubMed:18722353). Acetylates 'Lys-131' of ALX1 and acts as its coactivator (PubMed:12929931). Acetylates SIRT2 and is proposed to indirectly increase the transcriptional activity of p53/TP53 through acetylation and subsequent attenuation of SIRT2 deacetylase function (PubMed:18722353). Following DNA damage, forms a stress-responsive p53/TP53 coactivator complex with JMY which mediates p53/TP53 acetylation, thereby increasing p53/TP53-dependent transcription and apoptosis (PubMed:11511361, PubMed:15448695). Promotes chromatin acetylation in heat shock responsive HSP genes during the heat shock response (HSR), thereby stimulating HSR transcription (PubMed:18451878). Acetylates HDAC1 leading to its inactivation and modulation of transcription (PubMed:16762839). Acetylates 'Lys-247' of EGR2 (By similarity). Acts as a TFAP2A-mediated transcriptional coactivator in presence of CITED2 (PubMed:12586840). Plays a role as a coactivator of NEUROD1-dependent transcription of the secretin and p21 genes and controls terminal differentiation of cells in the intestinal epithelium. Promotes cardiac myocyte enlargement. Can also mediate transcriptional repression. Acetylates FOXO1 and enhances its transcriptional activity (PubMed:15890677). Acetylates BCL6 wich disrupts its ability to recruit histone deacetylases and hinders its transcriptional repressor activity (PubMed:12402037). Participates in CLOCK or NPAS2-regulated rhythmic gene transcription; exhibits a circadian association with CLOCK or NPAS2, correlating with increase in PER1/2 mRNA and histone H3 acetylation on the PER1/2 promoter (PubMed:14645221). Acetylates MTA1 at 'Lys-626' which is essential for its transcriptional coactivator activity (PubMed:16617102). Acetylates XBP1 isoform 2; acetylation increases protein stability of XBP1 isoform 2 and enhances its transcriptional activity (PubMed:20955178). Acetylates PCNA; acetylation promotes removal of chromatin-bound PCNA and its degradation during nucleotide excision repair (NER) (PubMed:24939902). Acetylates MEF2D (PubMed:21030595). Acetylates and stabilizes ZBTB7B protein by antagonizing ubiquitin conjugation and degradation, this mechanism may be involved in CD4/CD8 lineage differentiation (PubMed:20810990). Acetylates GABPB1, impairing GABPB1 heterotetramerization and activity (By similarity). Acetylates PCK1 and promotes PCK1 anaplerotic activity (PubMed:30193097). Acetylates RXRA and RXRG (PubMed:17761950). In addition to protein acetyltransferase, can use different acyl-CoA substrates, such as (2E)-butenoyl-CoA (crotonyl-CoA), butanoyl-CoA (butyryl-CoA), 2-hydroxyisobutanoyl-CoA (2-hydroxyisobutyryl-CoA), lactoyl-CoA or propanoyl-CoA (propionyl-CoA), and is able to mediate protein crotonylation, butyrylation, 2-hydroxyisobutyrylation, lactylation or propionylation, respectively (PubMed:17267393, PubMed:25818647, PubMed:29775581, PubMed:31645732). Acts as a histone crotonyltransferase; crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors (PubMed:25818647). Histone crotonyltransferase activity is dependent on the concentration of (2E)-butenoyl-CoA (crotonyl-CoA) substrate and such activity is weak when (2E)-butenoyl-CoA (crotonyl-CoA) concentration is low (PubMed:25818647). Also acts as a histone butyryltransferase; butyrylation marks active promoters (PubMed:17267393). Catalyzes histone lactylation in macrophages by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription (PubMed:31645732). Acts as a protein-lysine 2-hydroxyisobutyryltransferase; regulates glycolysis by mediating 2-hydroxyisobutyrylation of glycolytic enzymes (PubMed:29775581). Functions as a transcriptional coactivator for SMAD4 in the TGF-beta signaling pathway (PubMed:25514493).FUNCTION (Microbial infection) In case of HIV-1 infection, it is recruited by the viral protein Tat. Regulates Tat's transactivating activity and may help inducing chromatin remodeling of proviral genes. Binds to and may be involved in the transforming capacity of the adenovirus E1A protein.SUBUNIT Interacts with HIF1A; the interaction is stimulated in response to hypoxia and inhibited by CITED2 (PubMed:9887100, PubMed:11959990). Probably part of a complex with HIF1A and CREBBP (PubMed:8917528). Interacts (via N-terminus) with TFAP2A (via N-terminus); the interaction requires CITED2 (PubMed:12586840). Interacts (via CH1 domain) with CITED2 (via C-terminus) (PubMed:12586840, PubMed:12778114). Interacts with CITED1 (unphosphorylated form preferentially and via C-terminus) (PubMed:10722728, PubMed:16864582). Interacts with ESR1; the interaction is estrogen-dependent and enhanced by CITED1 (PubMed:11581164). Interacts with HIPK2 (By similarity). Interacts with DTX1, EID1, ELF3, FEN1, LEF1, NCOA1, NCOA6, NR3C1, PCAF, PELP1, PRDM6, SP1, SP3, SPIB, SRY, TCF7L2, DDX5, DDX17, SATB1, SRCAP and TRERF1 (PubMed:11073989, PubMed:11073990, PubMed:10823961, PubMed:11349124, PubMed:11430825, PubMed:11481323, PubMed:11564735, PubMed:11581372, PubMed:11864910, PubMed:12446687, PubMed:12527917, PubMed:12837748, PubMed:14605447, PubMed:15075319, PubMed:15297880, PubMed:16478997, PubMed:8684459, PubMed:17226766, PubMed:9590696). Interacts with JMY, the complex activates p53/TP53 transcriptional activity (PubMed:10518217, PubMed:11511361). Interacts with TTC5/STRAP; the interaction facilitates the association between JMY and p300/EP300 cofactors (PubMed:11511361). Interacts with p53/TP53; the interation is facilitated by TTC5/STRAP (PubMed:15186775, PubMed:15448695, PubMed:19217391). Forms a complex with TTC5/STRAP and HSF1; these interactions augment chromatin-bound HSF1 and p300/EP300 histone acetyltransferase activity (PubMed:18451878). Part of a complex containing CARM1 and NCOA2/GRIP1 (PubMed:11701890, PubMed:11997499, PubMed:15731352). Interacts with ING4 and this interaction may be indirect (PubMed:12750254). Interacts with ING5 (PubMed:12750254). Interacts with the C-terminal region of CITED4 (PubMed:11744733). Non-sumoylated EP300 preferentially interacts with SENP3 (PubMed:19680224). Interacts with SS18L1/CREST (PubMed:14716005). Interacts with ALX1 (via homeobox domain) (PubMed:12929931). Interacts with NEUROD1; the interaction is inhibited by NR0B2 (PubMed:14752053). Interacts with TCF3 (PubMed:14752053). Interacts (via CREB-binding domain) with MYOCD (via C-terminus) (By similarity). Interacts with ROCK2 and PPARG (PubMed:11518699, PubMed:16574662). Forms a complex made of CDK9, CCNT1/cyclin-T1, EP300 and GATA4 that stimulates hypertrophy in cardiomyocytes (PubMed:20081228). Interacts with IRF1 and this interaction enhances acetylation of p53/TP53 and stimulation of its activity (PubMed:15509808). Interacts with FOXO1; the interaction acetylates FOXO1 and enhances its transcriptional activity (PubMed:15890677). Interacts with ALKBH4 and DDIT3/CHOP (PubMed:17872950, PubMed:23145062). Interacts with KLF15 (PubMed:23999430). Interacts with CEBPB and RORA (PubMed:9862959). Interacts with NPAS2, ARNTL/BMAL1 and CLOCK (PubMed:14645221). Interacts with SIRT2 isoform 1, isoform 2 and isoform 5 (PubMed:24177535). Interacts with MTA1 (PubMed:16617102). Interacts with HDAC4 and HDAC5 in the presence of TFAP2C (PubMed:24413532). Interacts with TRIP4 (PubMed:25219498). Directly interacts with ZBTB49; this interaction leads to synergistic transactivation of CDKN1A (PubMed:25245946). Interacts with NR4A3 (By similarity). Interacts with ZNF451 (PubMed:24324267). Interacts with ATF5; EP300 is required for ATF5 and CEBPB interaction and DNA binding (By similarity). Interacts with HSF1 (PubMed:27189267). Interacts with ZBTB48/TZAP (PubMed:24382891). Interacts with STAT1; the interaction is enhanced upon IFN-gamma stimulation (PubMed:26479788). Interacts with HNRNPU (via C-terminus); this interaction enhances DNA-binding of HNRNPU to nuclear scaffold/matrix attachment region (S/MAR) elements (PubMed:11909954). Interacts with BCL11B (PubMed:27959755, PubMed:16809611). Interacts with SMAD4; negatively regulated by ZBTB7A (PubMed:25514493). Interacts with DUX4 (via C-terminus) (PubMed:26951377). Interacts with NUPR1; this interaction enhances the effect of EP300 on PAX2 transcription factor activity (PubMed:11940591). Interacts with RXRA; the interaction is decreased by 9-cis retinoic acid (PubMed:17761950). NR4A1 competes with EP300 for interaction with RXRA and thereby attenuates EP300 mediated acetylation of RXRA (PubMed:17761950). Interacts with RB1 (By similarity). Interacts with DDX3X; this interaction may facilitate HNF4A acetylation (PubMed:28128295). Interacts with SOX9 (PubMed:12732631). Interacts with ATF4; EP300/p300 stabilizes ATF4 and increases its transcriptional activity independently of its catalytic activity by preventing its ubiquitination (PubMed:16219772). Interacts with KAT5; promoting KAT5 autoacetylation (PubMed:24835996).SUBUNIT (Microbial infection) Interacts with human adenovirus 5 E1A protein; this interaction stimulates the acetylation of RB1 by recruiting EP300 and RB1 into a multimeric-protein complex.SUBUNIT (Microbial infection) Interacts with and acetylates HIV-1 Tat.SUBUNIT (Microbial infection) Interacts with HTLV-1 proteins Tax, p30II and HBZ.DOMAIN The CRD1 domain (cell cycle regulatory domain 1) mediates transcriptional repression of a subset of p300 responsive genes; it can be de-repressed by CDKN1A/p21WAF1 at least at some promoters. It conatins sumoylation and acetylation sites and the same lysine residues may be targeted for the respective modifications. It is proposed that deacetylation by SIRT1 allows sumoylation leading to suppressed activity.PTM Acetylated on Lys at up to 17 positions by intermolecular autocatalysis. Deacetylated in the transcriptional repression domain (CRD1) by SIRT1, preferentially at Lys-1020. Deacetylated by SIRT2, preferentially at Lys-418, Lys-423, Lys-1542, Lys-1546, Lys-1549, Lys-1699, Lys-1704 and Lys-1707.PTM Citrullinated at Arg-2142 by PADI4, which impairs methylation by CARM1 and promotes interaction with NCOA2/GRIP1.PTM Methylated at Arg-580 and Arg-604 in the KIX domain by CARM1, which blocks association with CREB, inhibits CREB signaling and activates apoptotic response. Also methylated at Arg-2142 by CARM1, which impairs interaction with NCOA2/GRIP1.PTM Sumoylated; sumoylation in the transcriptional repression domain (CRD1) mediates transcriptional repression. Desumoylated by SENP3 through the removal of SUMO2 and SUMO3.PTM Probable target of ubiquitination by FBXO3, leading to rapid proteasome-dependent degradation.PTM Phosphorylated by HIPK2 in a RUNX1-dependent manner. This phosphorylation that activates EP300 happens when RUNX1 is associated with DNA and CBFB. Phosphorylated by ROCK2 and this enhances its activity. Phosphorylation at Ser-89 by AMPK reduces interaction with nuclear receptors, such as PPARG.DISEASE Defects in EP300 may play a role in epithelial cancer.DISEASE Chromosomal aberrations involving EP300 may be a cause of acute myeloid leukemias. Translocation t(8;22)(p11;q13) with KAT6A. UniProt Q09472 2 EQUAL 2414 EQUAL Reactome Database ID Release 81 381325 Database 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=381325 Reactome R-HSA-381325 1 Reactome 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-381325.1 NOTCH1 PEST Domain Mutants Coactivator Complex Reactome DB_ID: 2220989 1 1 1 1 1 Reactome Database ID Release 81 2220989 Database 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=2220989 Reactome R-HSA-2220989 1 Reactome 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-2220989.1 Reactome Database ID Release 81 2220964 Database 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=2220964 Reactome R-HSA-2220964 2 Reactome 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-2220964.2 16530044 Pubmed 2006 Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes Nam, Y Sliz, P Song, L Aster, JC Blacklow, SC Cell 124:973-83 12391150 Pubmed 2002 p300 and PCAF act cooperatively to mediate transcriptional activation from chromatin templates by notch intracellular domains in vitro Wallberg, AE Pedersen, K Lendahl, U Roeder, RG Mol Cell Biol 22:7812-9 12050117 Pubmed 2002 Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex Fryer, CJ Lamar, E Turbachova, I Kintner, C Jones, KA Genes Dev 16:1397-411 LEFT-TO-RIGHT NOTCH1 PEST domain mutants bind HES1 promoter NICD1 PEST domain mutants-containing coactivator complexes are expected to bind HES1 promoter in a similar manner to the wild-type NOTCH1 Coactivator Complex (Jarriault et al. 1995). Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 HES1 gene Reactome DB_ID: 2197548 ENSEMBL:ENSG00000114315 HES1 HES1 BHLHB39 HL HRY ENSEMBL ENSG00000114315 Reactome Database ID Release 81 2197548 Database 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=2197548 Reactome R-HSA-2197548 2 Reactome 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-2197548.2 NOTCH1 PEST Domain Mutants Coactivator Complex:HES1 Gene Reactome DB_ID: 4396396 1 1 Reactome Database ID Release 81 4396396 Database 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=4396396 Reactome R-HSA-4396396 1 Reactome 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-4396396.1 Reactome Database ID Release 81 4396392 Database 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=4396392 Reactome R-HSA-4396392 2 Reactome 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-4396392.2 7566092 Pubmed 1995 Signalling downstream of activated mammalian Notch Jarriault, S Brou, C Logeat, F Schroeter, EH Kopan, R Israel, A Nature 377:355-8 LEFT-TO-RIGHT NOTCH1 PEST domain mutants stimulate HES1 transcription NICD1 PEST domain mutants are expected to stimulate HES1 transcription in a similar manner to wild-type NICD1 (Jarriault et al. 1995). Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 HES1 Hairy and enhancer of split 1 Transcription factor HES-1 Reactome DB_ID: 210825 UniProt:Q14469 HES1 HES1 BHLHB39 HL HRY FUNCTION Transcriptional repressor of genes that require a bHLH protein for their transcription. May act as a negative regulator of myogenesis by inhibiting the functions of MYOD1 and ASH1. Binds DNA on N-box motifs: 5'-CACNAG-3' with high affinity and on E-box motifs: 5'-CANNTG-3' with low affinity (By similarity). May play a role in a functional FA core complex response to DNA cross-link damage, being required for the stability and nuclear localization of FA core complex proteins, as well as for FANCD2 monoubiquitination in response to DNA damage.SUBUNIT Transcription repression requires formation of a complex with a corepressor protein of the Groucho/TLE family. Interacts (via WPRW motif) with TLE1, and more weakly with TLE2. Interacts with HES6 (By similarity). Interacts with SIRT1. Interacts with an FA complex, composed of FANCA, FANCF, FANCG and FANCL, but not of FANCC, nor FANCE.DOMAIN Has a particular type of basic domain (presence of a helix-interrupting proline) that binds to the N-box (CACNAG), rather than the canonical E-box (CANNTG).DOMAIN The C-terminal WRPW motif is a transcriptional repression domain necessary for the interaction with Groucho/TLE family members, transcriptional corepressors recruited to specific target DNA by Hairy-related proteins.DOMAIN The bHLH, as well as cooperation between the central Orange domain and the C-terminal WRPW motif, is required for transcriptional repressor activity. UniProt Q14469 1 EQUAL 280 EQUAL Reactome Database ID Release 81 210825 Database 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=210825 Reactome R-HSA-210825 1 Reactome 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-210825.1 Reactome Database ID Release 81 2220979 Database 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=2220979 Reactome R-HSA-2220979 3 Reactome 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-2220979.3 ACTIVATION activeUnit: #Complex23 Reactome Database ID Release 81 2220991 Database 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=2220991 Reactome R-HSA-2220991 1 Reactome 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-2220991.1 LEFT-TO-RIGHT NOTCH1 PEST domain mutants bind HES5 promoter NICD1 PEST domain mutants coactivator complexes are expected to bind HES5 promoter in a similar manner to the wild-type NOTCH1 Coactivator Complex (Arnett et al. 2010). Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 HES5 gene Reactome DB_ID: 2197557 ENSEMBL:ENSG00000197921 HES5 HES5 BHLHB38 ENSEMBL ENSG00000197921 Reactome Database ID Release 81 2197557 Database 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=2197557 Reactome R-HSA-2197557 2 Reactome 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-2197557.2 NOTCH1 PEST Domain Mutants Coactivator Complex:HES5 Gene Reactome DB_ID: 4396397 1 1 Reactome Database ID Release 81 4396397 Database 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=4396397 Reactome R-HSA-4396397 1 Reactome 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-4396397.1 Reactome Database ID Release 81 4396401 Database 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=4396401 Reactome R-HSA-4396401 2 Reactome 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-4396401.2 20972443 Pubmed 2010 Structural and mechanistic insights into cooperative assembly of dimeric Notch transcription complexes Arnett, KL Hass, M McArthur, DG Ilagan, Ma Xenia Aster, JC Kopan, R Blacklow, SC Nat Struct Mol Biol 17:1312-7 LEFT-TO-RIGHT NOTCH1 PEST domain mutants stimulate HES5 transcription NICD1 PEST domain mutants are expected to stimulate HES5 transcription in a similar manner to wild-type NICD1 (Arnett et al. 2010). Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 HES5 Transcription factor HES-5 Class B basic helix-loop-helix protein 38 Hairy and enhancer of split 5 BHLHB38 Reactome DB_ID: 1606739 UniProt:Q5TA89 HES5 HES5 BHLHB38 FUNCTION Transcriptional repressor of genes that require a bHLH protein for their transcription. Plays an important role as neurogenesis negative regulator (By similarity).SUBUNIT Transcription repression requires formation of a complex with a corepressor protein of the Groucho/TLE family.TISSUE SPECIFICITY Expressed in fetal heart and brain tumors.DOMAIN Has a particular type of basic domain (presence of a helix-interrupting proline) that binds to the N-box (CACNAG), rather than the canonical E-box (CANNTG).DOMAIN The C-terminal WRPW motif is a transcriptional repression domain necessary for the interaction with Groucho/TLE family members, transcriptional corepressors recruited to specific target DNA by Hairy-related proteins. UniProt Q5TA89 1 EQUAL 166 EQUAL Reactome Database ID Release 81 1606739 Database 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=1606739 Reactome R-HSA-1606739 1 Reactome 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-1606739.1 Reactome Database ID Release 81 2220966 Database 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=2220966 Reactome R-HSA-2220966 3 Reactome 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-2220966.3 ACTIVATION activeUnit: #Complex23 Reactome Database ID Release 81 2220983 Database 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=2220983 Reactome R-HSA-2220983 1 Reactome 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-2220983.1 LEFT-TO-RIGHT NOTCH1 PEST domain mutants bind promoters of HEY genes NICD1 PEST domain mutant coactivator complexes are expected to bind promoters of HEY genes (HEY1, HEY2 and HEYL) in a similar manner to the wild-type NOTCH1 Coactivator Complex (Maier and Gessler 2000, Arnett et al. 2010). Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 Converted from EntitySet in Reactome HEY Genes Reactome DB_ID: 4396360 HEY1 gene Reactome DB_ID: 4396358 ENSEMBL:ENSG00000164683 HEY1 HEY1 BHLHB31 CHF2 HERP2 HESR1 HRT1 ENSEMBL ENSG00000164683 Reactome Database ID Release 81 4396358 Database 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=4396358 Reactome R-HSA-4396358 2 Reactome 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-4396358.2 HEY2 gene Reactome DB_ID: 4396355 ENSEMBL:ENSG00000135547 HEY2 HEY2 BHLHB32 CHF1 GRL HERP HERP1 HRT2 ENSEMBL ENSG00000135547 Reactome Database ID Release 81 4396355 Database 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=4396355 Reactome R-HSA-4396355 2 Reactome 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-4396355.2 HEYL Gene Reactome DB_ID: 4396348 ENSEMBL:ENSG00000163909 HEYL HEYL BHLHB33 HRT3 ENSEMBL ENSG00000163909 Reactome Database ID Release 81 4396348 Database 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=4396348 Reactome R-HSA-4396348 1 Reactome 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-4396348.1 Reactome Database ID Release 81 4396360 Database 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=4396360 Reactome R-HSA-4396360 1 Reactome 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-4396360.1 NOTCH1 PEST Domain Mutants Coactivator Complex:HEY Genes Reactome DB_ID: 4396391 1 1 Reactome Database ID Release 81 4396391 Database 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=4396391 Reactome R-HSA-4396391 1 Reactome 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-4396391.1 Reactome Database ID Release 81 4396402 Database 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=4396402 Reactome R-HSA-4396402 2 Reactome 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-4396402.2 10964718 Pubmed 2000 Comparative analysis of the human and mouse Hey1 promoter: Hey genes are new Notch target genes Maier, MM Gessler, M Biochem Biophys Res Commun 275:652-60 LEFT-TO-RIGHT NOTCH1 PEST domain mutants stimulate HEY transcription NICD1 PEST domain mutants are expected to stimulate transcription of HEY genes (HEY1, HEY2 and HEYL) in a similar manner to wild-type NICD1 (Fischer et al. 2004, Leimeister et al. 2000, Maier et al. 2000, Arnett et al. 2010). Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 Converted from EntitySet in Reactome HEY Reactome DB_ID: 1911450 HEY1 Hairy/enhancer-of-split related with YRPW motif protein 1 Cardiovascular helix-loop-helix factor 2 Class B basic helix-loop-helix protein 31 HES-related repressor protein 1 Hairy and enhancer of split-related protein 1 Hairy-related transcription factor 1 BHLHB31 CHF2 HERP2 HESR1 HRT1 Reactome DB_ID: 1606744 UniProt:Q9Y5J3 HEY1 HEY1 BHLHB31 CHF2 HERP2 HESR1 HRT1 FUNCTION Transcriptional repressor which binds preferentially to the canonical E box sequence 5'-CACGTG-3' (PubMed:11095750). Downstream effector of Notch signaling required for cardiovascular development. Specifically required for the Notch-induced endocardial epithelial to mesenchymal transition, which is itself criticial for cardiac valve and septum development. May be required in conjunction with HEY2 to specify arterial cell fate or identity. Promotes maintenance of neuronal precursor cells and glial versus neuronal fate specification. Represses transcription by the cardiac transcriptional activators GATA4 and GATA6 and by the neuronal bHLH factors ASCL1/MASH1 and NEUROD4/MATH3 (PubMed:15485867). Involved in the regulation of liver cancer cells self-renewal (PubMed:25985737).SUBUNIT Self-associates. Interacts with HES1 and HEYL. Interacts with HDAC1, NCOR1 and SIN3A. Interacts with GATA4 and GATA6. Interacts with CCDC89/BOIP.TISSUE SPECIFICITY Expressed in the somitic mesoderm, the central nervous system, the kidney, the heart, nasal epithelium, and limbs.SIMILARITY Belongs to the HEY family. UniProt Q9Y5J3 1 EQUAL 304 EQUAL Reactome Database ID Release 81 1606744 Database 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=1606744 Reactome R-HSA-1606744 1 Reactome 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-1606744.1 GRL HEY2 Hairy/enhancer-of-split related with YRPW motif protein 2 Cardiovascular helix-loop-helix factor 1 Class B basic helix-loop-helix protein 32 HES-related repressor protein 2 Hairy and enhancer of split-related protein 2 Hairy-related transcription factor 2 BHLHB32 CHF1 HERP HERP1 HRT2 Reactome DB_ID: 1606745 UniProt:Q9UBP5 HEY2 HEY2 BHLHB32 CHF1 GRL HERP HERP1 HRT2 FUNCTION Downstream effector of Notch signaling which may be required for cardiovascular development. Transcriptional repressor which binds preferentially to the canonical E box sequence 5'-CACGTG-3'. Represses transcription by the cardiac transcriptional activators GATA4 and GATA6.SUBUNIT May self-associate (By similarity). Interacts with GATA4, HES1 and HEYL (By similarity). Interacts with HDAC1, NCOR1 and SIN3A (By similarity). Interacts with ARNT and GATA6.SIMILARITY Belongs to the HEY family. UniProt Q9UBP5 1 EQUAL 337 EQUAL Reactome Database ID Release 81 1606745 Database 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=1606745 Reactome R-HSA-1606745 1 Reactome 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-1606745.1 HEYL Hairy/enhancer-of-split related with YRPW motif-like protein Class B basic helix-loop-helix protein 33 Hairy-related transcription factor 3 BHLHB33 HRT3 Reactome DB_ID: 1606748 UniProt:Q9NQ87 HEYL HEYL BHLHB33 HRT3 FUNCTION Downstream effector of Notch signaling which may be required for cardiovascular development (By similarity). Transcriptional repressor which binds preferentially to the canonical E box sequence 5'-CACGTG-3' (By similarity). Represses transcription by the cardiac transcriptional activators GATA4 and GATA6.SUBUNIT Self-associates. Interacts with GATA4, GATA6, HES1, HEY1 and HEY2. Interacts with HDAC1, NCOR1 and SIN3A.INDUCTION By activation of the Notch signaling pathway.SIMILARITY Belongs to the HEY family. UniProt Q9NQ87 1 EQUAL 328 EQUAL Reactome Database ID Release 81 1606748 Database 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=1606748 Reactome R-HSA-1606748 1 Reactome 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-1606748.1 Reactome Database ID Release 81 1911450 Database 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=1911450 Reactome R-HSA-1911450 1 Reactome 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-1911450.1 Reactome Database ID Release 81 2220981 Database 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=2220981 Reactome R-HSA-2220981 3 Reactome 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-2220981.3 11044625 Pubmed 2000 Analysis of HeyL expression in wild-type and Notch pathway mutant mouse embryos Leimeister, C Schumacher, N Steidl, C Gessler, M Mech Dev 98:175-8 15107403 Pubmed 2004 The Notch target genes Hey1 and Hey2 are required for embryonic vascular development Fischer, A Schumacher, N Maier, M Sendtner, M Gessler, M Genes Dev 18:901-11 ACTIVATION Reactome Database ID Release 81 2220973 Database 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=2220973 Reactome R-HSA-2220973 1 Reactome 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-2220973.1 LEFT-TO-RIGHT NOTCH1 PEST domain mutants bind MYC promoter NICD1 PEST domain mutant coactivator complexes are expected to bind MYC promoter in a similar manner to the wild-type NOTCH1 Coactivator Complex (Palomero et al. 2006). Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 MYC gene MYC gene on chromosome 8 Reactome DB_ID: 2127254 ENSEMBL:ENSG00000136997 MYC MYC BHLHE39 ENSEMBL ENSG00000136997 Reactome Database ID Release 81 2127254 Database 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=2127254 Reactome R-HSA-2127254 2 Reactome 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-2127254.2 NOTCH1 PEST Domain Mutants Coactivator Complex:MYC Gene Reactome DB_ID: 4396404 1 1 Reactome Database ID Release 81 4396404 Database 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=4396404 Reactome R-HSA-4396404 1 Reactome 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-4396404.1 Reactome Database ID Release 81 4396393 Database 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=4396393 Reactome R-HSA-4396393 2 Reactome 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-4396393.2 17114293 Pubmed 2006 NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth Palomero, T Lim, WK Odom, DT Sulis, ML Real, PJ Margolin, A Barnes, KC O'Neil, J Neuberg, D Weng, AP Aster, JC Sigaux, F Soulier, J Look, AT Young, RA Califano, A Ferrando, Adolfo A Proc Natl Acad Sci U S A 103:18261-6 LEFT-TO-RIGHT NOTCH1 PEST domain mutants stimulate MYC transcription NICD1 PEST domain mutants are expected to stimulate MYC transcription in a similar manner to wild-type NICD1 (Palomero et al. 2006). Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 MYC Reactome DB_ID: 188379 UniProt:P01106 MYC MYC BHLHE39 FUNCTION Transcription factor that binds DNA in a non-specific manner, yet also specifically recognizes the core sequence 5'-CAC[GA]TG-3' (PubMed:24940000, PubMed:25956029). Activates the transcription of growth-related genes (PubMed:24940000, PubMed:25956029). Binds to the VEGFA promoter, promoting VEGFA production and subsequent sprouting angiogenesis (PubMed:24940000, PubMed:25956029). Regulator of somatic reprogramming, controls self-renewal of embryonic stem cells (By similarity). Functions with TAF6L to activate target gene expression through RNA polymerase II pause release (By similarity). Positively regulates transcription of HNRNPA1, HNRNPA2 and PTBP1 which in turn regulate splicing of pyruvate kinase PKM by binding repressively to sequences flanking PKM exon 9, inhibiting exon 9 inclusion and resulting in exon 10 inclusion and production of the PKM M2 isoform (PubMed:20010808).SUBUNIT Efficient DNA binding requires dimerization with another bHLH protein. Binds DNA as a heterodimer with MAX (PubMed:9680483). Interacts with TAF1C and SPAG9. Interacts with PARP10. Interacts with KDM5A and KDM5B. Interacts (when phosphorylated at Thr-58 and Ser-62) with FBXW7(PubMed:25775507, PubMed:17558397). Interacts with PIM2. Interacts with RIOX1. The heterodimer MYC:MAX interacts with ABI1; the interaction may enhance MYC:MAX transcriptional activity. Interacts with TRIM6 (By similarity). Interacts with NPM1; the binary complex is recruited to the promoter of MYC target genes and enhances their transcription (PubMed:25956029). Interacts with CIP2A; leading to the stabilization of MYC (PubMed:17632056).DOMAIN The 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.PTM Phosphorylated by PRKDC (PubMed:1597196). Phosphorylation at Ser-329 by PIM2 leads to the stabilization of MYC (By similarity). Phosphorylation at Ser-62 by CDK2 prevents Ras-induced senescence (PubMed:19966300, PubMed:20713526). Phosphorylated at Ser-62 by DYRK2; this primes the protein for subsequent phosphorylation by GSK3B at Thr-58 (PubMed:22307329). Phosphorylation at Thr-58 and Ser-62 by GSK3 is required for ubiquitination and degradation by the proteasome (PubMed:15103331, PubMed:17558397, PubMed:8386367). Dephosphorylation at Ser-62 by protein phosphatase 2A (PPP2CA) promotes its degradation; interaction with PPP2CA is enhanced by AMBRA1 (PubMed:25803737, PubMed:25438055).PTM Ubiquitinated by the SCF(FBXW7) complex when phosphorylated at Thr-58 and Ser-62, leading to its degradation by the proteasome (PubMed:15103331, PubMed:17558397, PubMed:25775507). In the nucleoplasm, ubiquitination is counteracted by USP28, which interacts with isoform 1 of FBXW7 (FBW7alpha), leading to its deubiquitination and preventing degradation (PubMed:17873522, PubMed:17558397). In the nucleolus, however, ubiquitination is not counteracted by USP28 but by USP36, due to the lack of interaction between isoform 3 of FBXW7 (FBW7gamma) and USP28, explaining the selective MYC degradation in the nucleolus (PubMed:17558397, PubMed:25775507). Also polyubiquitinated by the DCX(TRPC4AP) complex (PubMed:20551172, PubMed:29779948). Ubiquitinated by TRIM6 in a phosphorylation-independent manner (By similarity).DISEASE A chromosomal aberration involving MYC may be a cause of a form of B-cell chronic lymphocytic leukemia. Translocation t(8;12)(q24;q22) with BTG1.BIOTECHNOLOGY POU5F1/OCT4, SOX2, MYC/c-Myc and KLF4 are the four Yamanaka factors. When combined, these factors are sufficient to reprogram differentiated cells to an embryonic-like state designated iPS (induced pluripotent stem) cells. iPS cells exhibit the morphology and growth properties of ES cells and express ES cell marker genes. UniProt P01106 1 EQUAL 439 EQUAL Reactome Database ID Release 81 188379 Database 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=188379 Reactome R-HSA-188379 1 Reactome 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-188379.1 Reactome Database ID Release 81 2220985 Database 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=2220985 Reactome R-HSA-2220985 3 Reactome 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-2220985.3 ACTIVATION activeUnit: #Complex23 Reactome Database ID Release 81 2220974 Database 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=2220974 Reactome R-HSA-2220974 1 Reactome 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-2220974.1 LEFT-TO-RIGHT NOTCH1 PEST domain mutants coactivator complex binds CDK8:CCNC MAML is expected to recruit CDK8 to NICD1 PEST domain mutants like it recruits CDK8 to wild-type NICD1 (Fryer et al. 2004). Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 CDK8:CCNC Reactome DB_ID: 1604465 CDK8 Reactome DB_ID: 212440 UniProt:P49336 CDK8 CDK8 FUNCTION Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional pre-initiation complex with RNA polymerase II and the general transcription factors. Phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex. Phosphorylates CCNH leading to down-regulation of the TFIIH complex and transcriptional repression. Recruited through interaction with MAML1 to hyperphosphorylate the intracellular domain of NOTCH, leading to its degradation.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. The cylin/CDK pair formed by CCNC/CDK8 also associates with the large subunit of RNA polymerase II. Interacts with CTNNB1, GLI3 and MAML1.SIMILARITY Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily. UniProt P49336 1 EQUAL 464 EQUAL Reactome Database ID Release 81 212440 Database 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=212440 Reactome R-HSA-212440 1 Reactome 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-212440.1 1 CCNC CycC Reactome DB_ID: 212418 UniProt:P24863 CCNC CCNC FUNCTION Component of the Mediator complex, a coactivator involved in regulated gene transcription of nearly all RNA polymerase II-dependent genes. Mediator functions as a bridge to convey information from gene-specific regulatory proteins to the basal RNA polymerase II transcription machinery. Mediator is recruited to promoters by direct interactions with regulatory proteins and serves as a scaffold for the assembly of a functional preinitiation complex with RNA polymerase II and the general transcription factors. Binds to and activates cyclin-dependent kinase CDK8 that phosphorylates the CTD (C-terminal domain) of the large subunit of RNA polymerase II (RNAp II), which may inhibit the formation of a transcription initiation complex.SUBUNIT Component of the Mediator complex, which is composed of MED1, MED4, MED6, MED7, MED8, MED9, MED10, MED11, MED12, MED13, MED13L, MED14, MED15, MED16, MED17, MED18, MED19, MED20, MED21, MED22, MED23, MED24, MED25, MED26, MED27, MED29, MED30, MED31, CCNC, CDK8 and CDC2L6/CDK11. The MED12, MED13, CCNC and CDK8 subunits form a distinct module termed the CDK8 module. Mediator containing the CDK8 module is less active than Mediator lacking this module in supporting transcriptional activation. Individual preparations of the Mediator complex lacking one or more distinct subunits have been variously termed ARC, CRSP, DRIP, PC2, SMCC and TRAP. The cylin/CDK pair formed by CCNC/CDK8 also associates with the large subunit of RNA polymerase II.TISSUE SPECIFICITY Highest levels in pancreas. High levels in heart, liver, skeletal muscle and kidney. Low levels in brain.SIMILARITY Belongs to the cyclin family. Cyclin C subfamily. UniProt P24863 1 EQUAL 283 EQUAL Reactome Database ID Release 81 212418 Database 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=212418 Reactome R-HSA-212418 1 Reactome 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-212418.1 1 Reactome Database ID Release 81 1604465 Database 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=1604465 Reactome R-HSA-1604465 1 Reactome 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-1604465.1 ComplexPortal CPX-1969 NOTCH1 PEST Domain Mutants Coactivator Complex:CDK8:CCNC Reactome DB_ID: 2220980 1 1 Reactome Database ID Release 81 2220980 Database 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=2220980 Reactome R-HSA-2220980 1 Reactome 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-2220980.1 Reactome Database ID Release 81 2220957 Database 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=2220957 Reactome R-HSA-2220957 2 Reactome 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-2220957.2 15546612 Pubmed 2004 Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover Fryer, CJ White, JB Jones, KA Mol Cell 16:509-20 LEFT-TO-RIGHT 2.7.11.22 CDK8 phosphorylates NICD1 PEST domain mutants While CDK8 can probably phosphorylate the TAD domain of NICD1 PEST domain mutants, it cannot phosphorylate the PEST domain of these mutants as it is partially or completely truncated (Fryer et al. 2004). Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 ATP Adenosine 5'-triphosphate ATP(4-) Reactome DB_ID: 29358 ATP(4-) [ChEBI:30616] ATP(4-) ATP atp Adenosine 5'-triphosphate ChEBI CHEBI:30616 Reactome Database ID Release 81 29358 Database 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=29358 Reactome R-ALL-29358 3 Reactome 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-ALL-29358.3 COMPOUND C00002 Converted from EntitySet in Reactome p-NICD1 PEST domain mutants Reactome DB_ID: 2220958 p-NICD1 P2514Rfs*4 p-NICD1 Pro2514Argfs*3 p-NICD1mutPEST P2514Rfs*4 p-NICD1 PEST domain mutant P2514Rfs*4 Reactome DB_ID: 2159809 O-phospho-L-serine MOD MOD:00046 1755 EQUAL 2516 EQUAL Reactome Database ID Release 81 2159809 Database 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=2159809 Reactome R-HSA-2159809 1 Reactome 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-2159809.1 COSMIC COSV53024776 COSMIC COSM33946 p-NICD1 Q2395* p-NICD1 Gln2395* Reactome DB_ID: 2902205 1754 EQUAL 2394 EQUAL Reactome Database ID Release 81 2902205 Database 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=2902205 Reactome R-HSA-2902205 1 Reactome 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-2902205.1 COSMIC COSV53056886 p-NICD1 Q2440* p-NICD1 Gln2440* Reactome DB_ID: 2902207 1754 EQUAL 2439 EQUAL Reactome Database ID Release 81 2902207 Database 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=2902207 Reactome R-HSA-2902207 1 Reactome 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-2902207.1 COSMIC COSV53024887 p-NICD1 P2474Afs*4 Reactome DB_ID: 2902204 1754 EQUAL 2476 EQUAL Reactome Database ID Release 81 2902204 Database 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=2902204 Reactome R-HSA-2902204 1 Reactome 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-2902204.1 COSMIC COSV53084788 Reactome Database ID Release 81 2220958 Database 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=2220958 Reactome R-HSA-2220958 1 Reactome 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-2220958.1 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 113582 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5'-O-[(phosphonatooxy)phosphinato]adenosine ADP trianion ChEBI CHEBI:456216 Reactome Database ID Release 81 113582 Database 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=113582 Reactome R-ALL-113582 3 Reactome 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-ALL-113582.3 COMPOUND C00008 RBPJ:SNW1 Reactome DB_ID: 1911412 1 1 Reactome Database ID Release 81 1911412 Database 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=1911412 Reactome R-HSA-1911412 1 Reactome 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-1911412.1 ACTIVATION GENE ONTOLOGY GO:0004693 Reactome Database ID Release 81 2220956 Database 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=2220956 Reactome Database ID Release 81 2220971 Database 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=2220971 Reactome R-HSA-2220971 2 Reactome 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-2220971.2 LEFT-TO-RIGHT p-NICD1 PEST domain mutants do not bind FBXW7 As binding of WD40 repeats of FBXW7 requires conserved phosphodegron in the PEST domain of NICD1, especially phosphorylation of threonine residue T2511 and serine residue S2513, FBXW7 cannot bind NICD1 PEST domain mutants which lack the conserved phosphodegron due to truncation of the PEST domain, or are not phosphorylated on conserved threonine and serine residues due to point mutations. Inability to bind FBXW7 and undergo FBXW7-mediated ubiquitination and degradation prolongs the half-life of NICD1 PEST domain mutants and results in persistent NOTCH1 signaling (O'Neil et al. 2007, Thompson et al. 2007). Authored: Orlic-Milacic, M, 2013-01-04 Reviewed: Haw, R, 2013-02-10 Edited: Jassal, B, 2013-01-09 FBXW7:SKP1:CUL1:RBX1 Reactome DB_ID: 1604469 SKP1 Skp1 Reactome DB_ID: 187538 UniProt:P63208 SKP1 SKP1 EMC19 OCP2 SKP1A TCEB1L FUNCTION 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. UniProt P63208 2 EQUAL 163 EQUAL Reactome Database ID Release 81 187538 Database 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=187538 Reactome R-HSA-187538 1 Reactome 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-187538.1 1 CUL1 Cul-1_1 Reactome DB_ID: 187551 UniProt:Q13616 CUL1 CUL1 FUNCTION 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 (PubMed:20596027). Interacts with CCNF (PubMed:26818844). 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 UBE2M (PubMed:21940857). 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). Part of a complex that contains DCUN1D5, CUL1 and RBX1; this complex is bridged by CUL1 (PubMed:24192928). Interacts (unneddylated form) with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5; these interactions promote the cullin neddylation (PubMed:24192928, PubMed:26906416, PubMed:23201271, PubMed:21940857, PubMed:25349211, PubMed:28581483).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. UniProt Q13616 1 EQUAL 776 EQUAL Reactome Database ID Release 81 187551 Database 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=187551 Reactome R-HSA-187551 1 Reactome 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-187551.1 1 Converted from EntitySet in Reactome FBXW7alpha/gamma Reactome DB_ID: 1602299 FBXW7 FBXW7alpha FBXW7-1 Reactome DB_ID: 1602296 UniProt:Q969H0-1 FBXW7 FBXW7 FBW7 FBX30 SEL10 FUNCTION 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 (PubMed:22748924, PubMed:17434132, PubMed:26976582, PubMed:28727686). Recognizes and binds phosphorylated sites/phosphodegrons within target proteins and thereafter bring them to the SCF complex for ubiquitination (PubMed:22748924, PubMed:26774286, PubMed:17434132, PubMed:26976582, PubMed:28727686). Identified substrates include cyclin-E (CCNE1 or CCNE2), DISC1, JUN, MYC, NOTCH1 released notch intracellular domain (NICD), NFE2L1, NOTCH2, MCL1, and probably PSEN1 (PubMed:11565034, PubMed:12354302, PubMed:11585921, PubMed:15103331, PubMed:14739463, PubMed:17558397, PubMed:17873522, PubMed:22608923, PubMed:22748924, PubMed:29149593, PubMed:25775507, PubMed:28007894, PubMed:26976582, PubMed:28727686). Acts as a negative regulator of JNK signaling by binding to phosphorylated JUN and promoting its ubiquitination and subsequent degradation (PubMed:14739463). Involved in bone homeostasis and negative regulation of osteoclast differentiation (PubMed:29149593). Regulates the amplitude of the cyclic expression of hepatic core clock genes and genes involved in lipid and glucose metabolism via ubiquitination and proteasomal degradation of their transcriptional repressor NR1D1; CDK1-dependent phosphorylation of NR1D1 is necessary for SCF(FBXW7)-mediated ubiquitination (PubMed:27238018). Also able to promote 'Lys-63'-linked ubiquitination in response to DNA damage (PubMed:26774286). The SCF(FBXW7) complex facilitates double-strand break repair following phosphorylation by ATM: phosphorylation promotes localization to sites of double-strand breaks and 'Lys-63'-linked ubiquitination of phosphorylated XRCC4, enhancing DNA non-homologous end joining (PubMed:26774286).SUBUNIT Homodimer; homodimerization plays a role in substrate binding and/or ubiquitination and degradation (PubMed:22608923, PubMed:17434132, PubMed:28007894). Component of the SCF(FBXW7) complex consisting of CUL1, RBX1, SKP1 and FBXW7 (PubMed:11565034, PubMed:15103331, PubMed:22748924, PubMed:26774286, PubMed:28007894, PubMed:26976582, PubMed:28727686). Interacts (via F-box domain) with SKP1 (PubMed:11585921, PubMed:17434132, PubMed:28007894, PubMed:26976582, PubMed:28727686). Interacts (via F-box domain) with pseudophosphatase STYX; the interaction is direct and prevents FBXW7 interaction with SKP1 (PubMed:28007894). Interacts with cyclin-E (CCNE1 or CCNE2) (PubMed:11565034, PubMed:17434132). Interacts with PSEN1 (PubMed:12354302). Forms a trimeric complex with NOTCH1 and SGK1 (PubMed:21147854). Interacts with NOTCH1 intracellular domain/NICD and NOTCH4 intracellular domain/NICD (PubMed:11585921). Interacts with NOTCH2 intracellular domain (N2ICD) (PubMed:29149593). Interacts with MYC (when phosphorylated) (PubMed:17873522, PubMed:25775507, PubMed:28007894). Interacts with USP28, leading to counteract ubiquitination of MYC (PubMed:17873522). Interacts with JUN (PubMed:14739463, PubMed:22608923). Found in a complex with JUN and PRR7 (PubMed:27458189). Interacts with JUN and PRR7; the interaction inhibits ubiquitination-mediated JUN degradation promoting its phosphorylation and transcriptional activity (PubMed:27458189). Interacts (when phosphorylated at Thr-205) with PIN1, leading to disrupt FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation (PubMed:22608923). Interacts with UBE2QL1 (PubMed:24000165). Interacts with FAM83D; promotes FBXW7 degradation (PubMed:24344117). Interacts with MYCN; FBXW7 competes with AURKA for binding to unphosphorylated MYCN but not for binding to phosphorylated MYCN (PubMed:27837025). Interacts with STOML1 (PubMed:23082202). Interacts with NFE2L1 (By similarity). Interacts with USP36, leading to counteract ubiquitination of MYC (PubMed:25775507). Interacts with NR1D1 (PubMed:27238018).SUBUNIT (Microbial infection) Interacts (via WD repeats) with SV40 large T antigen (via CPD region).DOMAIN The WD repeats mediate interaction with substrates of the SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex.DOMAIN The F-box domain mediates interaction with SKP1.PTM Phosphorylation at Thr-205 promotes interaction with PIN1, leading to disrupt FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation (PubMed:22608923). Phosphorylated by ATM at Ser-26 in response to DNA damage, promoting recruitment to DNA damage sites and 'Lys-63'-linked ubiquitination of phosphorylated XRCC4 (PubMed:26774286).PTM Ubiquitinated: autoubiquitinates following phosphorylation at Thr-205 and subsequent interaction with PIN1. Ubiquitination leads to its proteasomal degradation (PubMed:22608923). UniProt Isoform Q969H0-1 1 EQUAL 707 EQUAL Reactome Database ID Release 81 1602296 Database 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=1602296 Reactome R-HSA-1602296 2 Reactome 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-1602296.2 FBXW7-4 FBXW7gamma Reactome DB_ID: 1602297 UniProt:Q969H0-4 FBXW7 FBXW7 FBW7 FBX30 SEL10 FUNCTION 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 (PubMed:22748924, PubMed:17434132, PubMed:26976582, PubMed:28727686). Recognizes and binds phosphorylated sites/phosphodegrons within target proteins and thereafter bring them to the SCF complex for ubiquitination (PubMed:22748924, PubMed:26774286, PubMed:17434132, PubMed:26976582, PubMed:28727686). Identified substrates include cyclin-E (CCNE1 or CCNE2), DISC1, JUN, MYC, NOTCH1 released notch intracellular domain (NICD), NFE2L1, NOTCH2, MCL1, and probably PSEN1 (PubMed:11565034, PubMed:12354302, PubMed:11585921, PubMed:15103331, PubMed:14739463, PubMed:17558397, PubMed:17873522, PubMed:22608923, PubMed:22748924, PubMed:29149593, PubMed:25775507, PubMed:28007894, PubMed:26976582, PubMed:28727686). Acts as a negative regulator of JNK signaling by binding to phosphorylated JUN and promoting its ubiquitination and subsequent degradation (PubMed:14739463). Involved in bone homeostasis and negative regulation of osteoclast differentiation (PubMed:29149593). Regulates the amplitude of the cyclic expression of hepatic core clock genes and genes involved in lipid and glucose metabolism via ubiquitination and proteasomal degradation of their transcriptional repressor NR1D1; CDK1-dependent phosphorylation of NR1D1 is necessary for SCF(FBXW7)-mediated ubiquitination (PubMed:27238018). Also able to promote 'Lys-63'-linked ubiquitination in response to DNA damage (PubMed:26774286). The SCF(FBXW7) complex facilitates double-strand break repair following phosphorylation by ATM: phosphorylation promotes localization to sites of double-strand breaks and 'Lys-63'-linked ubiquitination of phosphorylated XRCC4, enhancing DNA non-homologous end joining (PubMed:26774286).SUBUNIT Homodimer; homodimerization plays a role in substrate binding and/or ubiquitination and degradation (PubMed:22608923, PubMed:17434132, PubMed:28007894). Component of the SCF(FBXW7) complex consisting of CUL1, RBX1, SKP1 and FBXW7 (PubMed:11565034, PubMed:15103331, PubMed:22748924, PubMed:26774286, PubMed:28007894, PubMed:26976582, PubMed:28727686). Interacts (via F-box domain) with SKP1 (PubMed:11585921, PubMed:17434132, PubMed:28007894, PubMed:26976582, PubMed:28727686). Interacts (via F-box domain) with pseudophosphatase STYX; the interaction is direct and prevents FBXW7 interaction with SKP1 (PubMed:28007894). Interacts with cyclin-E (CCNE1 or CCNE2) (PubMed:11565034, PubMed:17434132). Interacts with PSEN1 (PubMed:12354302). Forms a trimeric complex with NOTCH1 and SGK1 (PubMed:21147854). Interacts with NOTCH1 intracellular domain/NICD and NOTCH4 intracellular domain/NICD (PubMed:11585921). Interacts with NOTCH2 intracellular domain (N2ICD) (PubMed:29149593). Interacts with MYC (when phosphorylated) (PubMed:17873522, PubMed:25775507, PubMed:28007894). Interacts with USP28, leading to counteract ubiquitination of MYC (PubMed:17873522). Interacts with JUN (PubMed:14739463, PubMed:22608923). Found in a complex with JUN and PRR7 (PubMed:27458189). Interacts with JUN and PRR7; the interaction inhibits ubiquitination-mediated JUN degradation promoting its phosphorylation and transcriptional activity (PubMed:27458189). Interacts (when phosphorylated at Thr-205) with PIN1, leading to disrupt FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation (PubMed:22608923). Interacts with UBE2QL1 (PubMed:24000165). Interacts with FAM83D; promotes FBXW7 degradation (PubMed:24344117). Interacts with MYCN; FBXW7 competes with AURKA for binding to unphosphorylated MYCN but not for binding to phosphorylated MYCN (PubMed:27837025). Interacts with STOML1 (PubMed:23082202). Interacts with NFE2L1 (By similarity). Interacts with USP36, leading to counteract ubiquitination of MYC (PubMed:25775507). Interacts with NR1D1 (PubMed:27238018).SUBUNIT (Microbial infection) Interacts (via WD repeats) with SV40 large T antigen (via CPD region).DOMAIN The WD repeats mediate interaction with substrates of the SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex.DOMAIN The F-box domain mediates interaction with SKP1.PTM Phosphorylation at Thr-205 promotes interaction with PIN1, leading to disrupt FBXW7 dimerization and promoting FBXW7 autoubiquitination and degradation (PubMed:22608923). Phosphorylated by ATM at Ser-26 in response to DNA damage, promoting recruitment to DNA damage sites and 'Lys-63'-linked ubiquitination of phosphorylated XRCC4 (PubMed:26774286).PTM Ubiquitinated: autoubiquitinates following phosphorylation at Thr-205 and subsequent interaction with PIN1. Ubiquitination leads to its proteasomal degradation (PubMed:22608923). UniProt Isoform Q969H0-4 1 EQUAL 589 EQUAL Reactome Database ID Release 81 1602297 Database 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=1602297 Reactome R-HSA-1602297 1 Reactome 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-1602297.1 Reactome Database ID Release 81 1602299 Database 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=1602299 Reactome R-HSA-1602299 1 Reactome 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-1602299.1 1 ZYP RBX1 RNF75 ROC1 E3 ubiquitin-protein ligase RBX1 Reactome DB_ID: 1234142 UniProt:P62877 RBX1 RBX1 RNF75 ROC1 FUNCTION E3 ubiquitin ligase component of multiple cullin-RING-based E3 ubiquitin-protein ligase (CRLs) complexes which mediate the ubiquitination and subsequent proteasomal degradation of target proteins, including proteins involved in cell cycle progression, signal transduction, transcription and transcription-coupled nucleotide excision repair (PubMed:10230407, PubMed:10579999, PubMed:15983046, PubMed:16678110, PubMed:19112177, PubMed:19679664, PubMed:23455478, PubMed:27565346, PubMed:29769719, PubMed:11961546, PubMed:22748924). CRLs complexes and ARIH1 collaborate in tandem to mediate ubiquitination of target proteins, ARIH1 mediating addition of the first ubiquitin on CRLs targets (PubMed:27565346). The functional specificity of the E3 ubiquitin-protein ligase complexes depends on the variable substrate recognition components. As a component of the CSA complex promotes the ubiquitination of ERCC6 resulting in proteasomal degradation. Recruits the E2 ubiquitin-conjugating enzyme CDC34 to the complex and brings it into close proximity to the substrate. Probably also stimulates CDC34 autoubiquitination. May be required for histone H3 and histone H4 ubiquitination in response to ultraviolet and for subsequent DNA repair. Promotes the neddylation of CUL1, CUL2, CUL4 and CUL4 via its interaction with UBE2M. Involved in the ubiquitination of KEAP1, ENC1 and KLHL41. In concert with ATF2 and CUL3, promotes degradation of KAT5 thereby attenuating its ability to acetylate and activate ATM.PATHWAY Protein modification; protein ubiquitination.SUBUNIT Part of a SCF complex consisting of CUL1, RBX1, SKP1 and SKP2 (PubMed:11961546). Part of a SCF-like complex consisting of CUL7, RBX1, SKP1 and FBXW8. Part of CBC(VHL) complexes with elongin BC complex (ELOB and ELOC), CUL2 or CUL5 and VHL. Part of the CSA complex (DCX(ERCC8) complex), a DCX E3 ubiquitin-protein ligase complex containing ERCC8, RBX1, DDB1 and CUL4A; the CSA complex interacts with RNA polymerase II; upon UV irradiation it interacts with the COP9 signalosome and preferentially with the hyperphosphorylated form of RNA polymerase II. Part of multisubunit E3 ubiquitin ligase complexes with elongin BC complex (ELOB and ELOC), CUL2 and MED8; elongin BC complex (ELOB and ELOC), CUL5 and MUF1. Part of multisubunit complexes with elongin BC complex (ELOB and ELOC), elongin A/ELOA or SOCS1 or WSB1 and CUL5. Interacts directly with CUL1 and probably also with CUL2, CUL3, CUL4A, CUL4B, CUL5 and CUL7. Interacts with CDC34 (PubMed:22748924). Interacts with GLMN. GLMN competes for the binding site of the E2 ubiquitin-conjugating enzyme CDC34 and disrupts CDC34 binding (PubMed:22748924). Interacts with COPS6. Component of the DCX DET1-COP1 ubiquitin ligase complex at least composed of RBX1, DET1, DDB1, CUL4A and COP1. Part of an E3 ligase complex composed of RBX1, DDB1, DDB2 and CUL4A or CUL4B. Interacts with UBE2M. Part of a SCF complex consisting of CUL1, FBXO3, RBX1 and SKP1; this complex interacts with PML via FBXO3. Component of the SCF(Cyclin F) complex consisting of CUL1, RBX1, SKP1 and CCNF. Identified in a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin ligase complex together with HINT1 and CDC34. Component of multiple BCR (BTB-CUL3-RBX1) E3 ubiquitin-protein ligase complexes formed of CUL3, RBX1 and a variable BTB domain-containing protein. Part of the BCR(ENC1) complex containing ENC1. Part of the BCR(GAN) complex containing GAN. Part of the BCR(KLHL41) complex containing KLHL41. Part of the BCR(KEAP1) complex containing KEAP1. Interacts with SESN1 and SESN2 (PubMed:23274085). Interacts with NOTCH2 (PubMed:29149593). Component of the BCR(KLHL22) E3 ubiquitin ligase complex, at least composed of CUL3, KLHL22 and RBX1 (PubMed:23455478). Interacts with DCUN1D1, DCUN1D2, DCUN1D3, DCUN1D4 and DCUN1D5 (PubMed:26906416, PubMed:24192928, PubMed:25349211). Component of a BCR3 (BTB-CUL3-RBX1) E3 ubiquitin ligase complex, also named Cul3-RING ubiquitin ligase complex CUL3(KBTBD6/7), composed of CUL3, RBX1, KBTBD6 and KBTBD7 (PubMed:25684205).SUBUNIT (Microbial infection) Interacts with human adenovirus 5 protein E1A; this interaction inhibits RBX1-CUL1-dependent elongation reaction of ubiquitin chains by the SCF(FBW7) complex.TISSUE SPECIFICITY Widely expressed.DOMAIN The RING-type zinc finger domain is essential for ubiquitin ligase activity (PubMed:10230407). It coordinates an additional third zinc ion (PubMed:11961546, PubMed:22748924).SIMILARITY Belongs to the RING-box family. UniProt P62877 2 EQUAL 108 EQUAL Reactome Database ID Release 81 1234142 Database 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=1234142 Reactome R-HSA-1234142 1 Reactome 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-1234142.1 1 Reactome Database ID Release 81 1604469 Database 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=1604469 Reactome R-HSA-1604469 1 Reactome 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-1604469.1 Reactome Database ID Release 81 2220967 Database 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=2220967 Reactome R-HSA-2220967 2 Reactome 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-2220967.2 17646408 Pubmed 2007 The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia Thompson, BJ Buonamici, S Sulis, ML Palomero, T Vilimas, T Basso, G Ferrando, Adolfo A Aifantis, I J Exp Med 204:1825-35 17646409 Pubmed 2007 FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors O'Neil, J Grim, J Strack, P Rao, S Tibbitts, D Winter, C Hardwick, J Welcker, M Meijerink, JP Pieters, R Draetta, G Sears, R Clurman, BE Look, AT J Exp Med 204:1813-24 Reactome Database ID Release 81 2644606 Database 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=2644606 Reactome R-HSA-2644606 1 Reactome 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-2644606.1 15472075 Pubmed 2004 Activating mutations of NOTCH1 in human T cell acute lymphoblastic leukemia Weng, AP Ferrando, Adolfo A Lee, W Morris JP, 4th Silverman, LB Sanchez-Irizarry, C Blacklow, SC Look, AT Aster, JC Science 306:269-71