BioPAX pathway converted from "Signaling by NOTCH" in the Reactome database. Signaling by NOTCH NOTCH Signaling Pathway The Notch Signaling Pathway (NSP) is a highly conserved pathway for cell-cell communication. NSP is involved in the regulation of cellular differentiation, proliferation, and specification. For example, it is utilised by continually renewing adult tissues such as blood, skin, and gut epithelium not only to maintain stem cells in a proliferative, pluripotent, and undifferentiated state but also to direct the cellular progeny to adopt different developmental cell fates. Analogously, it is used during embryonic development to create fine-grained patterns of differentiated cells, notably during neurogenesis where the NSP controls patches such as that of the vertebrate inner ear where individual hair cells are surrounded by supporting cells.<br>This process is known as lateral inhibition: a molecular mechanism whereby individual cells within a field are stochastically selected to adopt particular cell fates and the NSP inhibits their direct neighbours from doing the same. The NSP has been adopted by several other biological systems for binary cell fate choice. In addition, the NSP is also used during vertebrate segmentation to divide the growing embryo into regular blocks called somites which eventually form the vertebrae. The core of this process relies on regular pulses of Notch signaling generated from a molecular oscillator in the presomatic mesoderm.<br>The Notch receptor is synthesized in the rough endoplasmic reticulum as a single polypeptide precursor. Newly synthesized Notch receptor is proteolytically cleaved in the trans-golgi network, creating a heterodimeric mature receptor comprising of non-covalently associated extracellular and transmembrane subunits. This assembly travels to the cell surface ready to interact with specific ligands. Following ligand activation and further proteolytic cleavage, an intracellular domain is released and translocates to the nucleus where it regulates gene expression. Authored: Jassal, B, 2004-12-15 13:08:03 Reviewed: Joutel, A, 2004-12-15 Pre-NOTCH Expression and Processing In humans and other mammals the NOTCH gene family has four members, NOTCH1, NOTCH2, NOTCH3 and NOTCH4, encoded on four different chromosomes. Their transcription is developmentally regulated and tissue specific, but very little information exists on molecular mechanisms of transcriptional regulation. Translation of NOTCH mRNAs is negatively regulated by a number of recently discovered microRNAs (Li et al. 2009, Pang et al.2010, Ji et al. 2009, Kong et al. 2010, Marcet et al. 2011, Ghisi et al. 2011, Song et al. 2009, Hashimoto et al. 2010, Costa et al. 2009). <br><br> The nascent forms of NOTCH precursors, Pre-NOTCH1, Pre-NOTCH2, Pre-NOTCH3 and Pre-NOTCH4, undergo extensive posttranslational modifications in the endoplasmic reticulum and Golgi apparatus to become functional. In the endoplasmic reticulum, conserved serine and threonine residues in the EGF repeats of NOTCH extracellular domain are fucosylated and glucosylated by POFUT1 and POGLUT1, respectively (Yao et al. 2011, Stahl et al. 2008, Wang et al. 2001, Shao et al. 2003, Acar et al. 2008, Fernandez Valdivia et al. 2011). <br><br> In the Golgi apparatus, fucose groups attached to NOTCH EGF repeats can be elongated by additional glycosylation steps initiated by fringe enzymes (Bruckner et al. 2000, Moloney et al. 2000, Cohen et al. 1997, Johnston et al. 1997, Chen et al. 2001). Fringe-mediated modification modulates NOTCH signaling but is not an obligatory step in Pre-NOTCH processing. Typically, processing of Pre-NOTCH in the Golgi involves cleavage by FURIN convertase (Blaumueller et al. 1997, Logeat et al. 1998, Gordon et al. 2009, Rand et al. 2000, Chan et al. 1998). The cleavage of NOTCH results in formation of mature NOTCH heterodimers that consist of NOTCH extracellular domain (NEC i.e. NECD) and NOTCH transmembrane and intracellular domain (NTM i.e. NTMICD). NOTCH heterodimers translocate to the cell surface where they function in cell to cell signaling. Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: D'Eustachio, P, 2012-02-06 Pre-NOTCH Transcription and Translation In humans, the NOTCH protein family has four members: NOTCH1, NOTCH2, NOTCH3 and NOTCH4. NOTCH1 protein was identified first, as the product of a chromosome 9 gene translocated in T-cell acute lymphoblastic leukemia that was homologous to Drosophila Notch (Ellisen et al. 1991). At the same time, rat Notch1 was cloned (Weinmaster et al. 1991), followed by cloning of mouse Notch1, named Motch (Del Amo et al. 1992). NOTCH2 protein is the product of a gene on chromosome 1 (Larsson et al. 1994). NOTCH2 expression is differentially regulated during B-cell development (Bertrand et al. 2000). NOTCH2 mutations are a rare cause of Alagille syndrome (McDaniell et al. 2006). NOTCH3 is the product of a gene on chromosome 19. NOTCH3 mutations are the underlying cause of CADASIL, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (Joutel et al. 1996). NOTCH4, the last NOTCH protein discovered, is the product of a gene on chromosome 6 (Li et al. 1998). <br><br>MicroRNAs play an important negative role in translation and/or stability of NOTCH mRNAs. MicroRNAs miR-34 (miR-34A, miR-34B and mi-R34C), whose transcription is directly induced by the tumor suppressor protein p53 (Chang et al. 2007, Raver-Shapira et al. 2007, He et al. 2007, Corney et al. 2007) bind and negatively regulate translation of NOTCH1 mRNA (Li et al. 2009, Pang et al. 2010, Ji et al. 2009) and NOTCH2 mRNA (Li et al. 2009). NOTCH1 mRNA translation is also negatively regulated by microRNAs miR-200B and miR-200C (Kong et al. 2010), as well as miR-449A, miR-449B and miR-449C (Marcet et al. 2011). Translation of NOTCH3 mRNA is negatively regulated by microRNAs miR-150 (Ghisi et al. 2011) and miR-206 (Song et al. 2009). Translation of NOTCH4 mRNA is negatively regulated by microRNAs miR-181C (Hashimoto et al. 2010) and miR-302A (Costa et al. 2009). <br><br>Nascent NOTCH peptides are co-translationally targeted to the endoplasmic reticulum for further processing, followed by modification in the Golgi apparatus, before trafficking to the plasma membrane. Endoplasmic reticulum calcium ATPases, positively regulate NOTCH trafficking, possibly by contributing to accurate folding of NOTCH precursors (Periz et al. 1999). Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Reviewed: Haw, R, 2012-05-17 Reviewed: Haw, Robin, 2017-10-30 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, M, 2012-02-10 Edited: May, B, 2012-02-09 Edited: D'Eustachio, P, 2012-02-06 Edited: Jupe, S, 2011-09-27 Edited: Gillespie, ME, 2012-02-09 Edited: D'Eustachio, P, 2012-05-15 Edited: Orlic-Milacic, Marija, 2017-11-02 LEFT-TO-RIGHT CCND1:CREBBP binds NOTCH1 promoter CCND1 (cyclin D1) forms a complex with CREBBP and binds to the NOTCH1 promoter, stimulating NOTCH1 transcription. The involvement of CCND1 in transcriptional regulation of NOTCH1 was established in mouse retinas and the rat retinal precursor cell line R28 (Bienvenu et al. 2010). Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Reviewed: Haw, R, 2012-05-17 Edited: Orlic-Milacic, M, 2012-02-10 Edited: D'Eustachio, P, 2012-02-06 Edited: D'Eustachio, P, 2012-05-15 NOTCH1 gene Reactome DB_ID: 1911481 nucleoplasm GENE ONTOLOGY GO:0005654 ENSEMBL:ENSG00000148400 NOTCH1 NOTCH1 Gene NOTCH1 TAN1 Homo sapiens NCBI Taxonomy 9606 ENSEMBL ENSG00000148400 Reactome Database ID Release 81 1911481 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=1911481 Reactome R-HSA-1911481 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-1911481.1 Reactome http://www.reactome.org CCND1:CREBBP Reactome DB_ID: 2247939 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 1 CCND1 G1/S-specific cyclin D1 PRAD1 oncogene BCL-1 oncogene Reactome DB_ID: 113832 UniProt:P24385 CCND1 CCND1 BCL1 PRAD1 FUNCTION Regulatory component of the cyclin D1-CDK4 (DC) complex that phosphorylates and inhibits members of the retinoblastoma (RB) protein family including RB1 and regulates the cell-cycle during G(1)/S transition (PubMed:1833066, PubMed:1827756, PubMed:8114739, PubMed:8302605, PubMed:19412162, PubMed:33854235). Phosphorylation of RB1 allows dissociation of the transcription factor E2F from the RB/E2F complex and the subsequent transcription of E2F target genes which are responsible for the progression through the G(1) phase (PubMed:1833066, PubMed:1827756, PubMed:8114739, PubMed:8302605, PubMed:19412162). Hypophosphorylates RB1 in early G(1) phase (PubMed:1833066, PubMed:1827756, PubMed:8114739, PubMed:8302605, PubMed:19412162). Cyclin D-CDK4 complexes are major integrators of various mitogenenic and antimitogenic signals (PubMed:1833066, PubMed:1827756, PubMed:8302605, PubMed:19412162). Also substrate for SMAD3, phosphorylating SMAD3 in a cell-cycle-dependent manner and repressing its transcriptional activity (PubMed:15241418). Component of the ternary complex, cyclin D1/CDK4/CDKN1B, required for nuclear translocation and activity of the cyclin D-CDK4 complex (PubMed:9106657). Exhibits transcriptional corepressor activity with INSM1 on the NEUROD1 and INS promoters in a cell cycle-independent manner (PubMed:16569215, PubMed:18417529).SUBUNIT Interacts with either CDK4 or CDK6 protein kinase to form a serine/threonine kinase holoenzyme complex (PubMed:8114739, PubMed:19237565). The cyclin subunit imparts substrate specificity to the complex (PubMed:20399237, PubMed:19237565, PubMed:8302605, PubMed:9106657). Component of the ternary complex CCND1/CDK4/CDKN1B required for nuclear translocation and modulation of CDK4-mediated kinase activity (PubMed:9106657). Interacts directly with CDKN1B (By similarity). Can form similar complexes with either CDKN1A or CDKN2A (By similarity). Interacts with FBXO4 (By similarity). Interacts with UHRF2; the interaction ubiquitinates CCND1 and appears to occur independently of phosphorylation (PubMed:21952639). Interacts with USP2 (PubMed:19917254). Interacts (via cyclin N-terminal domain) with INSM1 (via N-terminal region); the interaction competes with the binding of CCND1 to CDK4 during cell cycle progression and inhibits CDK4 activity (PubMed:16569215, PubMed:18417529, PubMed:19124461). Interacts with CDK4; the interaction is prevented with the binding of CCND1 to INSM1 during cell cycle progression (PubMed:19124461).PTM Phosphorylation at Thr-286 by MAP kinases is required for ubiquitination and degradation by the DCX(AMBRA1) complex (PubMed:10766840, PubMed:33854232, PubMed:33854235, PubMed:33854239). It also plays an essential role for recognition by the FBXO31 component of SCF (SKP1-cullin-F-box) protein ligase complex following DNA damage (PubMed:19412162).PTM Ubiquitinated at Lys-269 by the DCX(AMBRA1) complex during the transition from G1 to S cell phase, leading to its degradation: ubiquitination is dependent on Thr-286 phosphorylation (PubMed:33854232, PubMed:33854235, PubMed:33854239). The DCX(AMBRA1) complex represents the major regulator of CCND1 stability during the G1/S transition (PubMed:33854232, PubMed:33854235, PubMed:33854239). Also ubiquitinated by a SCF (SKP1-CUL1-F-box protein) ubiquitin-protein ligase complex containing FBXO4 and CRYAB (By similarity). Following DNA damage it is ubiquitinated by some SCF (SKP1-cullin-F-box) protein ligase complex containing FBXO31 (PubMed:19412162). SCF-type ubiquitination is dependent on Thr-286 phosphorylation (PubMed:10766840, PubMed:19412162). Ubiquitinated also by UHRF2 apparently in a phosphorylation-independent manner (PubMed:21952639). Ubiquitination leads to its degradation and G1 arrest. Deubiquitinated by USP2; leading to its stabilization (PubMed:19917254).DISEASE A chromosomal aberration involving CCND1 may be a cause of B-lymphocytic malignancy, particularly mantle-cell lymphoma (MCL). Translocation t(11;14)(q13;q32) with immunoglobulin gene regions. Activation of CCND1 may be oncogenic by directly altering progression through the cell cycle.DISEASE A chromosomal aberration involving CCND1 may be a cause of parathyroid adenomas. Translocation t(11;11)(q13;p15) with the parathyroid hormone (PTH) enhancer.SIMILARITY Belongs to the cyclin family. Cyclin D subfamily. UniProt P24385 1 EQUAL 295 EQUAL Reactome Database ID Release 81 113832 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=113832 Reactome R-HSA-113832 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-113832.1 1 Reactome Database ID Release 81 2247939 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=2247939 Reactome R-HSA-2247939 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-2247939.1 CCND1:CREBBP:NOTCH1 Gene Reactome DB_ID: 4395224 1 1 Reactome Database ID Release 81 4395224 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=4395224 Reactome R-HSA-4395224 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-4395224.1 Reactome Database ID Release 81 4395227 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=4395227 Reactome R-HSA-4395227 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-4395227.1 20090754 Pubmed 2010 Transcriptional role of cyclin D1 in development revealed by a genetic-proteomic screen Bienvenu, Frédéric Jirawatnotai, Siwanon Elias, Joshua E Meyer, Clifford A Mizeracka, Karolina Marson, Alexander Frampton, Garrett M Cole, Megan F Odom, Duncan T Odajima, Junko Geng, Yan Zagozdzon, Agnieszka Jecrois, Marie Young, Richard A Liu, X Shirley Cepko, CL Gygi, SP Sicinski, Piotr Nature 463:374-8 LEFT-TO-RIGHT E2F1/3:DP1/2 binds NOTCH1 promoter E2F1 and E2F3 are able to bind to the NOTCH1 promoter and activate NOTCH1 transcription (Viatour et al. 2011). Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Reviewed: Haw, R, 2012-05-17 Edited: Orlic-Milacic, M, 2012-02-10 Edited: D'Eustachio, P, 2012-02-06 Edited: D'Eustachio, P, 2012-05-15 E2F1/3:DP1/2 Reactome DB_ID: 2248825 Converted from EntitySet in Reactome TFDP1,TFDP2 Reactome DB_ID: 1362227 DP-1 TFDP1 Transcription factor DP-1 (E2F dimerization partner 1)(DRTF1-polypeptide-1) (DRTF1) Transcription factor Dp-1 E2F dimerization partner 1 DRTF1- polypeptide-1 DRTF1 Reactome DB_ID: 68652 UniProt:Q14186 TFDP1 TFDP1 DP1 FUNCTION Can stimulate E2F-dependent transcription. Binds DNA cooperatively with E2F family members through the E2 recognition site, 5'-TTTC[CG]CGC-3', found in the promoter region of a number of genes whose products are involved in cell cycle regulation or in DNA replication (PubMed:8405995, PubMed:7739537). The E2F1:DP complex appears to mediate both cell proliferation and apoptosis. Blocks adipocyte differentiation by repressing CEBPA binding to its target gene promoters (PubMed:20176812).SUBUNIT Component of the E2F:DP transcription factor complex. Forms heterodimers with E2F family members. The complex can interact with hypophosphorylated retinoblastoma protein RB1 and related proteins (RBL1 and RBL2) that inhibit the E2F transactivation domain. This repression involves recruitment of histone deacetylase (HDAC). During the cell cycle, from mid-to-late G1 phase, RB family members become phosphorylated, detach from the DRTF1/E2F complex to render E2F transcriptionally active. Viral oncoproteins, notably E1A, T-antigen and HPV E7, are capable of sequestering RB protein, thus releasing the active complex. Part of the E2F6.com-1 complex in G0 phase is composed of E2F6, MGA, MAX, TFDP1, CBX3, BAT8, EUHMTASE1, RING1, RNF2, MBLR, L3MBTL2 YAF2. Component of the DREAM complex (also named LINC complex) at least composed of E2F4, E2F5, LIN9, LIN37, LIN52, LIN54, MYBL1, MYBL2, RBL1, RBL2, RBBP4, TFDP1 and TFDP2. The complex exists in quiescent cells where it represses cell cycle-dependent genes. It dissociates in S phase when LIN9, LIN37, LIN52 and LIN54 form a subcomplex that binds to MYBL2. The complex TFDP1:E2F1 interacts with CEBPA; the interaction prevents CEBPA binding to target gene promoters and represses its transcriptional activity (PubMed:20176812).TISSUE SPECIFICITY Highest levels in muscle. Also expressed in brain, placenta, liver and kidney. Lower levels in lung and pancreas. Not detected in heart.INDUCTION Down-regulated during differentiation.PTM Phosphorylation by E2F1-bound cyclin A-CDK2, in the S phase, inhibits E2F-mediated DNA binding and transactivation.PTM Ubiquitinated by the BCR(KBTBD5) complex, leading to its subsequent degradation.MISCELLANEOUS E2F/DP transactivation can be mediated by several cofactors including TBP, TFIIH, MDM2 and CBP.SIMILARITY Belongs to the E2F/DP family. UniProt Q14186 2 EQUAL 410 EQUAL Reactome Database ID Release 81 68652 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=68652 Reactome R-HSA-68652 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-68652.2 DP2 TFDP2 DP-2 Reactome DB_ID: 1362225 UniProt:Q14188 TFDP2 TFDP2 DP2 FUNCTION Can stimulate E2F-dependent transcription. Binds DNA cooperatively with E2F family members through the E2 recognition site, 5'-TTTC[CG]CGC-3', found in the promoter region of a number of genes whose products are involved in cell cycle regulation or in DNA replication. The TFDP2:E2F complex functions in the control of cell-cycle progression from G1 to S phase. The E2F1:DP complex appears to mediate both cell proliferation and apoptosis. Blocks adipocyte differentiation by repressing CEBPA binding to its target gene promoters (PubMed:20176812).SUBUNIT Component of the DRTF1/E2F transcription factor complex. Forms heterodimers with E2F family members. The complex can interact with hypophosphorylated retinoblastoma protein RB1 and related proteins (RBL1 and RBL2) that inhibit the E2F transactivation domain. During the cell cycle, RB becomes phosphorylated in mid-to-late G1 phase, detaches from the DRTF1/E2F complex rendering E2F transcriptionally active. Viral oncoproteins, notably E1A, T-antigen and HPV E7, are capable of sequestering RB protein, thus releasing the active complex. Interacts with GMCL (By similarity). Component of the DREAM complex (also named LINC complex) at least composed of E2F4, E2F5, LIN9, LIN37, LIN52, LIN54, MYBL1, MYBL2, RBL1, RBL2, RBBP4, TFDP1 and TFDP2. The complex exists in quiescent cells where it represses cell cycle-dependent genes. It dissociates in S phase when LIN9, LIN37, LIN52 and LIN54 form a subcomplex that binds to MYBL2. The complex TFDP2:E2F1 interacts with CEBPA; the interaction prevents CEBPA binding to target genes promoters and represses its transcriptional activity (PubMed:20176812).TISSUE SPECIFICITY High levels in heart and skeletal muscle. Also found in placenta, kidney, brain, lung and liver. The presence as well as the abundance of the different transcripts appear to vary significantly in different tissues and cell lines.PTM Ser-24 is probably phosphorylated by CDK2.SIMILARITY Belongs to the E2F/DP family. UniProt Q14188 1 EQUAL 446 EQUAL Reactome Database ID Release 81 1362225 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=1362225 Reactome R-HSA-1362225 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-1362225.1 Reactome Database ID Release 81 1362227 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=1362227 Reactome R-HSA-1362227 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-1362227.2 1 Converted from EntitySet in Reactome E2F1/E2F3 Reactome DB_ID: 187942 E2F1 Transcription factor E2F1 E2F-1 Retinoblastoma binding protein 3 RBBP-3 PRB-binding protein E2F-1 PBR3 Retinoblastoma-associated protein 1 RBAP-1 Reactome DB_ID: 68639 UniProt:Q01094 E2F1 E2F1 RBBP3 FUNCTION Transcription activator that binds DNA cooperatively with DP proteins through the E2 recognition site, 5'-TTTC[CG]CGC-3' found in the promoter region of a number of genes whose products are involved in cell cycle regulation or in DNA replication (PubMed:10675335, PubMed:12717439, PubMed:17704056, PubMed:17050006, PubMed:18625225, PubMed:28992046). The DRTF1/E2F complex functions in the control of cell-cycle progression from G1 to S phase (PubMed:10675335, PubMed:12717439, PubMed:17704056). E2F1 binds preferentially RB1 in a cell-cycle dependent manner (PubMed:10675335, PubMed:12717439, PubMed:17704056). It can mediate both cell proliferation and TP53/p53-dependent apoptosis (PubMed:8170954). Blocks adipocyte differentiation by binding to specific promoters repressing CEBPA binding to its target gene promoters (PubMed:20176812). Directly activates transcription of PEG10 (PubMed:17050006, PubMed:18625225, PubMed:28992046). Positively regulates transcription of RRP1B (PubMed:20040599).ACTIVITY REGULATION BIRC2/c-IAP1 stimulates its transcriptional activity.SUBUNIT Component of the DRTF1/E2F transcription factor complex. Forms heterodimers with DP family members. The E2F1 complex binds specifically hypophosphorylated retinoblastoma protein RB1 (PubMed:8336704). During the cell cycle, RB1 becomes phosphorylated in mid-to-late G1 phase, detaches from the DRTF1/E2F complex, rendering E2F transcriptionally active. Viral oncoproteins, notably E1A, T-antigen and HPV E7, are capable of sequestering RB1, thus releasing the active complex. Interacts with TRRAP, which probably mediates its interaction with histone acetyltransferase complexes, leading to transcription activation. Binds TOPBP1 and EAPP. Interacts with ARID3A. Interacts with TRIM28; the interaction inhibits E2F1 acetylation through recruiting HDAC1 and represses its transcriptional activity. Interaction with KAT2B; the interaction acetylates E2F1 enhancing its DNA-binding and transcriptional activity. Interacts with BIRC2/c-IAP1 (via BIR domains). The complex TFDP1:E2F1 interacts with CEBPA; the interaction prevents CEBPA binding to target genes promoters and represses its transcriptional activity (PubMed:20176812). Interacts with RRP1B (PubMed:20040599). Interacts with HCFC1 (PubMed:23629655). Interacts with KMT2E; the interaction is probably indirect and is mediated via HCFC1 (PubMed:23629655).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL123.PTM Phosphorylated by CDK2 and cyclin A-CDK2 in the S-phase (PubMed:12717439, PubMed:7838523). Phosphorylation at Ser-364 by CHEK2 stabilizes E2F1 upon DNA damage and regulates its effect on transcription and apoptosis (PubMed:12717439). Phosphorylation at Ser-403 by GSK3B promotes interaction with USP11, leading to its deubiquitination and stabilization (PubMed:28992046).PTM Ubiquitinated via 'Lys-63'-linked ubiquitin, leading to its degradation (PubMed:28992046). Deubiquitinated by USP11 follwong phosphorylation by GSK3B, promoting its stability (PubMed:28992046).PTM Acetylation stimulates DNA-binding. Enhanced under stress conditions such as DNA damage and inhibited by retinoblastoma protein RB1. Regulated by KAP1/TRIM28 which recruits HDAC1 to E2F1 resulting in deacetylation. Acetylated by P/CAF/KAT2B.SIMILARITY Belongs to the E2F/DP family. UniProt Q01094 1 EQUAL 437 EQUAL Reactome Database ID Release 81 68639 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=68639 Reactome R-HSA-68639 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-68639.2 E2F3 Transcription factor E2F3 E2F-3 E2F3a Reactome DB_ID: 68655 UniProt:O00716 E2F3 E2F3 KIAA0075 FUNCTION Transcription activator that binds DNA cooperatively with DP proteins through the E2 recognition site, 5'-TTTC[CG]CGC-3' found in the promoter region of a number of genes whose products are involved in cell cycle regulation or in DNA replication. The DRTF1/E2F complex functions in the control of cell-cycle progression from G1 to S phase. E2F3 binds specifically to RB1 in a cell-cycle dependent manner. Inhibits adipogenesis, probably through the repression of CEBPA binding to its target gene promoters (By similarity).SUBUNIT Component of the DRTF1/E2F transcription factor complex. Binds cooperatively with TFDP1/Dp-1 to E2F sites. Interacts with retinoblastoma protein RB1 and related proteins (such as RBL1) that inhibit the E2F transactivation domain. Binds EAPP.SIMILARITY Belongs to the E2F/DP family. UniProt O00716 1 EQUAL 465 EQUAL Reactome Database ID Release 81 68655 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=68655 Reactome R-HSA-68655 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-68655.3 Reactome Database ID Release 81 187942 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=187942 Reactome R-HSA-187942 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-187942.1 1 Reactome Database ID Release 81 2248825 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=2248825 Reactome R-HSA-2248825 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-2248825.1 E2F1/3:DP1/2:NOTCH1 Gene Reactome DB_ID: 4395228 1 1 Reactome Database ID Release 81 4395228 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=4395228 Reactome R-HSA-4395228 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-4395228.1 Reactome Database ID Release 81 4395231 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=4395231 Reactome R-HSA-4395231 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-4395231.1 21875955 Pubmed 2011 Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway Viatour, P Ehmer, U Saddic, LA Dorrell, C Andersen, JB Lin, C Zmoos, AF Mazur, PK Schaffer, BE Ostermeier, A Vogel, H Sylvester, KG Thorgeirsson, SS Grompe, M Sage, J J Exp Med 208:1963-76 LEFT-TO-RIGHT NOTCH1 gene transcription NOTCH1 was cloned as a chromosome 9 gene involved in translocation t(7;9)(q34;q34.3) in several T-cell acute lymphoblastic leukemia (T-ALL) patients. The gene was found to be highly homologous to the Drosophila gene Notch and was initially named TAN-1 (translocation-associated Notch homolog). Transcripts of NOTCH1 were detected in many fetal and adult human and mouse tissues, with the highest abundance in lymphoid tissues. The translocation t(7;9)(q34;q34.3) found in a small fraction of T-ALL patients puts NOTCH1 transcription under the control of the T-cell receptor-beta (TCRB) locus, which results in expression of truncated peptides that lack the extracellular ligand binding domain and are constitutively active (reviewed by Grabher et al. 2006). Activating NOTCH1 point mutations, mainly affecting the extracellular heterodimerization domain and/or the C-terminal PEST domain, are found in more than 50% of human T-ALLs (Weng et al. 2004).<br><br>Studies of mouse Rbpj knockout embryos and zebrafish Mib (mindbomb) mutants indicate that the NOTCH1 coactivator complex positively regulates NOTCH1 transcription. The RBPJ-binding site(s) that the NOTCH1 coactivator complex normally binds have not been found in the NOTCH1 promoter, however, so this effect may be indirect and its mechanism is unknown (Del Monte et al. 2007). <br><br>CCND1 (cyclin D1) forms a complex with CREBBP and binds to the NOTCH1 promoter, stimulating NOTCH1 transcription. The involvement of CCND1 in transcriptional regulation of NOTCH1 was established in mouse retinas and the rat retinal precursor cell line R28 (Bienvenu et al. 2010).<br><br> E2F1 and E2F3 are able to bind to the NOTCH1 promoter and activate NOTCH1 transcription (Viatour et al. 2011).<br><br> NOTCH1 promoter possesses two putative p53-binding sites. Chromatin immunoprecipitation (ChIP) assays of human primary keratinocytes showed binding of endogenous p53 protein to both sites. Experiments in which p53 was downregulated or overexpressed implicate p53 as a positive regulator of NOTCH1 expression in primary human keratinocytes. It is likely that p53-mediated regulation of NOTCH1 expression involves interplay with other cell-type specific determinants of gene expression (Lefort et al. 2007). In lymphoid cells, NOTCH1 expression may be negatively regulated by p53 (Laws and Osborne 2004). Other proteins implicated in the negative regulation of NOTCH1 transcription are KLF9 (Ying et al. 2011), JARID2 (Mysliwiec et al. 2011, Mysliwiec et al. 2012), KLF4 and SP3 (Lambertini et al. 2010), and p63 (Yugawa et al. 2010). Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Reviewed: Haw, R, 2012-05-17 Edited: Orlic-Milacic, M, 2012-02-10 Edited: D'Eustachio, P, 2012-02-06 Edited: D'Eustachio, P, 2012-05-15 NOTCH1 mRNA Reactome DB_ID: 1606559 cytosol GENE ONTOLOGY GO:0005829 ENSEMBL:ENST00000277541 NOTCH1 NOTCH1 mRNA NOTCH1 ENSEMBL ENST00000277541 1 EQUAL 9371 EQUAL Reactome Database ID Release 81 1606559 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=1606559 Reactome R-HSA-1606559 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-1606559.1 Reactome Database ID Release 81 1912416 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=1912416 Reactome R-HSA-1912416 4 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-1912416.4 22110129 Pubmed 2012 Jarid2 (Jumonji, AT rich interactive domain 2) regulates NOTCH1 expression via histone modification in the developing heart Mysliwiec, Matthew R Carlson, Clayton D Tietjen, Josh Hung, Holly Ansari, Aseem Z Lee, Youngsook J. Biol. Chem. 287:1235-41 20442293 Pubmed 2010 DeltaNp63alpha repression of the Notch1 gene supports the proliferative capacity of normal human keratinocytes and cervical cancer cells Yugawa, T Narisawa-Saito, M Yoshimatsu, Yuki Haga, Kei Ohno, S Egawa, Nagayasu Fujita, M Kiyono, T Cancer Res. 70:4034-44 16612405 Pubmed 2006 Notch 1 activation in the molecular pathogenesis of T-cell acute lymphoblastic leukaemia Grabher, C von Boehmer, H Look, AT Nat Rev Cancer 6:347-59 17344417 Pubmed 2007 Notch1 is a p53 target gene involved in human keratinocyte tumor suppression through negative regulation of ROCK1/2 and MRCKalpha kinases Lefort, K Mandinova, A Ostano, P Kolev, V Calpini, V Kolfschoten, I Devgan, V Lieb, J Raffoul, W Hohl, D Neel, V Garlick, J Chiorino, G Dotto, GP Genes Dev 21:562-77 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 20442780 Pubmed 2010 Differential control of Notch1 gene transcription by Klf4 and Sp3 transcription factors in normal versus cancer-derived keratinocytes Lambertini, Chiara Pantano, Serafino Dotto, G Paolo PLoS ONE 5:e10369 14991602 Pubmed 2004 p53 regulates thymic Notch1 activation Laws, Amy Osborne, Barbara Eur J Immunol 34:726-34 21280156 Pubmed 2011 Krüppel-like family of transcription factor 9, a differentiation-associated transcription factor, suppresses Notch1 signaling and inhibits glioblastoma-initiating stem cells Ying, Mingyao Sang, Yingying Li, Y Guerrero-Cazares, Hugo Quinones-Hinojosa, Alfredo Vescovi, Angelo L Eberhart, Charles G Xia, Shuli Laterra, John Stem Cells 29:20-31 21402699 Pubmed 2011 Endothelial Jarid2/Jumonji is required for normal cardiac development and proper Notch1 expression Mysliwiec, Matthew R Bresnick, Emery H Lee, Youngsook J. Biol. Chem. 286:17193-204 17685488 Pubmed 2007 Monitoring Notch1 activity in development: evidence for a feedback regulatory loop Del Monte, Gonzalo Grego-Bessa, Joaquím González-Rajal, Alvaro Bolós, Victoria De La Pompa, José Luis Dev. Dyn. 236:2594-614 1831692 Pubmed 1991 TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms Ellisen, LW Bird, J West, DC Soreng, AL Reynolds, TC Smith, SD Sklar, J Cell 66:649-61 ACTIVATION Reactome Database ID Release 81 2247933 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=2247933 Reactome R-HSA-2247933 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-2247933.1 NOTCH1 Coactivator Complex Reactome DB_ID: 1604462 1 NICD1:RBPJ:SNW1 Reactome DB_ID: 1604460 NICD1 NOTCH1(1754-2555) NICD 1 fragment NOTCH1 intracellular domain N1ICD Reactome DB_ID: 157939 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 1754 EQUAL 2555 EQUAL Reactome Database ID Release 81 157939 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=157939 Reactome R-HSA-157939 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-157939.1 1 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 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 1604460 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=1604460 Reactome R-HSA-1604460 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-1604460.1 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 1 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 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 1 Reactome Database ID Release 81 1604462 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=1604462 Reactome R-HSA-1604462 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-1604462.1 ACTIVATION activeUnit: #Complex3 Reactome Database ID Release 81 2248827 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=2248827 Reactome R-HSA-2248827 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-2248827.1 ACTIVATION activeUnit: #Complex1 Reactome Database ID Release 81 2247947 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=2247947 Reactome R-HSA-2247947 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-2247947.1 LEFT-TO-RIGHT NOTCH2 gene transcription The NOTCH2 gene maps to human chromosome 1. NOTCH2 gene expression is differentially regulated during human B-cell development, with NOTCH2 transcripts appearing at late developmental stages. NOTCH2 mutations are a rare cause of Alagille syndrome. Alagille syndrome is a dominant multisystem disorder mainly characterized by hepatic bile duct abnormalities, and is predominantly caused by mutations in JAG1, a NOTCH2 ligand. Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: D'Eustachio, P, 2012-02-06 NOTCH2 gene Reactome DB_ID: 1911484 ENSEMBL:ENSG00000134250 NOTCH2 NOTCH2 Gene NOTCH2 ENSEMBL ENSG00000134250 Reactome Database ID Release 81 1911484 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=1911484 Reactome R-HSA-1911484 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-1911484.1 NOTCH2 mRNA Reactome DB_ID: 1911477 ENSEMBL:ENST00000256646 NOTCH2 NOTCH2 mRNA NOTCH2 ENSEMBL ENST00000256646 1 EQUAL 11389 EQUAL Reactome Database ID Release 81 1911477 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=1911477 Reactome R-HSA-1911477 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-1911477.1 Reactome Database ID Release 81 1912407 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=1912407 Reactome R-HSA-1912407 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-1912407.1 7698746 Pubmed 1994 The human NOTCH1, 2, and 3 genes are located at chromosome positions 9q34, 1p13-p11, and 19p13.2-p13.1 in regions of neoplasia-associated translocation Larsson, C Lardelli, M White, I Lendahl, U Genomics 24:253-8 16773578 Pubmed 2006 NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway McDaniell, R Warthen, DM Sanchez-Lara, PA Pai, A Krantz, ID Piccoli, DA Spinner, NB Am J Hum Genet 79:169-73 11187898 Pubmed 2000 Notch-1 and Notch-2 exhibit unique patterns of expression in human B-lineage cells Bertrand, FE Eckfeldt, CE Lysholm, AS LeBien, TW Leukemia 14:2095-102 LEFT-TO-RIGHT NOTCH1 coactivator complex binds NOTCH3 gene NOTCH1 and RBPJ (CSL), likely in the form of the NOTCH1 coactivator complex, bind to the RBPJ response elements in the second intron of the NOTCH3 gene (Ohashi et al. 2010). Authored: Orlic-Milacic, Marija, 2017-09-20 Reviewed: Haw, Robin, 2017-10-30 Edited: Orlic-Milacic, Marija, 2017-11-02 NOTCH3 gene Reactome DB_ID: 1911492 ENSEMBL:ENSG00000074181 NOTCH3 NOTCH3 Gene NOTCH3 ENSEMBL ENSG00000074181 Reactome Database ID Release 81 1911492 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=1911492 Reactome R-HSA-1911492 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-1911492.1 NOTCH1 coactivator complex:NOTCH3 gene Reactome DB_ID: 9017845 1 1 Reactome Database ID Release 81 9017845 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=9017845 Reactome R-HSA-9017845 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-9017845.1 Reactome Database ID Release 81 9017835 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=9017835 Reactome R-HSA-9017835 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-9017835.1 20801121 Pubmed 2010 NOTCH1 and NOTCH3 coordinate esophageal squamous differentiation through a CSL-dependent transcriptional network Ohashi, Shinya Natsuizaka, Mitsuteru Yashiro-Ohtani, Yumi Kalman, Ross A Nakagawa, Momo Wu, L Klein-Szanto, Andres J Herlyn, Meenhard Diehl, J Alan Katz, Jonathan P Pear, Warren S Seykora, John T Nakagawa, H Gastroenterology 139:2113-23 GENE ONTOLOGY GO:0045747 gene ontology term for cellular process MI MI:0359 LEFT-TO-RIGHT 2.7.11.13 PRKCI phosphorylates ELF3 PRKCI (protein kinase C iota), activated in response to KRAS signaling, phosphorylates transcription factor ELF3 on serine residue S68. PRKCI-mediated phosphorylation of ELF3 promotes transcriptional activity of ELF3, probably by stimulating nuclear retention or import of ELF3 (Ali et al. 2016). Authored: Orlic-Milacic, Marija, 2017-09-20 Reviewed: Haw, Robin, 2017-10-30 Edited: Orlic-Milacic, Marija, 2017-11-02 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 additional information MI MI:0361 ELF3 ETS-related transcription factor Elf-3 ELF3_HUMAN Reactome DB_ID: 9021353 UniProt:P78545 ELF3 ELF3 ERT ESX JEN FUNCTION Transcriptional activator that binds and transactivates ETS sequences containing the consensus nucleotide core sequence GGA[AT]. Acts synergistically with POU2F3 to transactivate the SPRR2A promoter and with RUNX1 to transactivate the ANGPT1 promoter. Also transactivates collagenase, CCL20, CLND7, FLG, KRT8, NOS2, PTGS2, SPRR2B, TGFBR2 and TGM3 promoters. Represses KRT4 promoter activity. Involved in mediating vascular inflammation. May play an important role in epithelial cell differentiation and tumorigenesis. May be a critical downstream effector of the ERBB2 signaling pathway. May be associated with mammary gland development and involution. Plays an important role in the regulation of transcription with TATA-less promoters in preimplantation embryos, which is essential in preimplantation development (By similarity).SUBUNIT Interacts with TBP. Interacts with CREBBP and EP300; these act as transcriptional coactivators of ELF3 and positively modulate its function. Interacts with XRCC5/KU86 and XRCC6/KU70; these inhibit the ability of ELF3 to bind DNA and negatively modulate its transcriptional activity. Associated with CLND7 and POU2F3.TISSUE SPECIFICITY Expressed exclusively in tissues containing a high content of terminally differentiated epithelial cells including mammary gland, colon, trachea, kidney, prostate, uterus, stomach and skin.INDUCTION Transcriptionally regulated by ERBB2 receptor signaling in breast cancer epithelial cells. Up-regulated by phorbol 12-myristate 13-acetate (PMA) in bronchial epithelial cells. By retinoic acid in MCF-7 mammary epithelial cells (at protein level).DOMAIN the 9aaTAD motif is a transactivation domain present in a large number of yeast and animal transcription factors.SIMILARITY Belongs to the ETS family. UniProt P78545 1 EQUAL 371 EQUAL Reactome Database ID Release 81 9021353 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=9021353 Reactome R-HSA-9021353 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-9021353.1 p-S68-ELF3 Reactome DB_ID: 9021349 68 EQUAL O-phospho-L-serine MOD MOD:00046 1 EQUAL 371 EQUAL Reactome Database ID Release 81 9021349 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=9021349 Reactome R-HSA-9021349 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-9021349.2 ADP Adenosine 5'-diphosphate ADP(3-) Reactome DB_ID: 113582 ADP(3-) [ChEBI:456216] ADP(3-) ADP 5&apos;-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 ACTIVATION PRKCI Protein kinase C, iota type nPKC-iota Atypical protein kinase C-lamda/iota aPKC-lambda/iota Reactome DB_ID: 9021345 UniProt:P41743 PRKCI PRKCI DXS1179E FUNCTION Calcium- and diacylglycerol-independent serine/ threonine-protein kinase that plays a general protective role against apoptotic stimuli, is involved in NF-kappa-B activation, cell survival, differentiation and polarity, and contributes to the regulation of microtubule dynamics in the early secretory pathway. Is necessary for BCR-ABL oncogene-mediated resistance to apoptotic drug in leukemia cells, protecting leukemia cells against drug-induced apoptosis. In cultured neurons, prevents amyloid beta protein-induced apoptosis by interrupting cell death process at a very early step. In glioblastoma cells, may function downstream of phosphatidylinositol 3-kinase (PI(3)K) and PDPK1 in the promotion of cell survival by phosphorylating and inhibiting the pro-apoptotic factor BAD. Can form a protein complex in non-small cell lung cancer (NSCLC) cells with PARD6A and ECT2 and regulate ECT2 oncogenic activity by phosphorylation, which in turn promotes transformed growth and invasion. In response to nerve growth factor (NGF), acts downstream of SRC to phosphorylate and activate IRAK1, allowing the subsequent activation of NF-kappa-B and neuronal cell survival. Functions in the organization of the apical domain in epithelial cells by phosphorylating EZR. This step is crucial for activation and normal distribution of EZR at the early stages of intestinal epithelial cell differentiation. Forms a protein complex with LLGL1 and PARD6B independently of PARD3 to regulate epithelial cell polarity. Plays a role in microtubule dynamics in the early secretory pathway through interaction with RAB2A and GAPDH and recruitment to vesicular tubular clusters (VTCs). In human coronary artery endothelial cells (HCAEC), is activated by saturated fatty acids and mediates lipid-induced apoptosis. Involved in early synaptic long term potentiation phase in CA1 hippocampal cells and short term memory formation (By similarity).ACTIVITY REGULATION Atypical PKCs (PRKCI and PRKCZ) exhibit an elevated basal enzymatic activity (that may be due to the interaction with SMG1 or SQSTM1) and are not regulated by diacylglycerol, phosphatidylserine, phorbol esters or calcium ions. Two specific sites, Thr-412 (activation loop of the kinase domain) and Thr-564 (turn motif), need to be phosphorylated for its full activation (By similarity). Might also be a target for novel lipid activators that are elevated during nutrient-stimulated insulin secretion.SUBUNIT Forms a complex with SQSTM1 and MP2K5 (By similarity). Interacts directly with SQSTM1 (Probable). Interacts with IKBKB. Interacts with PARD6A, PARD6B and PARD6G. Part of a quaternary complex containing aPKC, PARD3, a PARD6 protein (PARD6A, PARD6B or PARD6G) and a GTPase protein (CDC42 or RAC1). Part of a complex with LLGL1 and PARD6B. Interacts with ADAP1/CENTA1. Interaction with SMG1, through the ZN-finger domain, activates the kinase activity. Interacts with CDK7. Forms a complex with RAB2A and GAPDH involved in recruitment onto the membrane of vesicular tubular clusters (VTCs). Interacts with ECT2 ('Thr-359' phosphorylated form). Interacts with VAMP2 (PubMed:17313651). Interacts with WDFY2 (via WD repeats 1-3) (PubMed:16792529).TISSUE SPECIFICITY Predominantly expressed in lung and brain, but also expressed at lower levels in many tissues including pancreatic islets. Highly expressed in non-small cell lung cancers.DOMAIN The PB1 domain mediates interaction with SQSTM1.DOMAIN The C1 zinc finger does not bind diacylglycerol (DAG).DOMAIN The pseudosubstrate motif resembles the sequence around sites phosphorylated on target proteins, except the presence of a non-phosphorylatable residue in place of Ser, it modulates activity by competing with substrates.PTM Phosphorylation at Thr-412 in the activation loop is not mandatory for activation (By similarity). Upon neuronal growth factor (NGF) stimulation, phosphorylated by SRC at Tyr-265, Tyr-280 and Tyr-334 (PubMed:11713277, PubMed:16452474). Phosphorylation at Tyr-265 facilitates binding to KPNB1/importin-beta regulating entry of PRKCI into the nucleus (PubMed:11891849). Phosphorylation on Tyr-334 is important for NF-kappa-B stimulation (PubMed:11713277). Phosphorylated at Thr-564 during the initial phase of long term potentiation (By similarity).SIMILARITY Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. PKC subfamily. UniProt P41743 2 EQUAL 596 EQUAL Reactome Database ID Release 81 9021345 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=9021345 Reactome R-HSA-9021345 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-9021345.1 GENE ONTOLOGY GO:0004697 gene ontology term for cellular function MI MI:0355 Same Catalyst Activity Reactome Database ID Release 81 9021348 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=9021348 Reactome Database ID Release 81 9021357 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=9021357 Reactome R-HSA-9021357 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-9021357.1 26977885 Pubmed 2016 Protein Kinase Cι Drives a NOTCH3-dependent Stem-like Phenotype in Mutant KRAS Lung Adenocarcinoma Ali, Syed A Justilien, Verline Jamieson, Lee Murray, Nicole R Fields, Alan P Cancer Cell 29:367-78 LEFT-TO-RIGHT ELF3 binds NOTCH3 gene promoter ELF3, phosphorylated by PRKCI (protein kinase C iota) on serine residue S68, binds multiple ELF3-binding sites in the NOTCH3 gene promoter (Ali et al. 2016). Authored: Orlic-Milacic, Marija, 2017-09-20 Reviewed: Haw, Robin, 2017-10-30 Edited: Orlic-Milacic, Marija, 2017-11-02 p-S68-ELF3:NOTCH3 gene Reactome DB_ID: 9021365 1 1 Reactome Database ID Release 81 9021365 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=9021365 Reactome R-HSA-9021365 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-9021365.1 Reactome Database ID Release 81 9021364 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=9021364 Reactome R-HSA-9021364 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-9021364.1 LEFT-TO-RIGHT NOTCH3 gene transcription The NOTCH3 gene maps to human chromosome 19. NOTCH3 transcript is ubiquitously expressed in fetal and adult human tissues. Mutations in NOTCH3 are found in cerebral arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), an autosomal dominant progressive disorder of small arterial vessels of the brain characterized by migraines, strokes, and white matter lesions, with the onset in early adulthood (Joutel et al. 1996).<br><br>NOTCH3 gene transcription is stimulated by the NOTCH3 coactivator complex but it is not known whether this effect is direct, or indirect (Liu et al. 2009).<p>NOTCH3 gene transcription is directly stimulated by the NOTCH1 coactivator complex and NOTCH1-mediated regulation of NOTCH3 is involved in differentiation of esophageal squamous cells (Ohashi et al. 2009).<p>NOTCH3 transcription is directly stimulated by transcription factor ELF3, activated by PRKCI (protein kinase C iota)-mediated phosphorylation downstream of KRAS signaling. The PRKCI-ELF3-NOTCH3 signaling controls the tumor-initiating cell phenotype in KRAS-mediated lung adenocarcinoma (Ali et al. 2016). Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Reviewed: Haw, R, 2012-05-17 Reviewed: Haw, Robin, 2017-10-30 Edited: Orlic-Milacic, M, 2012-02-10 Edited: D'Eustachio, P, 2012-02-06 Edited: D'Eustachio, P, 2012-05-15 Edited: Orlic-Milacic, Marija, 2017-11-02 NOTCH3 mRNA Reactome DB_ID: 1911478 ENSEMBL:ENST00000263388 NOTCH3 NOTCH3 mRNA NOTCH3 ENSEMBL ENST00000263388 1 EQUAL 8070 EQUAL Reactome Database ID Release 81 1911478 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=1911478 Reactome R-HSA-1911478 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-1911478.1 Reactome Database ID Release 81 1912415 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=1912415 Reactome R-HSA-1912415 4 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-1912415.4 8878478 Pubmed 1996 Notch3 mutations in CADASIL, a hereditary adult-onset condition causing stroke and dementia Joutel, A Corpechot, C Ducros, A Vahedi, K Chabriat, H Mouton, P Alamowitch, S Domenga, V Cécillion, M Maréchal, E Maciazek, J Vayssiere, C Cruaud, C Cabanis, EA Ruchoux, MM Weissenbach, J Bach, JF Bousser, MG Tournier-Lasserve, E Nature 383:707-10 19150886 Pubmed 2009 NOTCH3 expression is induced in mural cells through an autoregulatory loop that requires endothelial-expressed JAGGED1 Liu, Hua Kennard, Simone Lilly, Brenda Circ. Res. 104:466-75 ACTIVATION activeUnit: #Complex5 Reactome Database ID Release 81 9017841 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=9017841 Reactome R-HSA-9017841 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-9017841.1 ACTIVATION Reactome Database ID Release 81 2248835 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=2248835 Reactome R-HSA-2248835 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-2248835.1 NOTCH3 coactivator complex Reactome DB_ID: 2248837 NICD3 NOTCH3(1662-2321) NICD 3 fragment N3ICD Reactome DB_ID: 157928 UniProt:Q9UM47 NOTCH3 NOTCH3 FUNCTION Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination (PubMed:15350543). 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 (By similarity).SUBUNIT Heterodimer of a C-terminal fragment N(TM) and a N-terminal fragment N(EC) which are probably linked by disulfide bonds (By similarity). Interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH3. Interacts with PSMA1. Interacts with HIF1AN.TISSUE SPECIFICITY Ubiquitously expressed in fetal and adult tissues.DOMAIN The EGF-like domains 10 and 11 are required for binding the ligands JAG1 and DLL1.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. Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by TNF-alpha converting enzyme (TACE) to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT). This fragment is then cleaved by presenilin dependent gamma-secretase to release a notch-derived peptide containing the intracellular domain (NICD) from the membrane.PTM Phosphorylated.PTM Hydroxylated by HIF1AN.SIMILARITY Belongs to the NOTCH family. UniProt Q9UM47 1662 EQUAL 2321 EQUAL Reactome Database ID Release 81 157928 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=157928 Reactome R-HSA-157928 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-157928.1 1 1 1 Reactome Database ID Release 81 2248837 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=2248837 Reactome R-HSA-2248837 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-2248837.2 ACTIVATION activeUnit: #Protein22 Reactome Database ID Release 81 9021372 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=9021372 Reactome R-HSA-9021372 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-9021372.1 LEFT-TO-RIGHT NOTCH4 gene transcription The NOTCH4 gene maps to the short arm of human chromosome 6. High levels of NOTCH4 transcript are detectable in adult heart. NOTCH4 mRNA is also found in lung and placenta, and at low levels in liver, skeletal muscle, kidney, pancreas, spleen, thymus, lymph nodes and bone marrow (Li et al. 1998).<br><br>In vascular endothelium, NOTCH4 transcription is activated by c-JUN (AP-1) transcription factor. JUN, likely in complex with other transcription factors, binds AP-1 motif(s) in the NOTCH4 promoter and possibly within the first intron (Wu et al. 2005). Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Reviewed: Haw, R, 2012-05-17 Edited: Orlic-Milacic, M, 2012-02-10 Edited: D'Eustachio, P, 2012-02-06 Edited: D'Eustachio, P, 2012-05-15 NOTCH4 gene Reactome DB_ID: 1911501 ENSEMBL:ENSG00000206312 NOTCH4 NOTCH4 Gene NOTCH4 ENSEMBL ENSG00000206312 Reactome Database ID Release 81 1911501 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=1911501 Reactome R-HSA-1911501 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-1911501.1 NOTCH4 mRNA Reactome DB_ID: 1911475 ENSEMBL:ENST00000383264 NOTCH4 NOTCH4 mRNA NOTCH4 ENSEMBL ENST00000383264 1 EQUAL 6745 EQUAL Reactome Database ID Release 81 1911475 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=1911475 Reactome R-HSA-1911475 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-1911475.1 Reactome Database ID Release 81 1912401 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=1912401 Reactome R-HSA-1912401 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-1912401.3 15684396 Pubmed 2005 Molecular determinants of NOTCH4 transcription in vascular endothelium Wu, Jing Iwata, Fumiko Grass, Jeffrey A Osborne, Cameron S Elnitski, Laura Fraser, Peter Ohneda, Osamu Yamamoto, M Bresnick, Emery H Mol. Cell. Biol. 25:1458-74 9693032 Pubmed 1998 Cloning, characterization, and the complete 56.8-kilobase DNA sequence of the human NOTCH4 gene Li, L Huang, GM Banta, AB Deng, Y Smith, T Dong, P Friedman, C Chen, L Trask, BJ Spies, T Rowen, L Hood, L Genomics 51:45-58 GENE ONTOLOGY GO:0010628 ACTIVATION Reactome Database ID Release 81 2250429 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=2250429 Reactome R-HSA-2250429 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-2250429.1 JUN c-Jun AP1 Transcription factor AP-1 Reactome DB_ID: 450250 UniProt:P05412 JUN JUN FUNCTION Transcription factor that recognizes and binds to the AP-1 consensus motif 5'-TGA[GC]TCA-3' (PubMed:10995748, PubMed:22083952). Heterodimerizes with proteins of the FOS family to form an AP-1 transcription complex, thereby enhancing its DNA binding activity to the AP-1 consensus sequence 5'-TGA[GC]TCA-3' and enhancing its transcriptional activity (By similarity). Together with FOSB, plays a role in activation-induced cell death of T cells by binding to the AP-1 promoter site of FASLG/CD95L, and inducing its transcription in response to activation of the TCR/CD3 signaling pathway (PubMed:12618758). Promotes activity of NR5A1 when phosphorylated by HIPK3 leading to increased steroidogenic gene expression upon cAMP signaling pathway stimulation (PubMed:17210646). Involved in activated KRAS-mediated transcriptional activation of USP28 in colorectal cancer (CRC) cells (PubMed:24623306). Binds to the USP28 promoter in colorectal cancer (CRC) cells (PubMed:24623306).SUBUNIT Heterodimer with either BATF3 or ATF7 (PubMed:10376527, PubMed:12087103, PubMed:15467742). Heterodimer with FOS (By similarity). Heterodimer with FOSB isoform 1 and 2 (By similarity). Component of an AP-1 transcription factor complex composed of JUN-FOS heterodimers (By similarity). As part of the AP-1 transcription factor complex, forms heterodimers with FOSB, thereby binding to the AP-1 consensus sequence and stimulating transcription (By similarity). Interacts with FOS and FOSB isoform 1 and 2 (By similarity). The ATF7/JUN heterodimer is essential for ATF7 transactivation activity (PubMed:10376527). Interacts with DSIPI; the interaction inhibits the binding of active AP1 to its target DNA (By similarity). Interacts with HIVEP3 and MYBBP1A (By similarity). Interacts with SP1, SPIB and TCF20 (PubMed:10196196, PubMed:16478997, PubMed:8663478). Interacts with COPS5; the interaction leads indirectly to its phosphorylation (PubMed:8837781). Component of the SMAD3/SMAD4/JUN/FOS/complex which forms at the AP1 promoter site (PubMed:10995748). The SMAD3/SMAD4 heterodimer acts synergistically with the JUN/FOS heterodimer to activate transcription in response to TGF-beta (PubMed:9732876). Interacts (via its basic DNA binding and leucine zipper domains) with SMAD3 (via an N-terminal domain); the interaction is required for TGF-beta-mediated transactivation of the SMAD3/SMAD4/JUN/FOS/complex (PubMed:10995748). Interacts with methylated RNF187 (PubMed:20852630, PubMed:23624934). Binds to HIPK3. Interacts (when phosphorylated) with FBXW7 (PubMed:14739463). Found in a complex with PRR7 and FBXW7 (PubMed:27458189). Interacts with PRR7 and FBXW7; the interaction inhibits ubiquitination-mediated JUN degradation promoting its phosphorylation and transcriptional activity (PubMed:27458189). Interacts with RBM39 (By similarity). Interacts with PAGE4 (PubMed:24263171, PubMed:24559171, PubMed:26242913).TISSUE SPECIFICITY Expressed in the developing and adult prostate and prostate cancer cells.PTM Ubiquitinated by the SCF(FBXW7), leading to its degradation (PubMed:14739463, PubMed:27458189). Ubiquitination takes place following phosphorylation, that promotes interaction with FBXW7 (PubMed:14739463).PTM Phosphorylated by CaMK4 and PRKDC; phosphorylation enhances the transcriptional activity. Phosphorylated by HIPK3. Phosphorylated by DYRK2 at Ser-243; this primes the protein for subsequent phosphorylation by GSK3B at Thr-239. Phosphorylated at Thr-239, Ser-243 and Ser-249 by GSK3B; phosphorylation reduces its ability to bind DNA. Phosphorylated by PAK2 at Thr-2, Thr-8, Thr-89, Thr-93 and Thr-286 thereby promoting JUN-mediated cell proliferation and transformation. Phosphorylated by PLK3 following hypoxia or UV irradiation, leading to increase DNA-binding activity.PTM Acetylated at Lys-271 by EP300.SIMILARITY Belongs to the bZIP family. Jun subfamily. UniProt P05412 1 EQUAL 331 EQUAL Reactome Database ID Release 81 450250 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=450250 Reactome R-HSA-450250 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-450250.1 LEFT-TO-RIGHT TP53 binds promoters of MIR34 genes TP53 (p53) binds to the conserved p53 binding site located in the vicinity of the MIR34A transcription start (Chang et al. 2007, Raver-Shapira et al. 2007). TP53 also binds to conserved p53 binding sites in the promoter of clustered MIR34B and MIR34C genes, and the transcription of MIR34B and MIR34C microRNAs is directly positively regulated by p53 (He et al. 2007, Corney et al. 2007). Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: D'Eustachio, P, 2012-02-06 TP53 Tetramer Reactome DB_ID: 3209194 TP53 p53 protein P53_HUMAN Cellular tumor antigen p53 Tumor suppressor p53 Phosphoprotein p53 Antigen NY-CO-13 Reactome DB_ID: 69488 UniProt:P04637 TP53 TP53 P53 FUNCTION Acts as a tumor suppressor in many tumor types; induces growth arrest or apoptosis depending on the physiological circumstances and cell type. Involved in cell cycle regulation as a trans-activator that acts to negatively regulate cell division by controlling a set of genes required for this process. One of the activated genes is an inhibitor of cyclin-dependent kinases. Apoptosis induction seems to be mediated either by stimulation of BAX and FAS antigen expression, or by repression of Bcl-2 expression. Its pro-apoptotic activity is activated via its interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 (PubMed:12524540). However, this activity is inhibited when the interaction with PPP1R13B/ASPP1 or TP53BP2/ASPP2 is displaced by PPP1R13L/iASPP (PubMed:12524540). In cooperation with mitochondrial PPIF is involved in activating oxidative stress-induced necrosis; the function is largely independent of transcription. Induces the transcription of long intergenic non-coding RNA p21 (lincRNA-p21) and lincRNA-Mkln1. LincRNA-p21 participates in TP53-dependent transcriptional repression leading to apoptosis and seems to have an effect on cell-cycle regulation. Implicated in Notch signaling cross-over. Prevents CDK7 kinase activity when associated to CAK complex in response to DNA damage, thus stopping cell cycle progression. Isoform 2 enhances the transactivation activity of isoform 1 from some but not all TP53-inducible promoters. Isoform 4 suppresses transactivation activity and impairs growth suppression mediated by isoform 1. Isoform 7 inhibits isoform 1-mediated apoptosis. Regulates the circadian clock by repressing CLOCK-ARNTL/BMAL1-mediated transcriptional activation of PER2 (PubMed:24051492).SUBUNIT Forms homodimers and homotetramers (PubMed:19011621). Binds DNA as a homotetramer. Interacts with AXIN1. Probably part of a complex consisting of TP53, HIPK2 and AXIN1 (By similarity). Interacts with histone acetyltransferases EP300 and methyltransferases HRMT1L2 and CARM1, and recruits them to promoters. Interacts (via C-terminus) with TAF1; when TAF1 is part of the TFIID complex. Interacts with ING4; this interaction may be indirect. Found in a complex with CABLES1 and TP73. Interacts with HIPK1, HIPK2, and TP53INP1. Interacts with WWOX. May interact with HCV core protein. Interacts with USP7 and SYVN1. Interacts with HSP90AB1. Interacts with CHD8; leading to recruit histone H1 and prevent transactivation activity (By similarity). Interacts with ARMC10, CDKN2AIP, NUAK1, STK11/LKB1, UHRF2 and E4F1. Interacts with YWHAZ; the interaction enhances TP53 transcriptional activity. Phosphorylation of YWHAZ on 'Ser-58' inhibits this interaction. Interacts (via DNA-binding domain) with MAML1 (via N-terminus). Interacts with MKRN1. Interacts with PML (via C-terminus). Interacts with MDM2; leading to ubiquitination and proteasomal degradation of TP53. Directly interacts with FBXO42; leading to ubiquitination and degradation of TP53. Interacts (phosphorylated at Ser-15 by ATM) with the phosphatase PP2A-PPP2R5C holoenzyme; regulates stress-induced TP53-dependent inhibition of cell proliferation. Interacts with PPP2R2A. Interacts with AURKA, DAXX, BRD7 and TRIM24. Interacts (when monomethylated at Lys-382) with L3MBTL1. Isoform 1 interacts with isoform 2 and with isoform 4. Interacts with GRK5. Binds to the CAK complex (CDK7, cyclin H and MAT1) in response to DNA damage. Interacts with CDK5 in neurons. Interacts with AURKB, SETD2, UHRF2 and NOC2L. Interacts (via N-terminus) with PTK2/FAK1; this promotes ubiquitination by MDM2. Interacts with PTK2B/PYK2; this promotes ubiquitination by MDM2. Interacts with PRKCG. Interacts with PPIF; the association implicates preferentially tetrameric TP53, is induced by oxidative stress and is impaired by cyclosporin A (CsA). Interacts with SNAI1; the interaction induces SNAI1 degradation via MDM2-mediated ubiquitination and inhibits SNAI1-induced cell invasion. Interacts with KAT6A. Interacts with UBC9. Interacts with ZNF385B; the interaction is direct. Interacts (via DNA-binding domain) with ZNF385A; the interaction is direct and enhances p53/TP53 transactivation functions on cell-cycle arrest target genes, resulting in growth arrest. Interacts with ANKRD2. Interacts with RFFL and RNF34; involved in p53/TP53 ubiquitination. Interacts with MTA1 and COP1. Interacts with CCAR2 (via N-terminus). Interacts with MORC3 (PubMed:17332504). Interacts (via C-terminus) with POU4F2 isoform 1 (via C-terminus) (PubMed:17145718). Interacts (via oligomerization region) with NOP53; the interaction is direct and may prevent the MDM2-mediated proteasomal degradation of TP53 (PubMed:22522597). Interacts with AFG1L; mediates mitochondrial translocation of TP53 (PubMed:27323408). Interacts with UBD (PubMed:25422469). Interacts with TAF6 isoform 1 and isoform 4 (PubMed:20096117). Interacts with C10orf90/FATS; the interaction inhibits binding of TP53 and MDM2 (By similarity). Interacts with NUPR1; interaction is stress-dependent (PubMed:18690848). Forms a complex with EP300 and NUPR1; this complex binds CDKN1A promoter leading to transcriptional induction of CDKN1A (PubMed:18690848). Interacts with PRMT5 in response to DNA damage; the interaction is STRAP dependent (PubMed:19011621). Interacts with PPP1R13L (via SH3 domain and ANK repeats); the interaction inhibits pro-apoptotic activity of p53/TP53 (PubMed:12524540). Interacts with PPP1R13B/ASPP1 and TP53BP2/ASPP2; the interactions promotes pro-apoptotic activity (PubMed:12524540). When phosphorylated at Ser-15, interacts with DDX3X and gamma-tubulin (PubMed:28842590). Interacts with KAT7/HBO1; leading to inhibit histone acetyltransferase activity of KAT7/HBO1 (PubMed:17954561). Interacts (via N-terminus) with E3 ubiquitin-protein ligase MUL1; the interaction results in ubiquitination of cytoplasmic TP53 at Lys-24 and subsequent proteasomal degradation (PubMed:21597459). Interacts with S100A4; this interaction promotes TP53 degradation (PubMed:23752197, PubMed:32442400). Interacts with BANP (By similarity). Interacts with TTC5/STRAP; the interaction may result in increased mitochondrial-dependent apoptosis (PubMed:25168243).SUBUNIT (Microbial infection) Interacts with cancer-associated/HPV E6 viral proteins leading to ubiquitination and degradation of TP53 giving a possible model for cell growth regulation. This complex formation requires an additional factor, E6-AP, which stably associates with TP53 in the presence of E6.SUBUNIT (Microbial infection) Interacts with human cytomegalovirus/HHV-5 protein UL123.SUBUNIT (Microbial infection) Interacts (via N-terminus) with human adenovirus 5 E1B-55K protein; this interaction leads to the inhibition of TP53 function and/or its degradation.SUBUNIT (Microbial infection) Interacts with Kaposi's sarcoma-associated herpesvirus/HHV-8 protein ORF45; this interaction results in the cytoplasmic localization of TP53 thereby decreasing its transcriptional activity.TISSUE SPECIFICITY Ubiquitous. Isoforms are expressed in a wide range of normal tissues but in a tissue-dependent manner. Isoform 2 is expressed in most normal tissues but is not detected in brain, lung, prostate, muscle, fetal brain, spinal cord and fetal liver. Isoform 3 is expressed in most normal tissues but is not detected in lung, spleen, testis, fetal brain, spinal cord and fetal liver. Isoform 7 is expressed in most normal tissues but is not detected in prostate, uterus, skeletal muscle and breast. Isoform 8 is detected only in colon, bone marrow, testis, fetal brain and intestine. Isoform 9 is expressed in most normal tissues but is not detected in brain, heart, lung, fetal liver, salivary gland, breast or intestine.INDUCTION Up-regulated in response to DNA damage. Isoform 2 is not induced in tumor cells in response to stress.DOMAIN The nuclear export signal acts as a transcriptional repression domain. The TADI and TADII motifs (residues 17 to 25 and 48 to 56) correspond both to 9aaTAD motifs which are transactivation domains present in a large number of yeast and animal transcription factors.PTM Acetylated. Acetylation of Lys-382 by CREBBP enhances transcriptional activity. Acetylation of Lys-382 by EP300. Deacetylation of Lys-382 by SIRT1 impairs its ability to induce proapoptotic program and modulate cell senescence. Deacetylation by SIRT2 impairs its ability to induce transcription activation in a AKT-dependent manner.PTM Phosphorylation on Ser residues mediates transcriptional activation. Phosphorylated by HIPK1 (By similarity). Phosphorylation at Ser-9 by HIPK4 increases repression activity on BIRC5 promoter. Phosphorylated on Thr-18 by VRK1. Phosphorylated on Ser-20 by CHEK2 in response to DNA damage, which prevents ubiquitination by MDM2. Phosphorylated on Ser-20 by PLK3 in response to reactive oxygen species (ROS), promoting p53/TP53-mediated apoptosis. Phosphorylated on Thr-55 by TAF1, which promotes MDM2-mediated degradation. Phosphorylated on Ser-33 by CDK7 in a CAK complex in response to DNA damage. Phosphorylated on Ser-46 by HIPK2 upon UV irradiation. Phosphorylation on Ser-46 is required for acetylation by CREBBP. Phosphorylated on Ser-392 following UV but not gamma irradiation. Phosphorylated by NUAK1 at Ser-15 and Ser-392; was initially thought to be mediated by STK11/LKB1 but it was later shown that it is indirect and that STK11/LKB1-dependent phosphorylation is probably mediated by downstream NUAK1 (PubMed:21317932). It is unclear whether AMP directly mediates phosphorylation at Ser-15. Phosphorylated on Thr-18 by isoform 1 and isoform 2 of VRK2. Phosphorylation on Thr-18 by isoform 2 of VRK2 results in a reduction in ubiquitination by MDM2 and an increase in acetylation by EP300. Stabilized by CDK5-mediated phosphorylation in response to genotoxic and oxidative stresses at Ser-15, Ser-33 and Ser-46, leading to accumulation of p53/TP53, particularly in the nucleus, thus inducing the transactivation of p53/TP53 target genes. Phosphorylated by DYRK2 at Ser-46 in response to genotoxic stress. Phosphorylated at Ser-315 and Ser-392 by CDK2 in response to DNA-damage. Phosphorylation at Ser-15 is required for interaction with DDX3X and gamma-tubulin (PubMed:28842590).PTM Dephosphorylated by PP2A-PPP2R5C holoenzyme at Thr-55. SV40 small T antigen inhibits the dephosphorylation by the AC form of PP2A.PTM May be O-glycosylated in the C-terminal basic region. Studied in EB-1 cell line.PTM Ubiquitinated by MDM2 and SYVN1, which leads to proteasomal degradation (PubMed:10722742, PubMed:12810724, PubMed:15340061, PubMed:17170702, PubMed:19880522). Ubiquitinated by RFWD3, which works in cooperation with MDM2 and may catalyze the formation of short polyubiquitin chains on p53/TP53 that are not targeted to the proteasome (PubMed:10722742, PubMed:12810724, PubMed:20173098). Ubiquitinated by MKRN1 at Lys-291 and Lys-292, which leads to proteasomal degradation (PubMed:19536131). Deubiquitinated by USP10, leading to its stabilization (PubMed:20096447). Ubiquitinated by TRIM24, RFFL, RNF34 and RNF125, which leads to proteasomal degradation (PubMed:19556538). Ubiquitination by TOPORS induces degradation (PubMed:19473992). Deubiquitination by USP7, leading to stabilization (PubMed:15053880). Isoform 4 is monoubiquitinated in an MDM2-independent manner (PubMed:15340061). Ubiquitinated by COP1, which leads to proteasomal degradation (PubMed:19837670). Ubiquitination and subsequent proteasomal degradation is negatively regulated by CCAR2 (PubMed:25732823). Polyubiquitinated by C10orf90/FATS, polyubiquitination is 'Lys-48'-linkage independent and non-proteolytic, leading to TP53 stabilization (By similarity). Polyubiquitinated by MUL1 at Lys-24 which leads to proteasomal degradation (PubMed:21597459).PTM Monomethylated at Lys-372 by SETD7, leading to stabilization and increased transcriptional activation (PubMed:15525938, PubMed:16415881). Monomethylated at Lys-370 by SMYD2, leading to decreased DNA-binding activity and subsequent transcriptional regulation activity (PubMed:17108971). Lys-372 monomethylation prevents interaction with SMYD2 and subsequent monomethylation at Lys-370 (PubMed:17108971). Dimethylated at Lys-373 by EHMT1 and EHMT2 (PubMed:20118233). Monomethylated at Lys-382 by KMT5A, promoting interaction with L3MBTL1 and leading to repress transcriptional activity (PubMed:17707234). Dimethylation at Lys-370 and Lys-382 diminishes p53 ubiquitination, through stabilizing association with the methyl reader PHF20 (PubMed:22864287). Demethylation of dimethylated Lys-370 by KDM1A prevents interaction with TP53BP1 and represses TP53-mediated transcriptional activation (PubMed:17805299). Monomethylated at Arg-333 and dimethylated at Arg-335 and Arg-337 by PRMT5; methylation is increased after DNA damage and might possibly affect TP53 target gene specificity (PubMed:19011621).PTM Sumoylated with SUMO1. Sumoylated at Lys-386 by UBC9.DISEASE TP53 is found in increased amounts in a wide variety of transformed cells. TP53 is frequently mutated or inactivated in about 60% of cancers. TP53 defects are found in Barrett metaplasia a condition in which the normally stratified squamous epithelium of the lower esophagus is replaced by a metaplastic columnar epithelium. The condition develops as a complication in approximately 10% of patients with chronic gastroesophageal reflux disease and predisposes to the development of esophageal adenocarcinoma.SIMILARITY Belongs to the p53 family.CAUTION Interaction with BANP was reported to enhance phosphorylation on Ser-15 upon ultraviolet irradiation (PubMed:15701641). However, the publication has been retracted due to image duplication and manipulation. Interaction with BANP has been confirmed in mouse studies (By similarity). Phosphorylation at Ser-15 has been confirmed by other studies (PubMed:10570149, PubMed:11554766, PubMed:16219768, PubMed:15866171, PubMed:17317671, PubMed:17954561, PubMed:20959462, PubMed:25772236). Its nuclear and cytoplasmic localization has been confirmed by other studies (PubMed:15340061, PubMed:17170702, PubMed:19011621, PubMed:21597459, PubMed:22726440, PubMed:17591690, PubMed:18206965). UniProt P04637 1 EQUAL 393 EQUAL Reactome Database ID Release 81 69488 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=69488 Reactome R-HSA-69488 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-69488.1 4 Reactome Database ID Release 81 3209194 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=3209194 Reactome R-HSA-3209194 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-3209194.1 Converted from EntitySet in Reactome MIR34 genes Reactome DB_ID: 1852586 MIR34A gene Reactome DB_ID: 1852580 ENSEMBL:ENSG00000207865 MIR34A MIR34A gene MIR34A ENSEMBL ENSG00000207865 Reactome Database ID Release 81 1852580 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=1852580 Reactome R-HSA-1852580 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-1852580.1 MIR34B gene Reactome DB_ID: 1852582 ENSEMBL:ENSG00000207811 MIR34B MIR34B gene MIR34B ENSEMBL ENSG00000207811 Reactome Database ID Release 81 1852582 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=1852582 Reactome R-HSA-1852582 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-1852582.1 MIR34C gene Reactome DB_ID: 1852583 ENSEMBL:ENSG00000207562 MIR34C MIR34C gene MIR34C ENSEMBL ENSG00000207562 Reactome Database ID Release 81 1852583 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=1852583 Reactome R-HSA-1852583 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-1852583.1 Reactome Database ID Release 81 1852586 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=1852586 Reactome R-HSA-1852586 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-1852586.2 TP53 Tetramer:MIR34 genes Reactome DB_ID: 4395237 1 1 Reactome Database ID Release 81 4395237 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=4395237 Reactome R-HSA-4395237 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-4395237.1 Reactome Database ID Release 81 4395236 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=4395236 Reactome R-HSA-4395236 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-4395236.1 17823410 Pubmed 2007 MicroRNA-34b and MicroRNA-34c are targets of p53 and cooperate in control of cell proliferation and adhesion-independent growth Corney, DC Flesken-Nikitin, A Godwin, AK Wang, Wei Nikitin, AY Cancer Res 67:8433-8 17540599 Pubmed 2007 Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis Chang, TC Wentzel, EA Kent, OA Ramachandran, K Mullendore, M Lee, KH Feldmann, G Yamakuchi, M Ferlito, M Lowenstein, CJ Arking, DE Beer, MA Maitra, A Mendell, JT Mol Cell 26:745-52 17540598 Pubmed 2007 Transcriptional activation of miR-34a contributes to p53-mediated apoptosis Raver-Shapira, N Marciano, E Meiri, E Spector, Y Rosenfeld, N Moskovits, N Bentwich, Z Oren, M Mol Cell 26:731-43 17554337 Pubmed 2007 A microRNA component of the p53 tumour suppressor network He, L He, Xi Lim, LP de Stanchina, E Xuan, Z Liang, Y Xue, W Zender, L Magnus, J Ridzon, D Jackson, AL Linsley, PS Chen, C Lowe, SW Cleary, MA Hannon, GJ Nature 447:1130-4 LEFT-TO-RIGHT p53 positively regulates transcription of MIR34 microRNAs Transcription of microRNA MIR34A is directly induced by the tumor suppressor p53, which binds to the conserved p53 binding site located in the vicinity of the MIR34A transcription start (Chang et al. 2007, Raver-Shapira et al. 2007). Genomic loss of the chromosomal band 1p36, harboring the MIR34A gene, is a frequent event in pancreatic cancer, and MIR34A is considered to act as a tumor suppressor. Conserved p53 binding sites were also mapped to the promoter of clustered MIR34B and MIR34C genes, and the transcription of MIR34B and MIR34C microRNAs was shown to be positively regulated by p53 (He et al. 2007, Corney et al. 2007). The steps involved in processing of pri-microRNA into pre-microRNA have been omitted in this event - please refer to the diagram of Regulatory RNA Pathways for details. Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: D'Eustachio, P, 2012-02-06 Converted from EntitySet in Reactome miR-34 RISC miR-34-induced Silencing Complex Reactome DB_ID: 1606685 miR-34 Endonucleolytic RISC Reactome DB_ID: 1606684 MOV10 Putative helicase MOV-10 MOV10_HUMAN Reactome DB_ID: 427772 UniProt:Q9HCE1 MOV10 MOV10 KIAA1631 FUNCTION 5' to 3' RNA helicase contributing to UPF1 mRNA target degradation by translocation along 3' UTRs (PubMed:24726324). Required for microRNA (miRNA)-mediated gene silencing by the RNA-induced silencing complex (RISC). Required for both miRNA-mediated translational repression and miRNA-mediated cleavage of complementary mRNAs by RISC (PubMed:16289642, PubMed:17507929, PubMed:22791714). In cooperation with FMR1, regulates miRNA-mediated translational repression by AGO2 (PubMed:25464849). Restricts retrotransposition of long interspersed element-1 (LINE-1) in cooperation with TUT4 and TUT7 counteracting the RNA chaperonne activity of L1RE1 (PubMed:30122351, PubMed:23093941). Facilitates LINE-1 uridylation by TUT4 and TUT7 (PubMed:30122351). Required for embryonic viability and for normal central nervous system development and function. Plays two critical roles in early brain development: suppresses retroelements in the nucleus by directly inhibiting cDNA synthesis, while regulates cytoskeletal mRNAs to influence neurite outgrowth in the cytosol (By similarity). May function as a messenger ribonucleoprotein (mRNP) clearance factor (PubMed:24726324). Exhibits antiviral activity against dengue virus (DENV) (PubMed:27974568).FUNCTION (Microbial infection) Required for RNA-directed transcription and replication of the human hepatitis delta virus (HDV). Interacts with small capped HDV RNAs derived from genomic hairpin structures that mark the initiation sites of RNA-dependent HDV RNA transcription.SUBUNIT Interacts with DICER1, AGO2, TARBP2, EIF6 and RPL7A (60S ribosome subunit); they form a large RNA-induced silencing complex (RISC) (PubMed:17507929). Interacts with APOBEC3G in an RNA-dependent manner. Interacts with TRIM71 (via NHL repeats) in an RNA-dependent manner (PubMed:23125361). Interacts with both protein products of LIRE1, ORF1p and ORF2p (PubMed:23093941). Interacts with TUT4 and, to a lesser extent, TUT7; the interactions are RNA-dependent (PubMed:30122351). Interacts with AGO2, TNRC6B and UPF1; the interactions are direct and RNA-dependent (PubMed:24726324). Interacts with FMR1; this interaction is direct, occurs in an RNA-dependent manner on polysomes and induces association of MOV10 with RNAs (PubMed:25464849). Interacts with SHFL; the interaction increases in presence of RNA (PubMed:27974568). Interacts with DHX34; the interaction is RNA-independent (PubMed:25220460).SUBUNIT (Microbial infection) Interacts with the human hepatitis delta virus (HDV) antigen HDAg.SIMILARITY Belongs to the DNA2/NAM7 helicase family. SDE3 subfamily. UniProt Q9HCE1 1 EQUAL 1003 EQUAL Reactome Database ID Release 81 427772 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=427772 Reactome R-HSA-427772 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-427772.1 1 miR-34 Endonucleolytic Minimal RISC Argonaute2: miR-34 (single-stranded) Reactome DB_ID: 1606688 AGO2 EIF2C2 Argonaute-2 Reactome DB_ID: 209723 UniProt:Q9UKV8 AGO2 AGO2 EIF2C2 FUNCTION Required for RNA-mediated gene silencing (RNAi) by the RNA-induced silencing complex (RISC). The 'minimal RISC' appears to include AGO2 bound to a short guide RNA such as a microRNA (miRNA) or short interfering RNA (siRNA). These guide RNAs direct RISC to complementary mRNAs that are targets for RISC-mediated gene silencing. The precise mechanism of gene silencing depends on the degree of complementarity between the miRNA or siRNA and its target. Binding of RISC to a perfectly complementary mRNA generally results in silencing due to endonucleolytic cleavage of the mRNA specifically by AGO2. Binding of RISC to a partially complementary mRNA results in silencing through inhibition of translation, and this is independent of endonuclease activity. May inhibit translation initiation by binding to the 7-methylguanosine cap, thereby preventing the recruitment of the translation initiation factor eIF4-E. May also inhibit translation initiation via interaction with EIF6, which itself binds to the 60S ribosomal subunit and prevents its association with the 40S ribosomal subunit. The inhibition of translational initiation leads to the accumulation of the affected mRNA in cytoplasmic processing bodies (P-bodies), where mRNA degradation may subsequently occur. In some cases RISC-mediated translational repression is also observed for miRNAs that perfectly match the 3' untranslated region (3'-UTR). Can also up-regulate the translation of specific mRNAs under certain growth conditions. Binds to the AU element of the 3'-UTR of the TNF (TNF-alpha) mRNA and up-regulates translation under conditions of serum starvation. Also required for transcriptional gene silencing (TGS), in which short RNAs known as antigene RNAs or agRNAs direct the transcriptional repression of complementary promoter regions.ACTIVITY REGULATION Inhibited by EDTA.SUBUNIT Interacts with DICER1 through its Piwi domain and with TARBP2 during assembly of the RNA-induced silencing complex (RISC)(PubMed:14749716, PubMed:16271387, PubMed:16289642, PubMed:16357216, PubMed:15973356, PubMed:17507929, PubMed:18690212, PubMed:18178619, PubMed:33199684). Together, DICER1, AGO2 and TARBP2 constitute the trimeric RISC loading complex (RLC), or micro-RNA (miRNA) loading complex (miRLC). Within the RLC/miRLC, DICER1 and TARBP2 are required to process precursor miRNAs (pre-miRNAs) to mature miRNAs and then load them onto AGO2. AGO2 bound to the mature miRNA constitutes the minimal RISC and may subsequently dissociate from DICER1 and TARBP2. Note however that the term RISC has also been used to describe the trimeric RLC/miRLC. The formation of RISC complexes containing siRNAs rather than miRNAs appears to occur independently of DICER1. Interacts with AGO1. Also interacts with DDB1, DDX5, DDX6, DDX20, DHX30, DHX36, DDX47, DHX9, ELAVL, FXR1, GEMIN4, HNRNPF, IGF2BP1, ILF3, IMP8, MATR3, PABPC1, PRMT5, P4HA1, P4HB, RBM4, SART3, TNRC6A, TNRC6B, UPF1 and YBX1. Interacts with the P-body components DCP1A and XRN1. Associates with polysomes and messenger ribonucleoproteins (mNRPs). Interacts with RBM4; the interaction is modulated under stress-induced conditions, occurs under both cell proliferation and differentiation conditions and in an RNA- and phosphorylation-independent manner. Interacts with LIMD1, WTIP and AJUBA. Interacts with TRIM71; the interaction increases in presence of RNA (PubMed:23125361). Interacts with APOBEC3G in an RNA-dependent manner. Interacts with APOBEC3A, APOBEC3C, APOBEC3F and APOBEC3H. Interacts with DICER1, TARBP2, EIF6, MOV10 and RPL7A (60S ribosome subunit); they form a large RNA-induced silencing complex (RISC) (PubMed:17507929, PubMed:24726324). Interacts with FMR1 (PubMed:14703574). Interacts with ZFP36 (PubMed:15766526). Found in a complex, composed of AGO2, CHD7 and FAM172A (By similarity). Interacts with RC3H1; the interaction is RNA independent (PubMed:25697406). Interacts with SND1 (PubMed:14508492, PubMed:28546213). Interacts with SYT11 (By similarity). Interacts with CLNK (PubMed:26009488). Interacts with GARRE1 (PubMed:29395067).DOMAIN The Piwi domain may perform RNA cleavage by a mechanism similar to that of RNase H. However, while RNase H utilizes a triad of Asp-Asp-Glu (DDE) for metal ion coordination, this protein appears to utilize a triad of Asp-Asp-His (DDH).PTM Hydroxylated. 4-hydroxylation appears to enhance protein stability but is not required for miRNA-binding or endonuclease activity.PTM Ubiquitinated on surface-exposed lysines by a SCF-like E3 ubiquitin-protein ligase complex containing ZSWIM8 during target-directed microRNA degradation (TDMD), a process that mediates degradation of microRNAs (miRNAs) (PubMed:33184234, PubMed:33184237). Ubiquitination by the SCF-like E3 ubiquitin-protein ligase complex containing ZSWIM8 leads to its subsequent degradation, thereby exposing miRNAs for degradation (PubMed:33184234, PubMed:33184237). ZSWIM8 recognizes and binds AGO2 when it is engaged with a TDMD target (PubMed:33184237).PTM Phosphorylated. A phosphorylation cycle of C-terminal serine cluster (Ser-824-Ser-834) regulates the release of target mRNAs. Target-binding leads to phosphorylation of these residues by CSNK1A1, which reduces the affinity of AGO2 for mRNA and enables target release. The ANKRD52-PPP6C phosphatase complex dephosphorylates the residues, which primes AGO2 for binding a new target.PTM Phosphorylation at Ser-387 by AKT3; leads to up-regulate translational repression of microRNA target and down-regulate endonucleolytic cleavage.SIMILARITY Belongs to the argonaute family. Ago subfamily. UniProt Q9UKV8 1 EQUAL 859 EQUAL Reactome Database ID Release 81 209723 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=209723 Reactome R-HSA-209723 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-209723.2 1 Converted from EntitySet in Reactome MIR34 miR-34 Reactome DB_ID: 1606690 MIR34A miR-34A Reactome DB_ID: 1606699 miRBase:MI0000268 MIR34A MIR34A microRNA miR-34A microRNA microRNA 34a MIR34A miRBase MI0000268 22 EQUAL 43 EQUAL Reactome Database ID Release 81 1606699 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=1606699 Reactome R-HSA-1606699 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-1606699.1 MIR34B miR-34B Reactome DB_ID: 1606694 miRBase:MI0000742 MIR34B MIR34B microRNA miR-34B microRNA microRNA 34b MIR34B miRBase MI0000742 50 EQUAL 71 EQUAL Reactome Database ID Release 81 1606694 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=1606694 Reactome R-HSA-1606694 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-1606694.1 MIR34C miR-34C Reactome DB_ID: 1606687 miRBase:MI0000743 MIR34C MIR34C microRNA miR-34C microRNA microRNA 34c MIR34C miRBase MI0000743 13 EQUAL 35 EQUAL Reactome Database ID Release 81 1606687 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=1606687 Reactome R-HSA-1606687 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-1606687.1 Reactome Database ID Release 81 1606690 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=1606690 Reactome R-HSA-1606690 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-1606690.2 1 Reactome Database ID Release 81 1606688 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=1606688 Reactome R-HSA-1606688 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-1606688.1 1 Converted from EntitySet in Reactome TNRC6 (GW182) Reactome DB_ID: 427775 TNRC6A Trinucleotide repeat-containing gene 6A protein TNR6A_HUMAN Reactome DB_ID: 427769 UniProt:Q8NDV7 TNRC6A TNRC6A CAGH26 KIAA1460 TNRC6 FUNCTION Plays a role in RNA-mediated gene silencing by both micro-RNAs (miRNAs) and short interfering RNAs (siRNAs). Required for miRNA-dependent repression of translation and for siRNA-dependent endonucleolytic cleavage of complementary mRNAs by argonaute family proteins. As a scaffolding protein, associates with argonaute proteins bound to partially complementary mRNAs, and can simultaneously recruit CCR4-NOT and PAN deadenylase complexes.SUBUNIT Interacts with AGO2 (PubMed:16284623, PubMed:16284622, PubMed:18690212, PubMed:19304925, PubMed:19324964, PubMed:19383768). Interacts with AGO1, AGO3 and AGO4 (PubMed:19324964, PubMed:19383768). Interacts with CNOT1; the interaction is direct and mediates the association with the CCR4-NOT complex (PubMed:21981923). Interacts with ZC3H12A (PubMed:26134560). Interacts with SND1 (PubMed:28546213). Interacts with GARRE1 (PubMed:29395067).TISSUE SPECIFICITY Ubiquitous.INDUCTION By exogenous short interfering RNA (siRNA).MISCELLANEOUS Antibodies against TNRC6A are found in sera from patients with Sjoegren syndrome (SS), ataxia and sensor neuropathy diseases that developed autoantibodies against protein of the GWB structure. Autoantibodies were mapped to the GW-rich mid-part, the non-GW-rich region and the C-terminus of the protein.SIMILARITY Belongs to the GW182 family. UniProt Q8NDV7 1 EQUAL 1962 EQUAL Reactome Database ID Release 81 427769 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=427769 Reactome R-HSA-427769 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-427769.1 TNRC6B Trinucleotide repeat-containing gene 6B protein TNR6B_HUMAN Reactome DB_ID: 427777 UniProt:Q9UPQ9 TNRC6B TNRC6B KIAA1093 FUNCTION Plays a role in RNA-mediated gene silencing by both micro-RNAs (miRNAs) and short interfering RNAs (siRNAs) (PubMed:16289642, PubMed:19167051, PubMed:19304925, PubMed:32354837). Required for miRNA-dependent translational repression and siRNA-dependent endonucleolytic cleavage of complementary mRNAs by argonaute family proteins (PubMed:16289642, PubMed:19167051, PubMed:19304925, PubMed:32354837). As scaffolding protein associates with argonaute proteins bound to partially complementary mRNAs and simultaneously can recruit CCR4-NOT and PAN deadenylase complexes (PubMed:21981923).SUBUNIT Interacts with AGO1, AGO2, AGO3 and AGO4 (PubMed:16289642, PubMed:18690212, PubMed:19167051, PubMed:19304925, PubMed:19383768). Interacts with CNOT1; the interaction mediates the association with the CCR4-NOT complex (PubMed:21981923, PubMed:21984185). Interacts with PAN3; the interaction mediates the association with the PAN complex (PubMed:21981923). Interacts with MOV10; the interaction is direct and RNA-dependent (PubMed:24726324).SIMILARITY Belongs to the GW182 family. UniProt Q9UPQ9 1 EQUAL 1833 EQUAL Reactome Database ID Release 81 427777 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=427777 Reactome R-HSA-427777 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-427777.1 TNRC6C Trinucleotide repeat-containing gene 6C protein TNR6C_HUMAN Reactome DB_ID: 427776 UniProt:Q9HCJ0 TNRC6C TNRC6C KIAA1582 FUNCTION Plays a role in RNA-mediated gene silencing by micro-RNAs (miRNAs). Required for miRNA-dependent translational repression of complementary mRNAs by argonaute family proteins. As scaffoldng protein associates with argonaute proteins bound to partially complementary mRNAs and simultaneously can recruit CCR4-NOT and PAN deadenylase complexes.SUBUNIT Interacts with one or more of the argonaute family proteins AGO1, AGO2, AGO3 and AGO4. Interacts with PABPC1 and EIF4G1. Interacts with CNOT1; the interaction is direct and mediates the association with the CCR4-NOT complex. Interacts with PAN3; the interaction mediates the association with the PAN complex.DOMAIN The silencing domain, also known as C-terminal effector domain (CED), can act in autonomous repression, including both translational inhibition and mRNA degradation.SIMILARITY Belongs to the GW182 family. UniProt Q9HCJ0 1 EQUAL 1690 EQUAL Reactome Database ID Release 81 427776 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=427776 Reactome R-HSA-427776 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-427776.1 Reactome Database ID Release 81 427775 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=427775 Reactome R-HSA-427775 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-427775.1 1 Reactome Database ID Release 81 1606684 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=1606684 Reactome R-HSA-1606684 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-1606684.1 miR-34 Nonendonucleolytic RISC Reactome DB_ID: 1606692 Argonaute1/3/4: miR-34 miR-34 Nonendonucleolytic Minimal RISC Reactome DB_ID: 1606686 1 Converted from EntitySet in Reactome Nonendonucleolytic Argonaute Reactome DB_ID: 210613 AGO1 EIF2C1 Argonaute-1 Reactome DB_ID: 210616 UniProt:Q9UL18 AGO1 AGO1 EIF2C1 FUNCTION Required for RNA-mediated gene silencing (RNAi). Binds to short RNAs such as microRNAs (miRNAs) or short interfering RNAs (siRNAs), and represses the translation of mRNAs which are complementary to them. Lacks endonuclease activity and does not appear to cleave target mRNAs. Also required for transcriptional gene silencing (TGS) of promoter regions which are complementary to bound short antigene RNAs (agRNAs).SUBUNIT Interacts with DDB1, DDX5, DDX6, DHX30, DHX36, DDX47, DICER1, AGO2, ELAVL1, HNRNPF, IGF2BP1, ILF3, IMP8, MATR3, MOV10, PABPC1, PRMT5, RBM4, SART3, TNRC6B, UPF1 and YBX1. Associates with polysomes and messenger ribonucleoproteins (mNRPs). Interacts with LIMD1, WTIP and AJUBA. Interacts with APOBEC3F, APOBEC3G and APOBEC3H.PTM Ubiquitinated on surface-exposed lysines by a SCF-like E3 ubiquitin-protein ligase complex containing ZSWIM8 during target-directed microRNA degradation (TDMD), a process that mediates degradation of microRNAs (miRNAs). Ubiquitination by the SCF-like E3 ubiquitin-protein ligase complex containing ZSWIM8 leads to its subsequent degradation, thereby exposing miRNAs for degradation. ZSWIM8 recognizes and binds AGO1 when it is engaged with a TDMD target.MISCELLANEOUS Lacks RNA cleavage activity due to the absence of the conserved His at position 805, but also because it binds the RNA in a subtly different manner that precludes efficient cleavage.SIMILARITY Belongs to the argonaute family. Ago subfamily. UniProt Q9UL18 1 EQUAL 857 EQUAL Reactome Database ID Release 81 210616 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=210616 Reactome R-HSA-210616 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-210616.1 AGO3 EIF2C3 Argonaute-3 Reactome DB_ID: 210615 UniProt:Q9H9G7 AGO3 AGO3 EIF2C3 FUNCTION Required for RNA-mediated gene silencing (RNAi). Binds to short RNAs such as microRNAs (miRNAs) and represses the translation of mRNAs which are complementary to them. Proposed to be involved in stabilization of small RNA derivates (siRNA) derived from processed RNA polymerase III-transcribed Alu repeats containing a DR2 retinoic acid response element (RARE) in stem cells and in the subsequent siRNA-dependent degradation of a subset of RNA polymerase II-transcribed coding mRNAs by recruiting a mRNA decapping complex involving EDC4. Possesses RNA slicer activity but only on select RNAs bearing 5'- and 3'-flanking sequences to the region of guide-target complementarity (PubMed:29040713).SUBUNIT Interacts with EIF4B, IMP8, PRMT5 and TNRC6B. Interacts with APOBEC3F, APOBEC3G and APOBEC3H. Interacts with EDC4.PTM Ubiquitinated on surface-exposed lysines by a SCF-like E3 ubiquitin-protein ligase complex containing ZSWIM8 during target-directed microRNA degradation (TDMD), a process that mediates degradation of microRNAs (miRNAs). Ubiquitination by the SCF-like E3 ubiquitin-protein ligase complex containing ZSWIM8 leads to its subsequent degradation, thereby exposing miRNAs for degradation. ZSWIM8 recognizes and binds AGO3 when it is engaged with a TDMD target.SIMILARITY Belongs to the argonaute family. Ago subfamily. UniProt Q9H9G7 1 EQUAL 860 EQUAL Reactome Database ID Release 81 210615 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=210615 Reactome R-HSA-210615 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-210615.1 AGO4 EIF2C4 Argonaute-4 Reactome DB_ID: 210612 UniProt:Q9HCK5 AGO4 AGO4 EIF2C4 KIAA1567 FUNCTION Required for RNA-mediated gene silencing (RNAi). Binds to short RNAs such as microRNAs (miRNAs) and represses the translation of mRNAs which are complementary to them. Lacks endonuclease activity and does not appear to cleave target mRNAs. Also required for RNA-directed transcription and replication of the human hapatitis delta virus (HDV).SUBUNIT Interacts with EIF4B, IMP8, PRMT5, TNRC6A and TNRC6B (PubMed:19167051). Interacts with ZFP36 (PubMed:15766526).PTM Ubiquitinated on surface-exposed lysines by a SCF-like E3 ubiquitin-protein ligase complex containing ZSWIM8 during target-directed microRNA degradation (TDMD), a process that mediates degradation of microRNAs (miRNAs). Ubiquitination by the SCF-like E3 ubiquitin-protein ligase complex containing ZSWIM8 leads to its subsequent degradation, thereby exposing miRNAs for degradation. ZSWIM8 recognizes and binds AGO4 when it is engaged with a TDMD target.SIMILARITY Belongs to the argonaute family. Ago subfamily. UniProt Q9HCK5 1 EQUAL 861 EQUAL Reactome Database ID Release 81 210612 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=210612 Reactome R-HSA-210612 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-210612.1 Reactome Database ID Release 81 210613 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=210613 Reactome R-HSA-210613 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-210613.1 1 Reactome Database ID Release 81 1606686 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=1606686 Reactome R-HSA-1606686 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-1606686.1 1 1 1 Reactome Database ID Release 81 1606692 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=1606692 Reactome R-HSA-1606692 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-1606692.1 Reactome Database ID Release 81 1606685 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=1606685 Reactome R-HSA-1606685 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-1606685.1 Reactome Database ID Release 81 1912406 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=1912406 Reactome R-HSA-1912406 4 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-1912406.4 ACTIVATION Reactome Database ID Release 81 2152394 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=2152394 Reactome R-HSA-2152394 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-2152394.1 LEFT-TO-RIGHT MIR34 microRNAs bind 3'UTR of NOTCH1 mRNA Translation of NOTCH1 mRNA is inhibited by MIR34 microRNAs (MIR34A, MIR34B and MIR34C), which bind to the 3'UTR of NOTCH1 mRNA. Expression of MIR34 microRNAs is directly regulated by the p53 (TP53) tumor suppressor gene (Chang et al. 2007, Raver-Shapira et al. 2007), and MIR34-mediated downregulation of NOTCH1 signaling is thought to negatively regulate cell survival, motility and maintenance of an undifferentiated state. Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: May, B, 2012-02-09 Edited: D'Eustachio, P, 2012-02-06 Edited: Jupe, S, 2011-09-27 Edited: Gillespie, ME, 2012-02-09 NOTCH1 mRNA:miR-34 RISC Reactome DB_ID: 1606698 1 1 Reactome Database ID Release 81 1606698 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=1606698 Reactome R-HSA-1606698 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-1606698.1 Reactome Database ID Release 81 1606682 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=1606682 Reactome R-HSA-1606682 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-1606682.1 19773441 Pubmed 2009 MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes Li, Y Guessous, F Zhang, Y DiPierro, C Kefas, B Johnson, E Marcinkiewicz, L Jiang, J Yang, Y Schmittgen, TD Lopes, B Schiff, D Purow, B Abounader, R Cancer Res 69:7569-76 19714243 Pubmed 2009 MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells Ji, Q Hao, X Zhang, M Tang, W Meng, Y Li, L Xiang, D DeSano, JT Bommer, GT Fan, D Fearon, ER Lawrence, TS Xu, L PLoS One 4:e6816 20351093 Pubmed 2010 MicroRNA-34a suppresses invasion through downregulation of Notch1 and Jagged1 in cervical carcinoma and choriocarcinoma cells Pang, RT Leung, CON Ye, TM Liu, W Chiu, PCN Lam, KKW Lee, KF Yeung, WS Carcinogenesis 31:1037-44 LEFT-TO-RIGHT MIR200B/C microRNAs bind NOTCH1 mRNA Translation of NOTCH1 mRNA is inhibited by microRNAs miR-200B and miR-200C, which bind to the 3'UTR of NOTCH1 mRNA. Levels of miR-200B and miR-200C are decreased in pancreatic cancer cells with an EMT (epithelial to mesenchymal transition) phenotype, and the EMT phenotype is reversed by exogenous overexpression of miR-200B/C microRNAs, suggesting that miR-200B and mir-200C may be acting as tumor suppressors. Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: May, B, 2012-02-09 Edited: D'Eustachio, P, 2012-02-06 Edited: Jupe, S, 2011-09-27 Edited: Gillespie, ME, 2012-02-09 Converted from EntitySet in Reactome miR-200B/C RISC miR-200B/C-induced Silencing Complex Reactome DB_ID: 1614237 miR-200B/C Endonucleolytic RISC Reactome DB_ID: 1614231 miR-200B/C Endonucleolytic Minimal RISC Argonaute2: miR-200B/C (single-stranded) Reactome DB_ID: 1614235 1 Converted from EntitySet in Reactome MIR200B/C miR-200B/C Reactome DB_ID: 1614240 MIR200B miR-200B microRNA 200b Reactome DB_ID: 1606776 miRBase:MI0000342 MIR200B miR-200B microRNA MIR200B microRNA microRNA 200b MIR200B miRBase MI0000342 57 EQUAL 78 EQUAL Reactome Database ID Release 81 1606776 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=1606776 Reactome R-HSA-1606776 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-1606776.1 MIR200C miR-200c-3p miR-200c microRNA 200c Reactome DB_ID: 1606774 miRBase:MI0000650 MIR200C miR-200C microRNA MIR200C microRNA microRNA 200c MIR200C miRBase MI0000650 44 EQUAL 66 EQUAL Reactome Database ID Release 81 1606774 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=1606774 Reactome R-HSA-1606774 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-1606774.2 Reactome Database ID Release 81 1614240 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=1614240 Reactome R-HSA-1614240 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-1614240.1 1 Reactome Database ID Release 81 1614235 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=1614235 Reactome R-HSA-1614235 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-1614235.1 1 1 1 Reactome Database ID Release 81 1614231 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=1614231 Reactome R-HSA-1614231 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-1614231.1 miR-200B/C Nonendonucleolytic RISC Reactome DB_ID: 1614236 1 Argonaute1/3/4: miR-200B/C miR-200B/C Nonendonucleolytic Minimal RISC Reactome DB_ID: 1614234 1 1 Reactome Database ID Release 81 1614234 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=1614234 Reactome R-HSA-1614234 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-1614234.1 1 1 Reactome Database ID Release 81 1614236 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=1614236 Reactome R-HSA-1614236 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-1614236.1 Reactome Database ID Release 81 1614237 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=1614237 Reactome R-HSA-1614237 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-1614237.1 NOTCH1 mRNA:miR-200B/C RISC Reactome DB_ID: 1911483 1 1 Reactome Database ID Release 81 1911483 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=1911483 Reactome R-HSA-1911483 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-1911483.1 Reactome Database ID Release 81 1912363 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=1912363 Reactome R-HSA-1912363 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-1912363.1 20805998 Pubmed 2010 Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells Kong, D Banerjee, S Ahmad, A Sethi, S Sarkar, FH Wang, Z Li, Y PLoS One 5:e12445 LEFT-TO-RIGHT MIR449 microRNAs bind 3'UTR of NOTCH1 mRNA Translation of NOTCH1 mRNA is negatively regulated by MIR449 microRNAs (MIR449A, MIR449B and MIR449C), which bind to the 3'UTR of NOTCH1. Downregulation of NOTCH1 signaling by the MIR449 cluster appears to be an evolutionarily conserved mechanism involved in regulation of vertebrate multiciliogenesis. DLL1 mRNA is also a target of the MIR449 cluster. Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: May, B, 2012-02-09 Edited: D'Eustachio, P, 2012-02-06 Edited: Jupe, S, 2011-09-27 Edited: Gillespie, ME, 2012-02-09 Converted from EntitySet in Reactome miR-449 RISC miR-449-induced Silencing Complex Reactome DB_ID: 1606557 miR-449 Endonucleolytic RISC Reactome DB_ID: 1606551 1 miR-449 Endonucleolytic Minimal RISC Argonaute2: miR-449 (single-stranded) Reactome DB_ID: 1606549 Converted from EntitySet in Reactome MIR449 miR-449 Reactome DB_ID: 1606508 MIR449A miR-449A Reactome DB_ID: 1606491 miRBase:MI0001648 MIR449A MIR449A microRNA miR-449A microRNA microRNA 449a MIR449A miRBase MI0001648 16 EQUAL 37 EQUAL Reactome Database ID Release 81 1606491 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=1606491 Reactome R-HSA-1606491 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-1606491.1 MIR449B miR-449B Reactome DB_ID: 1606503 miRBase:MI0003673 MIR449B MIR449B microRNA miR-449B microRNA microRNA 449b MIR449B miRBase MI0003673 16 EQUAL 37 EQUAL Reactome Database ID Release 81 1606503 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=1606503 Reactome R-HSA-1606503 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-1606503.1 MIR449C miR-449C Reactome DB_ID: 1606506 miRBase:MI0003823 MIR449C MIR449C microRNA miR-449C microRNA microRNA 449c MIR449C miRBase MI0003823 17 EQUAL 41 EQUAL Reactome Database ID Release 81 1606506 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=1606506 Reactome R-HSA-1606506 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-1606506.1 Reactome Database ID Release 81 1606508 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=1606508 Reactome R-HSA-1606508 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-1606508.1 1 1 Reactome Database ID Release 81 1606549 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=1606549 Reactome R-HSA-1606549 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-1606549.1 1 1 Reactome Database ID Release 81 1606551 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=1606551 Reactome R-HSA-1606551 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-1606551.1 miR-449 Nonendonucleolytic RISC Reactome DB_ID: 1606554 Argonaute1/3/4: miR-449 miR-449 Nonendonucleolytic Minimal RISC Reactome DB_ID: 1606553 1 1 Reactome Database ID Release 81 1606553 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=1606553 Reactome R-HSA-1606553 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-1606553.1 1 1 1 Reactome Database ID Release 81 1606554 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=1606554 Reactome R-HSA-1606554 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-1606554.1 Reactome Database ID Release 81 1606557 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=1606557 Reactome R-HSA-1606557 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-1606557.1 NOTCH1 mRNA:miR-449 RISC Reactome DB_ID: 1606562 1 1 Reactome Database ID Release 81 1606562 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=1606562 Reactome R-HSA-1606562 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-1606562.1 Reactome Database ID Release 81 1606561 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=1606561 Reactome R-HSA-1606561 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-1606561.1 21602795 Pubmed 2011 Control of vertebrate multiciliogenesis by miR-449 through direct repression of the Delta/Notch pathway Marcet, B Chevalier, B Luxardi, G Coraux, C Zaragosi, LE Cibois, M Robbe-Sermesant, K Jolly, T Cardinaud, B Moreilhon, C Giovannini-Chami, L Nawrocki-Raby, B Birembaut, P Waldmann, R Kodjabachian, L Barbry, P Nat Cell Biol 13:693-9 LEFT-TO-RIGHT MIR34 microRNAs bind 3'UTR of NOTCH2 mRNA Translation of NOTCH2 mRNA is inhibited by MIR34 microRNAs (MIR34A, MIR34B and MIR34C), which bind to the 3'UTR of NOTCH2 mRNA. Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: May, B, 2012-02-09 Edited: D'Eustachio, P, 2012-02-06 Edited: Jupe, S, 2011-09-27 Edited: Gillespie, ME, 2012-02-09 NOTCH2 mRNA:miR-34 RISC Reactome DB_ID: 1911490 1 1 Reactome Database ID Release 81 1911490 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=1911490 Reactome R-HSA-1911490 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-1911490.1 Reactome Database ID Release 81 1912367 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=1912367 Reactome R-HSA-1912367 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-1912367.1 LEFT-TO-RIGHT MIR150 microRNA binds 3'UTR of NOTCH3 mRNA Translation of NOTCH3 mRNA is inhibited by miR-150 microRNA which binds to the 3'UTR of NOTCH3 mRNA. miR-150 is involved in regulation of differentiation of B-cells and T-cells. Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: May, B, 2012-02-09 Edited: D'Eustachio, P, 2012-02-06 Edited: Jupe, S, 2011-09-27 Edited: Gillespie, ME, 2012-02-09 Converted from EntitySet in Reactome miR-150 RISC miR-150-induced Silencing Complex Reactome DB_ID: 1852612 miR-150 Endonucleolytic RISC Reactome DB_ID: 1852609 1 miR-150 Endonucleolytic Minimal RISC Argonaute2: miR-150 (single-stranded) Reactome DB_ID: 1852610 MIR150 miR-150 microRNA 150 mir-150-5p Reactome DB_ID: 1852607 miRBase:MI0000479 MIR150 miR-150 microRNA MIR150 microRNA microRNA 150 MIR150 miRBase MI0000479 16 EQUAL 37 EQUAL Reactome Database ID Release 81 1852607 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=1852607 Reactome R-HSA-1852607 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-1852607.2 1 1 Reactome Database ID Release 81 1852610 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=1852610 Reactome R-HSA-1852610 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-1852610.1 1 1 Reactome Database ID Release 81 1852609 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=1852609 Reactome R-HSA-1852609 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-1852609.1 miR-150 Nonendonucleolytic RISC Reactome DB_ID: 1852611 1 Argonaute1/3/4: miR-150 miR-150 Nonendonucleolytic Minimal RISC Reactome DB_ID: 1852614 1 1 Reactome Database ID Release 81 1852614 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=1852614 Reactome R-HSA-1852614 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-1852614.1 1 1 Reactome Database ID Release 81 1852611 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=1852611 Reactome R-HSA-1852611 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-1852611.1 Reactome Database ID Release 81 1852612 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=1852612 Reactome R-HSA-1852612 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-1852612.1 NOTCH3 mRNA:miR-150 RISC Reactome DB_ID: 1911497 1 1 Reactome Database ID Release 81 1911497 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=1911497 Reactome R-HSA-1911497 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-1911497.1 Reactome Database ID Release 81 1912362 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=1912362 Reactome R-HSA-1912362 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-1912362.1 21551231 Pubmed 2011 Modulation of microRNA expression in human T-cell development: targeting of NOTCH3 by miR-150 Ghisi, M Corradin, A Basso, K Frasson, C Serafin, V Mukherjee, S Mussolin, L Ruggero, K Bonanno, L Guffanti, A De Bellis, G Gerosa, G Stellin, G D'Agostino, DM Basso, G Bronte, V Indraccolo, S Amadori, A Zanovello, P Blood 117:7053-62 LEFT-TO-RIGHT MIR206 microRNA binds 3'UTR of NOTCH3 mRNA Translation of NOTCH3 mRNA is inhibited by microRNA miR-206 which binds to the 3'UTR of NOTCH3 mRNA. Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: May, B, 2012-02-09 Edited: D'Eustachio, P, 2012-02-06 Edited: Jupe, S, 2011-09-27 Edited: Gillespie, ME, 2012-02-09 Converted from EntitySet in Reactome miR-206 RISC miR-206-induced Silencing Complex Reactome DB_ID: 1614243 miR-206 Endonucleolytic RISC Reactome DB_ID: 1614241 1 1 miR-206 Endonucleolytic Minimal RISC Argonaute2: miR-206 (single-stranded) Reactome DB_ID: 1614233 1 MIR206 miR-206 microRNA 206 Reactome DB_ID: 1614232 miRBase:MI0000490 MIR206 miR-206 microRNA MIR206 microRNA microRNA 206 MIR206 miRBase MI0000490 53 EQUAL 74 EQUAL Reactome Database ID Release 81 1614232 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=1614232 Reactome R-HSA-1614232 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-1614232.1 1 Reactome Database ID Release 81 1614233 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=1614233 Reactome R-HSA-1614233 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-1614233.1 1 Reactome Database ID Release 81 1614241 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=1614241 Reactome R-HSA-1614241 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-1614241.1 miR-206 Nonendonucleolytic RISC Reactome DB_ID: 1614230 1 Argonaute1/3/4: miR-206 miR-206 Nonendonucleolytic Minimal RISC Reactome DB_ID: 1614239 1 1 Reactome Database ID Release 81 1614239 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=1614239 Reactome R-HSA-1614239 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-1614239.1 1 1 Reactome Database ID Release 81 1614230 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=1614230 Reactome R-HSA-1614230 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-1614230.1 Reactome Database ID Release 81 1614243 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=1614243 Reactome R-HSA-1614243 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-1614243.1 NOTCH3 mRNA:miR-206 RISC Reactome DB_ID: 1911498 1 1 Reactome Database ID Release 81 1911498 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=1911498 Reactome R-HSA-1911498 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-1911498.1 Reactome Database ID Release 81 1912366 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=1912366 Reactome R-HSA-1912366 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-1912366.1 19723635 Pubmed 2009 MicroRNA-206 targets notch3, activates apoptosis, and inhibits tumor cell migration and focus formation Song, G Zhang, Y Wang, L J Biol Chem 284:31921-7 LEFT-TO-RIGHT MIR181C microRNA binds 3'UTR of NOTCH4 mRNA miR-181C microRNA inhibits translation of NOTCH4 mRNA by binding to its 3'UTR. miR181c is a candidate tumor suppressor in gastric cancer. Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: May, B, 2012-02-09 Edited: D'Eustachio, P, 2012-02-06 Edited: Jupe, S, 2011-09-27 Edited: Gillespie, ME, 2012-02-09 Converted from EntitySet in Reactome miR-181C RISC miR-181C-induced Silencing Complex Reactome DB_ID: 1852604 miR-181C Endonucleolytic RISC Reactome DB_ID: 1852605 1 miR-181C Endonucleolytic Minimal RISC Argonaute2: miR-181C (single-stranded) Reactome DB_ID: 1852601 1 MIR181C miR-181C microRNA 181c Reactome DB_ID: 1852600 miRBase:MI0000271 MIR181C miR-181C microRNA MIR181C microRNA microRNA 181c MIR181C miRBase MI0000271 Reactome Database ID Release 81 1852600 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=1852600 Reactome R-HSA-1852600 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-1852600.1 1 Reactome Database ID Release 81 1852601 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=1852601 Reactome R-HSA-1852601 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-1852601.1 1 1 Reactome Database ID Release 81 1852605 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=1852605 Reactome R-HSA-1852605 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-1852605.1 miR-181C Nonendonucleolytic RISC Reactome DB_ID: 1852606 1 Argonaute1/3/4: miR-181C miR-181C Nonendonucleolytic Minimal RISC Reactome DB_ID: 1852602 1 1 Reactome Database ID Release 81 1852602 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=1852602 Reactome R-HSA-1852602 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-1852602.1 1 1 Reactome Database ID Release 81 1852606 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=1852606 Reactome R-HSA-1852606 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-1852606.1 Reactome Database ID Release 81 1852604 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=1852604 Reactome R-HSA-1852604 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-1852604.1 NOTCH4 mRNA:miR-181C RISC Reactome DB_ID: 1911502 1 1 Reactome Database ID Release 81 1911502 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=1911502 Reactome R-HSA-1911502 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-1911502.1 Reactome Database ID Release 81 1912364 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=1912364 Reactome R-HSA-1912364 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-1912364.2 20080834 Pubmed 2010 Involvement of epigenetically silenced microRNA-181c in gastric carcinogenesis Hashimoto, Y Akiyama, Y Otsubo, T Shimada, S Yuasa, Y Carcinogenesis 31:777-84 GENE ONTOLOGY GO:0010629 LEFT-TO-RIGHT MIR302A microRNA binds 3'UTR of NOTCH4 mRNA MicroRNA miR-302A, upregulated in melanoma, binds the 3'UTR of NOTCH4, resulting in inhibition of NOTCH4 mRNA translation. Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: May, B, 2012-02-09 Edited: D'Eustachio, P, 2012-02-06 Edited: Jupe, S, 2011-09-27 Edited: Gillespie, ME, 2012-02-09 Converted from EntitySet in Reactome miR-302A RISC miR-302A-induced Silencing Complex Reactome DB_ID: 1852598 miR-302A Endonucleolytic RISC Reactome DB_ID: 1852597 miR-302A Endonucleolytic Minimal RISC Argonaute2: miR-302A (single-stranded) Reactome DB_ID: 1852595 MIR302A miR-302A microRNA 302a Reactome DB_ID: 1852592 miRBase:MI0000738 MIR302A miR-302A microRNA MIR302A microRNA microRNA 302a MIR302A miRBase MI0000738 44 EQUAL 66 EQUAL Reactome Database ID Release 81 1852592 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=1852592 Reactome R-HSA-1852592 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-1852592.1 1 1 Reactome Database ID Release 81 1852595 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=1852595 Reactome R-HSA-1852595 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-1852595.1 1 1 1 Reactome Database ID Release 81 1852597 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=1852597 Reactome R-HSA-1852597 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-1852597.1 miR-302A Nonendonucleolytic RISC Reactome DB_ID: 1852593 1 Argonaute1/3/4: miR-302A miR-302A Nonendonucleolytic Minimal RISC Reactome DB_ID: 1852594 1 1 Reactome Database ID Release 81 1852594 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=1852594 Reactome R-HSA-1852594 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-1852594.1 1 1 Reactome Database ID Release 81 1852593 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=1852593 Reactome R-HSA-1852593 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-1852593.1 Reactome Database ID Release 81 1852598 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=1852598 Reactome R-HSA-1852598 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-1852598.1 NOTCH4 mRNA:miR-302A RISC Reactome DB_ID: 1911500 1 1 Reactome Database ID Release 81 1911500 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=1911500 Reactome R-HSA-1911500 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-1911500.1 Reactome Database ID Release 81 1912368 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=1912368 Reactome R-HSA-1912368 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-1912368.2 20495621 Pubmed 2009 Epigenetically reprogramming metastatic tumor cells with an embryonic microenvironment Costa, FF Seftor, EA Bischof, JM Kirschmann, DA Strizzi, L Arndt, K de Fatima Bonaldo, M Soares, MB Hendrix, MJC Epigenomics 1:387-398 LEFT-TO-RIGHT NOTCH1 mRNA translation controlled by miRNAs Translation of NOTCH1 mRNA is negatively regulated by microRNAs miR-200B and miR200C (Kong et al. 2010), miR-34 (Li et al. 2009, Ji et al. 2009) and miR-449 (Marcet et al. 2011). These miRNAs bind and cause degradation of NOTCH1 mRNA, resulting in decreased level of NOTCH1 protein product. Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: May, B, 2012-02-09 Edited: D'Eustachio, P, 2012-02-06 Edited: Jupe, S, 2011-09-27 Edited: Gillespie, ME, 2012-02-09 NOTCH1 Pre-NOTCH1 NOTCH1(19-2555) Notch 1 receptor precursor Reactome DB_ID: 157024 endoplasmic reticulum membrane GENE ONTOLOGY GO:0005789 19 EQUAL 2555 EQUAL Reactome Database ID Release 81 157024 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=157024 Reactome R-HSA-157024 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-157024.1 Reactome Database ID Release 81 1912412 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=1912412 Reactome R-HSA-1912412 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-1912412.2 INHIBITION activeUnit: #Complex18 Reactome Database ID Release 81 1980087 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=1980087 Reactome R-HSA-1980087 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-1980087.2 INHIBITION activeUnit: #Complex12 Reactome Database ID Release 81 1980089 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=1980089 Reactome R-HSA-1980089 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-1980089.2 INHIBITION activeUnit: #Complex24 Reactome Database ID Release 81 1980095 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=1980095 Reactome R-HSA-1980095 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-1980095.2 LEFT-TO-RIGHT NOTCH2 mRNA translation controlled by miRNAs Translation of NOTCH2 mRNA is negatively regulated by miR-34 microRNAs (Li et al. 2009). miR-34 miRNAs bind and cause degradation of NOTCH2 mRNA, resulting in decreased level of NOTCH2 protein product. Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: May, B, 2012-02-09 Edited: D'Eustachio, P, 2012-02-06 Edited: Jupe, S, 2011-09-27 Edited: Gillespie, ME, 2012-02-09 NOTCH2 Pre-NOTCH2 NOTCH2(26-2471) Notch 2 receptor precursor Reactome DB_ID: 157025 UniProt:Q04721 NOTCH2 NOTCH2 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 (PubMed:21378985, PubMed:21378989). Affects the implementation of differentiation, proliferation and apoptotic programs (By similarity). Involved in bone remodeling and homeostasis. In collaboration with RELA/p65 enhances NFATc1 promoter activity and positively regulates RANKL-induced osteoclast differentiation (PubMed:29149593). Positively regulates self-renewal of liver cancer cells (PubMed:25985737).SUBUNIT Heterodimer of a C-terminal fragment N(TM) and an N-terminal fragment N(EC) which are probably linked by disulfide bonds (By similarity). Interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH2. Interacts with RELA/p65 (By similarity). Interacts with HIF1AN. Interacts (via ANK repeats) with TCIM, the interaction inhibits the nuclear translocation of NOTCH2 N2ICD (PubMed:25985737). Interacts with CUL1, RBX1, SKP1 and FBXW7 that are SCF(FBXW7) E3 ubiquitin-protein ligase complex components (PubMed:29149593). Interacts with MINAR1; this interaction increases MINAR1 stability and function (PubMed:29329397). Interacts with NOTCH2NL (NOTCH2NLA, NOTCH2NLB and/or NOTCH2NLC); leading to enhance Notch signaling pathway in a non-cell-autonomous manner (PubMed:29856954). Interacts with MDK; this interaction mediates a nuclear accumulation of NOTCH2 and therefore activation of NOTCH2 signaling leading to interaction between HES1 and STAT3 (PubMed:18469519).TISSUE SPECIFICITY Expressed in the brain, heart, kidney, lung, skeletal muscle and liver. Ubiquitously expressed in the embryo.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) (By similarity). Following ligand binding, it is cleaved by TNF-alpha converting enzyme (TACE) to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT) (By similarity). This fragment is then cleaved by presenilin dependent gamma-secretase to release a notch-derived peptide containing the intracellular domain (NICD) from the membrane (By similarity).PTM Hydroxylated by HIF1AN.PTM Can be either O-glucosylated or O-xylosylated at Ser-613 by POGLUT1.PTM Phosphorylated by GSK3. GSK3-mediated phosphorylation is necessary for NOTCH2 recognition by FBXW7, ubiquitination and degradation via the ubiquitin proteasome pathway.SIMILARITY Belongs to the NOTCH family. UniProt Q04721 26 EQUAL 2471 EQUAL Reactome Database ID Release 81 157025 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=157025 Reactome R-HSA-157025 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-157025.1 Reactome Database ID Release 81 1912413 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=1912413 Reactome R-HSA-1912413 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-1912413.2 INHIBITION activeUnit: #Complex12 Reactome Database ID Release 81 1980097 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=1980097 Reactome R-HSA-1980097 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-1980097.2 LEFT-TO-RIGHT NOTCH3 mRNA translation controlled by miRNAs Translation of NOTCH3 mRNA is negatively regulated by miR-150 (Ghisi et al. 2011) and miR-206 microRNAs (Song et al. 2009). These miRNAs bind and cause degradation of NOTCH3 mRNA, resulting in decreased level of NOTCH3 protein product. Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: May, B, 2012-02-09 Edited: D'Eustachio, P, 2012-02-06 Edited: Jupe, S, 2011-09-27 Edited: Gillespie, ME, 2012-02-09 NOTCH3 Pre-NOTCH3 NOTCH3(40-2321) Notch 3 receptor precursor Reactome DB_ID: 157102 40 EQUAL 2321 EQUAL Reactome Database ID Release 81 157102 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=157102 Reactome R-HSA-157102 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-157102.1 Reactome Database ID Release 81 1912409 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=1912409 Reactome R-HSA-1912409 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-1912409.2 INHIBITION activeUnit: #Complex31 Reactome Database ID Release 81 1980091 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=1980091 Reactome R-HSA-1980091 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-1980091.2 INHIBITION activeUnit: #Complex37 Reactome Database ID Release 81 1980096 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=1980096 Reactome R-HSA-1980096 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-1980096.2 LEFT-TO-RIGHT NOTCH4 mRNA translation controlled by miRNAs Translation of NOTCH4 mRNA is negatively regulated by miR-181c (Hashimoto et al. 2010) and miR-302A microRNAs (Costa et al. 2009). These miRNAs bind and cause degradation of NOTCH4 mRNA, resulting in decreased level of NOTCH4 protein product. Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: May, B, 2012-02-09 Edited: D'Eustachio, P, 2012-02-06 Edited: Jupe, S, 2011-09-27 Edited: Gillespie, ME, 2012-02-09 NOTCH4 Pre-NOTCH4 NOTCH4(24-2003) Notch 4 receptor precursor Reactome DB_ID: 157121 UniProt:Q99466 NOTCH4 NOTCH4 INT3 FUNCTION Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 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. May regulate branching morphogenesis in the developing vascular system (By similarity).SUBUNIT Heterodimer of a C-terminal fragment N(TM) and a N-terminal fragment N(EC) which are probably linked by disulfide bonds (By similarity). Interacts with MAML1, MAML2 and MAML3 which act as transcriptional coactivators for NOTCH4.TISSUE SPECIFICITY Highly expressed in the heart, moderately in the lung and placenta and at low levels in the liver, skeletal muscle, kidney, pancreas, spleen, lymph node, thymus, bone marrow and fetal liver. No expression was seen in adult brain or peripheral blood leukocytes.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. Cleavage results in a C-terminal fragment N(TM) and a N-terminal fragment N(EC). Following ligand binding, it is cleaved by TNF-alpha converting enzyme (TACE) to yield a membrane-associated intermediate fragment called notch extracellular truncation (NEXT). This fragment is then cleaved by presenilin dependent gamma-secretase to release a notch-derived peptide containing the intracellular domain (NICD) from the membrane (By similarity).PTM Phosphorylated.POLYMORPHISM The poly-Leu region of NOTCH4 (in the signal peptide) is polymorphic and the number of Leu varies in the population (from 6 to 12).SIMILARITY Belongs to the NOTCH family. UniProt Q99466 24 EQUAL 2003 EQUAL Reactome Database ID Release 81 157121 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=157121 Reactome R-HSA-157121 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-157121.1 Reactome Database ID Release 81 1912410 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=1912410 Reactome R-HSA-1912410 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-1912410.2 GENE ONTOLOGY GO:0035278 INHIBITION activeUnit: #Complex49 Reactome Database ID Release 81 1980094 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=1980094 Reactome R-HSA-1980094 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-1980094.2 INHIBITION activeUnit: #Complex43 Reactome Database ID Release 81 1980092 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=1980092 Reactome R-HSA-1980092 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-1980092.2 LEFT-TO-RIGHT RUNX1 binds NOTCH4 gene The transcription factor RUNX1 binds to runx response elements in intron 29 of the NOTCH4 gene (Li et al. 2018). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 AML1 RUNX1 Runt-related transcription factor 1 Oncogene AML-1 Acute myeloid leukemia 1 protein Core-binding factor subunit alpha-2 CBF-alpha-2 CBFA2 Polyomavirus enhancer-binding protein 2 alpha B subunit PEA2-alpha B PEBP2-alpha B SL3-3 enhancer factor 1 alpha B subunit SL3/AKV core-binding factor alpha B subunit RUNX1_HUMAN Reactome DB_ID: 8865295 UniProt:Q01196 RUNX1 RUNX1 AML1 CBFA2 FUNCTION Forms the heterodimeric complex core-binding factor (CBF) with CBFB. RUNX members modulate the transcription of their target genes through recognizing the core consensus binding sequence 5'-TGTGGT-3', or very rarely, 5'-TGCGGT-3', within their regulatory regions via their runt domain, while CBFB is a non-DNA-binding regulatory subunit that allosterically enhances the sequence-specific DNA-binding capacity of RUNX. The heterodimers bind to the core site of a number of enhancers and promoters, including murine leukemia virus, polyomavirus enhancer, T-cell receptor enhancers, LCK, IL3 and GM-CSF promoters (Probable). Essential for the development of normal hematopoiesis (PubMed:17431401). Acts synergistically with ELF4 to transactivate the IL-3 promoter and with ELF2 to transactivate the BLK promoter (PubMed:10207087, PubMed:14970218). Inhibits KAT6B-dependent transcriptional activation (By similarity). Involved in lineage commitment of immature T cell precursors. CBF complexes repress ZBTB7B transcription factor during cytotoxic (CD8+) T cell development. They bind to RUNX-binding sequence within the ZBTB7B locus acting as transcriptional silencer and allowing for cytotoxic T cell differentiation. CBF complexes binding to the transcriptional silencer is essential for recruitment of nuclear protein complexes that catalyze epigenetic modifications to establish epigenetic ZBTB7B silencing (By similarity). Controls the anergy and suppressive function of regulatory T-cells (Treg) by associating with FOXP3. Activates the expression of IL2 and IFNG and down-regulates the expression of TNFRSF18, IL2RA and CTLA4, in conventional T-cells (PubMed:17377532). Positively regulates the expression of RORC in T-helper 17 cells (By similarity).FUNCTION Isoform AML-1G shows higher binding activities for target genes and binds TCR-beta-E2 and RAG-1 target site with threefold higher affinity than other isoforms. It is less effective in the context of neutrophil terminal differentiation.FUNCTION Isoform AML-1L interferes with the transactivation activity of RUNX1.SUBUNIT Heterodimer with CBFB. RUNX1 binds DNA as a monomer and through the Runt domain. DNA-binding is increased by heterodimerization. Isoform AML-1L can neither bind DNA nor heterodimerize. Interacts with TLE1 and ALYREF/THOC4 (PubMed:9119228, PubMed:9751710). Interacts with ELF1, ELF2 and SPI1 (PubMed:10207087). Interacts via its Runt domain with the ELF4 N-terminal region (PubMed:10207087). Interaction with ELF2 isoform 2 (NERF-1a) may act to repress RUNX1-mediated transactivation (PubMed:14970218). Interacts with KAT6A and KAT6B (PubMed:11742995, PubMed:11965546). Interacts with SUV39H1, leading to abrogation of transactivating and DNA-binding properties of RUNX1 (PubMed:12917624, PubMed:16652147). Interacts with YAP1 (PubMed:18280240). Interacts with HIPK2 (By similarity). Interaction with CDK6 prevents myeloid differentiation, reducing its transcription transactivation activity. Found in a complex with PRMT5, RUNX1 and CBFB. Interacts with FOXP3 (PubMed:17377532). Interacts with TBX21 (By similarity). Interacts with DPF2 (PubMed:28533407).TISSUE SPECIFICITY Expressed in all tissues examined except brain and heart. Highest levels in thymus, bone marrow and peripheral blood.INDUCTION Up-regulated by phorbol myristate acetate (PMA).DOMAIN A proline/serine/threonine rich region at the C-terminus is necessary for transcriptional activation of target genes.PTM Phosphorylated in its C-terminus upon IL-6 treatment. Phosphorylation enhances interaction with KAT6A.PTM Methylated.PTM Phosphorylated in Ser-249 Thr-273 and Ser-276 by HIPK2 when associated with CBFB and DNA. This phosphorylation promotes subsequent EP300 phosphorylation.DISEASE A chromosomal aberration involving RUNX1/AML1 is a cause of M2 type acute myeloid leukemia (AML-M2). Translocation t(8;21)(q22;q22) with RUNX1T1.DISEASE A chromosomal aberration involving RUNX1/AML1 is a cause of therapy-related myelodysplastic syndrome (T-MDS). Translocation t(3;21)(q26;q22) with EAP or MECOM.DISEASE A chromosomal aberration involving RUNX1/AML1 is a cause of chronic myelogenous leukemia (CML). Translocation t(3;21)(q26;q22) with EAP or MECOM.DISEASE A chromosomal aberration involving RUNX1/AML1 is found in childhood acute lymphoblastic leukemia (ALL). Translocation t(12;21)(p13;q22) with TEL. The translocation fuses the 3'-end of TEL to the alternate 5'-exon of AML-1H.DISEASE A chromosomal aberration involving RUNX1 is found in acute leukemia. Translocation t(11,21)(q13;q22) that forms a MACROD1-RUNX1 fusion protein.DISEASE A chromosomal aberration involving RUNX1/AML1 is found in therapy-related myeloid malignancies. Translocation t(16;21)(q24;q22) that forms a RUNX1-CBFA2T3 fusion protein.DISEASE A chromosomal aberration involving RUNX1/AML1 is a cause of chronic myelomonocytic leukemia. Inversion inv(21)(q21;q22) with USP16.DISEASE A chromosomal aberration involving RUNX1/AML1 is found in acute myeloid leukemia. Translocation t(20;21)(q11;q22) with CBFA2T2.CAUTION The fusion of AML1 with EAP in T-MDS induces a change of reading frame in the latter resulting in 17 AA unrelated to those of EAP. UniProt Q01196 1 EQUAL 453 EQUAL Reactome Database ID Release 81 8865295 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=8865295 Reactome R-HSA-8865295 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-8865295.1 RUNX1:NOTCH4 gene Reactome DB_ID: 9604705 1 1 Reactome Database ID Release 81 9604705 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=9604705 Reactome R-HSA-9604705 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-9604705.1 Reactome Database ID Release 81 9604703 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=9604703 Reactome R-HSA-9604703 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-9604703.1 29101237 Pubmed 2018 Human NOTCH4 is a key target of RUNX1 in megakaryocytic differentiation Li, Yueying Jin, Chen Bai, Hao Gao, Yongxing Sun, Shu Chen, L Qin, Lei Liu, Paul P Cheng, Linzhao Wang, Qian-Fei Blood 131:191-201 LEFT-TO-RIGHT NOTCH4 gene transcription is inhibited by RUNX1 RUNX1 binding to intron 29 of the NOTCH4 gene represses NOTCH4 transcription. RUNX1-mediated inhibition of NOTCH4 expression contributes to differentiation of human pluripotent stem cells into megakaryocytes (Li et al. 2018). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 Reactome Database ID Release 81 9604719 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=9604719 Reactome R-HSA-9604719 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-9604719.1 INHIBITION activeUnit: #Protein41 Reactome Database ID Release 81 9604723 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=9604723 LEFT-TO-RIGHT SIRT6 binds to acetylated histones at NOTCH1 and NOTCH4 gene promoters Based on studies in mice, histone deacetylase SIRT6 binds to histone H3 acetylated on lysine residue 10 (H3K9Ac epigenetic mark) at promoters of NOTCH1 and NOTCH4 genes (Liu et al. 2017). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 SIRT6 NAD-dependent protein deacetylase sirtuin-6 Regulatory protein SIR2 homolog 6 SIR2-like protein 6 SIR2L6 Reactome DB_ID: 5685963 UniProt:Q8N6T7 SIRT6 SIRT6 SIR2L6 FUNCTION NAD-dependent protein deacetylase involved in various processes including telomere maintenance and gene expression, and consequently has roles in genomic stability, cell senescence and apoptosis (PubMed:18337721, PubMed:19135889, PubMed:19625767, PubMed:21362626). Has very weak deacetylase activity and can bind NAD(+) in the absence of acetylated substrate (PubMed:21362626). Has deacetylase activity towards histone H3K9Ac and H3K56Ac (PubMed:19625767, PubMed:21362626). Modulates acetylation of histone H3 in telomeric chromatin during the S-phase of the cell cycle (PubMed:19625767). May also be required for the association of WRN with telomeres during S-phase and for normal telomere maintenance (PubMed:18337721). Deacetylates histone H3K9Ac at NF-kappa-B target promoters and may down-regulate the expression of a subset of NF-kappa-B target genes (PubMed:21362626). Deacetylation of nucleosomes interferes with RELA binding to target DNA (PubMed:19135889). Acts as a corepressor of the transcription factor Hif1a to control the expression of multiple glycolytic genes to regulate glucose homeostasis (By similarity). Required for normal IGF1 serum levels and normal glucose homeostasis (By similarity). Regulates the production of TNF protein (By similarity). Has a role in the regulation of life span (By similarity).SUBUNIT Interacts with RELA.MISCELLANEOUS The reported ADP-ribosyltransferase activity of sirtuins is likely some inefficient side reaction of the deacetylase activity and may not be physiologically relevant.SIMILARITY Belongs to the sirtuin family. Class IV subfamily.CAUTION Upon DNA damage, was reported to promote DNA end resection via deacetylation of RBBP8. However, this study was later retracted. UniProt Q8N6T7 2 EQUAL 355 EQUAL Reactome Database ID Release 81 5685963 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=5685963 Reactome R-HSA-5685963 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-5685963.1 2 Nucleosome (H3K9ac) Reactome DB_ID: 5250919 Converted from EntitySet in Reactome Histone H2A Reactome DB_ID: 181899 H2AFB1 Histone H2A-Bbd Reactome DB_ID: 181887 UniProt:P0C5Y9 H2AB1 H2AB1 H2AFB1 FUNCTION Atypical histone H2A which can replace conventional H2A in some nucleosomes and is associated with active transcription and mRNA processing (PubMed:22795134). Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability (PubMed:15257289, PubMed:16287874, PubMed:16957777, PubMed:17591702, PubMed:17726088, PubMed:18329190, PubMed:22795134). Nucleosomes containing this histone are less rigid and organize less DNA than canonical nucleosomes in vivo (PubMed:15257289, PubMed:16957777, PubMed:17591702, PubMed:24336483). They are enriched in actively transcribed genes and associate with the elongating form of RNA polymerase (PubMed:17591702, PubMed:24753410). They associate with spliceosome components and are required for mRNA splicing (PubMed:22795134).SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. May be incorporated into a proportion of nucleosomes, replacing one or more H2A molecules.TISSUE SPECIFICITY Present in mature sperm.DOMAIN The docking domain is responsible for the weaker heterodimerization with H2B.MISCELLANEOUS In contrast to other H2A histones, it does not contain the conserved residues that are the target of post-translational modifications.SIMILARITY Belongs to the histone H2A family.CAUTION Although related to variant histone H2AB1 in mouse (AC Q9CQ70), it is unclear whether human and mouse H2AB1 proteins are involved in similar processes. In mouse, variant histone H2AB1 is specifically required to direct the transformation of dissociating nucleosomes to protamine in male germ cells during spermatogenesis. It is however unclear whether human protein, which participates in mRNA processing and is associated with active transcription, is also involved in nucleosomes to protamine replacement (PubMed:22795134). UniProt P0C5Y9 1 EQUAL 115 EQUAL Reactome Database ID Release 81 181887 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=181887 Reactome R-HSA-181887 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-181887.1 HIST1H2AB Reactome DB_ID: 181888 UniProt:P04908 H2AC4 H2AC4 H2AFM HIST1H2AB H2AC8 H2AFA HIST1H2AE FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Deiminated on Arg-4 in granulocytes upon calcium entry.PTM Monoubiquitination of Lys-120 (H2AK119Ub) by RING1, TRIM37 and RNF2/RING2 complex gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. It is involved in the initiation of both imprinted and random X inactivation. Ubiquitinated H2A is enriched in inactive X chromosome chromatin. Ubiquitination of H2A functions downstream of methylation of 'Lys-27' of histone H3 (H3K27me). H2AK119Ub by RNF2/RING2 can also be induced by ultraviolet and may be involved in DNA repair. Monoubiquitination of Lys-120 (H2AK119Ub) by TRIM37 may promote transformation of cells in a number of breast cancers (PubMed:25470042). Following DNA double-strand breaks (DSBs), it is ubiquitinated through 'Lys-63' linkage of ubiquitin moieties by the E2 ligase UBE2N and the E3 ligases RNF8 and RNF168, leading to the recruitment of repair proteins to sites of DNA damage. Ubiquitination at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) in response to DNA damage is initiated by RNF168 that mediates monoubiquitination at these 2 sites, and 'Lys-63'-linked ubiquitin are then conjugated to monoubiquitin; RNF8 is able to extend 'Lys-63'-linked ubiquitin chains in vitro. Deubiquitinated by USP51 at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) after damaged DNA is repaired (PubMed:27083998). H2AK119Ub and ionizing radiation-induced 'Lys-63'-linked ubiquitination (H2AK13Ub and H2AK15Ub) are distinct events.PTM Phosphorylation on Ser-2 (H2AS1ph) is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1. Phosphorylation at Thr-121 (H2AT120ph) by DCAF1 is present in the regulatory region of many tumor suppresor genes and down-regulates their transcription.PTM Glutamine methylation at Gln-105 (H2AQ104me) by FBL is specifically dedicated to polymerase I. It is present at 35S ribosomal DNA locus and impairs binding of the FACT complex (PubMed:24352239).PTM Symmetric dimethylation on Arg-4 by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.MASS SPECTROMETRY Monoisotopic with N-acetylserine.SIMILARITY Belongs to the histone H2A family. UniProt P04908 2 EQUAL 130 EQUAL Reactome Database ID Release 81 181888 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=181888 Reactome R-HSA-181888 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-181888.1 HIST1H2AJ Histone H2A.e Reactome DB_ID: 181890 UniProt:Q99878 H2AC14 H2AC14 H2AFE HIST1H2AJ FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Deiminated on Arg-4 in granulocytes upon calcium entry.PTM Monoubiquitination of Lys-120 (H2AK119Ub) by RING1, TRIM37 and RNF2/RING2 complex gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. It is involved in the initiation of both imprinted and random X inactivation. Ubiquitinated H2A is enriched in inactive X chromosome chromatin. Ubiquitination of H2A functions downstream of methylation of 'Lys-27' of histone H3 (H3K27me). H2AK119Ub by RNF2/RING2 can also be induced by ultraviolet and may be involved in DNA repair. Monoubiquitination of Lys-120 (H2AK119Ub) by TRIM37 may promote transformation of cells in a number of breast cancers (PubMed:25470042). Following DNA double-strand breaks (DSBs), it is ubiquitinated through 'Lys-63' linkage of ubiquitin moieties by the E2 ligase UBE2N and the E3 ligases RNF8 and RNF168, leading to the recruitment of repair proteins to sites of DNA damage. Ubiquitination at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) in response to DNA damage is initiated by RNF168 that mediates monoubiquitination at these 2 sites, and 'Lys-63'-linked ubiquitin are then conjugated to monoubiquitin; RNF8 is able to extend 'Lys-63'-linked ubiquitin chains in vitro. Deubiquitinated by USP51 at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) after damaged DNA is repaired (PubMed:27083998). H2AK119Ub and ionizing radiation-induced 'Lys-63'-linked ubiquitination (H2AK13Ub and H2AK15Ub) are distinct events.PTM Phosphorylation on Ser-2 (H2AS1ph) is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1. Phosphorylation at Thr-121 (H2AT120ph) by DCAF1 is present in the regulatory region of many tumor suppresor genes and down-regulates their transcription.PTM Glutamine methylation at Gln-105 (H2AQ104me) by FBL is specifically dedicated to polymerase I. It is present at 35S ribosomal DNA locus and impairs binding of the FACT complex (PubMed:24352239).PTM Symmetric dimethylation on Arg-4 by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.MASS SPECTROMETRY Monoisotopic with N-acetylserine.SIMILARITY Belongs to the histone H2A family. UniProt Q99878 2 EQUAL 128 EQUAL Reactome Database ID Release 81 181890 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=181890 Reactome R-HSA-181890 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-181890.1 HIST1H2AD Histone H2A.g Reactome DB_ID: 181896 UniProt:P20671 H2AC7 H2AC7 H2AFG HIST1H2AD FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Deiminated on Arg-4 in granulocytes upon calcium entry.PTM Monoubiquitination of Lys-120 (H2AK119Ub) by RING1, TRIM37 and RNF2/RING2 complex gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. It is involved in the initiation of both imprinted and random X inactivation. Ubiquitinated H2A is enriched in inactive X chromosome chromatin. Ubiquitination of H2A functions downstream of methylation of 'Lys-27' of histone H3 (H3K27me). H2AK119Ub by RNF2/RING2 can also be induced by ultraviolet and may be involved in DNA repair. Monoubiquitination of Lys-120 (H2AK119Ub) by TRIM37 may promote transformation of cells in a number of breast cancers (PubMed:25470042). Following DNA double-strand breaks (DSBs), it is ubiquitinated through 'Lys-63' linkage of ubiquitin moieties by the E2 ligase UBE2N and the E3 ligases RNF8 and RNF168, leading to the recruitment of repair proteins to sites of DNA damage. Ubiquitination at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) in response to DNA damage is initiated by RNF168 that mediates monoubiquitination at these 2 sites, and 'Lys-63'-linked ubiquitin are then conjugated to monoubiquitin; RNF8 is able to extend 'Lys-63'-linked ubiquitin chains in vitro. Deubiquitinated by USP51 at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) after damaged DNA is repaired (PubMed:27083998). H2AK119Ub and ionizing radiation-induced 'Lys-63'-linked ubiquitination (H2AK13Ub and H2AK15Ub) are distinct events.PTM Phosphorylation on Ser-2 (H2AS1ph) is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1. Phosphorylation at Thr-121 (H2AT120ph) by DCAF1 is present in the regulatory region of many tumor suppresor genes and down-regulates their transcription.PTM Glutamine methylation at Gln-105 (H2AQ104me) by FBL is specifically dedicated to polymerase I. It is present at 35S ribosomal DNA locus and impairs binding of the FACT complex (PubMed:24352239).PTM Symmetric dimethylation on Arg-4 by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.MASS SPECTROMETRY Monoisotopic with N-acetylserine.SIMILARITY Belongs to the histone H2A family.CAUTION Was originally thought to originate from mouse. UniProt P20671 2 EQUAL 130 EQUAL Reactome Database ID Release 81 181896 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=181896 Reactome R-HSA-181896 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-181896.1 HIST1H2AC Histone H2A.l Reactome DB_ID: 181895 UniProt:Q93077 H2AC6 H2AC6 H2AFL HIST1H2AC FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Deiminated on Arg-4 in granulocytes upon calcium entry.PTM Monoubiquitination of Lys-120 (H2AK119Ub) by RING1, TRIM37 and RNF2/RING2 complex gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. It is involved in the initiation of both imprinted and random X inactivation. Ubiquitinated H2A is enriched in inactive X chromosome chromatin. Ubiquitination of H2A functions downstream of methylation of 'Lys-27' of histone H3 (H3K27me). H2AK119Ub by RNF2/RING2 can also be induced by ultraviolet and may be involved in DNA repair. Monoubiquitination of Lys-120 (H2AK119Ub) by TRIM37 may promote transformation of cells in a number of breast cancers (PubMed:25470042). Following DNA double-strand breaks (DSBs), it is ubiquitinated through 'Lys-63' linkage of ubiquitin moieties by the E2 ligase UBE2N and the E3 ligases RNF8 and RNF168, leading to the recruitment of repair proteins to sites of DNA damage. Ubiquitination at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) in response to DNA damage is initiated by RNF168 that mediates monoubiquitination at these 2 sites, and 'Lys-63'-linked ubiquitin are then conjugated to monoubiquitin; RNF8 is able to extend 'Lys-63'-linked ubiquitin chains in vitro. Deubiquitinated by USP51 at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) after damaged DNA is repaired (PubMed:27083998). H2AK119Ub and ionizing radiation-induced 'Lys-63'-linked ubiquitination (H2AK13Ub and H2AK15Ub) are distinct events.PTM Phosphorylation on Ser-2 (H2AS1ph) is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1. Phosphorylation at Thr-121 (H2AT120ph) by DCAF1 is present in the regulatory region of many tumor suppresor genes and down-regulates their transcription.PTM Glutamine methylation at Gln-105 (H2AQ104me) by FBL is specifically dedicated to polymerase I. It is present at 35S ribosomal DNA locus and impairs binding of the FACT complex (PubMed:24352239).PTM Symmetric dimethylation on Arg-4 by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.MASS SPECTROMETRY Monoisotopic with N-acetylserine.SIMILARITY Belongs to the histone H2A family. UniProt Q93077 2 EQUAL 130 EQUAL Reactome Database ID Release 81 181895 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=181895 Reactome R-HSA-181895 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-181895.1 HIST2H2AA3 Histone H2A.o Reactome DB_ID: 181891 UniProt:Q6FI13 H2AC18 H2AC18 H2AFO HIST2H2AA HIST2H2AA3 H2AC19 HIST2H2AA4 FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Deiminated on Arg-4 in granulocytes upon calcium entry.PTM Monoubiquitination of Lys-120 (H2AK119Ub) by RING1, TRIM37 and RNF2/RING2 complex gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. It is involved in the initiation of both imprinted and random X inactivation. Ubiquitinated H2A is enriched in inactive X chromosome chromatin. Ubiquitination of H2A functions downstream of methylation of 'Lys-27' of histone H3 (H3K27me). H2AK119Ub by RNF2/RING2 can also be induced by ultraviolet and may be involved in DNA repair. Monoubiquitination of Lys-120 (H2AK119Ub) by TRIM37 may promote transformation of cells in a number of breast cancers (PubMed:25470042). Following DNA double-strand breaks (DSBs), it is ubiquitinated through 'Lys-63' linkage of ubiquitin moieties by the E2 ligase UBE2N and the E3 ligases RNF8 and RNF168, leading to the recruitment of repair proteins to sites of DNA damage. Ubiquitination at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) in response to DNA damage is initiated by RNF168 that mediates monoubiquitination at these 2 sites, and 'Lys-63'-linked ubiquitin are then conjugated to monoubiquitin; RNF8 is able to extend 'Lys-63'-linked ubiquitin chains in vitro. Deubiquitinated by USP51 at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) after damaged DNA is repaired (PubMed:27083998). H2AK119Ub and ionizing radiation-induced 'Lys-63'-linked ubiquitination (H2AK13Ub and H2AK15Ub) are distinct events.PTM Phosphorylation on Ser-2 (H2AS1ph) is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1. Phosphorylation at Thr-121 (H2AT120ph) by DCAF1 is present in the regulatory region of many tumor suppresor genes and down-regulates their transcription.PTM Glutamine methylation at Gln-105 (H2AQ104me) by FBL is specifically dedicated to polymerase I. It is present at 35S ribosomal DNA locus and impairs binding of the FACT complex (PubMed:24352239).PTM Symmetric dimethylation on Arg-4 by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.MASS SPECTROMETRY Monoisotopic with N-acetylserine.SIMILARITY Belongs to the histone H2A family. UniProt Q6FI13 2 EQUAL 130 EQUAL Reactome Database ID Release 81 181891 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=181891 Reactome R-HSA-181891 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-181891.1 HIST2H2AC Histone H2A.q Reactome DB_ID: 181892 UniProt:Q16777 H2AC20 H2AC20 H2AFQ HIST2H2AC FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Deiminated on Arg-4 in granulocytes upon calcium entry.PTM Monoubiquitination of Lys-120 (H2AK119Ub) by RING1, TRIM37 and RNF2/RING2 complex gives a specific tag for epigenetic transcriptional repression and participates in X chromosome inactivation of female mammals. It is involved in the initiation of both imprinted and random X inactivation. Ubiquitinated H2A is enriched in inactive X chromosome chromatin. Ubiquitination of H2A functions downstream of methylation of 'Lys-27' of histone H3 (H3K27me). H2AK119Ub by RNF2/RING2 can also be induced by ultraviolet and may be involved in DNA repair. Monoubiquitination of Lys-120 (H2AK119Ub) by TRIM37 may promote transformation of cells in a number of breast cancers (PubMed:25470042). Following DNA double-strand breaks (DSBs), it is ubiquitinated through 'Lys-63' linkage of ubiquitin moieties by the E2 ligase UBE2N and the E3 ligases RNF8 and RNF168, leading to the recruitment of repair proteins to sites of DNA damage. Ubiquitination at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) in response to DNA damage is initiated by RNF168 that mediates monoubiquitination at these 2 sites, and 'Lys-63'-linked ubiquitin are then conjugated to monoubiquitin; RNF8 is able to extend 'Lys-63'-linked ubiquitin chains in vitro. Deubiquitinated by USP51 at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) after damaged DNA is repaired (PubMed:27083998). H2AK119Ub and ionizing radiation-induced 'Lys-63'-linked ubiquitination (H2AK13Ub and H2AK15Ub) are distinct events.PTM Phosphorylation on Ser-2 (H2AS1ph) is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1. Phosphorylation at Thr-121 (H2AT120ph) by DCAF1 is present in the regulatory region of many tumor suppresor genes and down-regulates their transcription.PTM Symmetric dimethylation on Arg-4 by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage.PTM Glutamine methylation at Gln-105 (H2AQ104me) by FBL is specifically dedicated to polymerase I. It is present at 35S ribosomal DNA locus and impairs binding of the FACT complex (PubMed:24352239).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.MASS SPECTROMETRY Monoisotopic with N-acetylserine.SIMILARITY Belongs to the histone H2A family. UniProt Q16777 2 EQUAL 129 EQUAL Reactome Database ID Release 81 181892 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=181892 Reactome R-HSA-181892 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-181892.1 H2AFJ Histone H2A.J H2AJ_HUMAN Reactome DB_ID: 8862432 UniProt:Q9BTM1 H2AJ H2AJ H2AFJ FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination of Lys-120 (H2AXK119ub) gives a specific tag for epigenetic transcriptional repression. Following DNA double-strand breaks (DSBs), it is ubiquitinated through 'Lys-63' linkage of ubiquitin moieties (By similarity).PTM Phosphorylation on Ser-2 (H2AS1ph) is enhanced during mitosis. Phosphorylation on Ser-2 by RPS6KA5/MSK1 directly represses transcription. Acetylation of H3 inhibits Ser-2 phosphorylation by RPS6KA5/MSK1. Phosphorylation at Thr-121 (H2AT120ph) by DCAF1 is present in the regulatory region of many tumor suppresor genes and down-regulates their transcription (By similarity).PTM Glutamine methylation at Gln-105 (H2AQ104me) by FBL is specifically dedicated to polymerase I. It is present at 35S ribosomal DNA locus and impairs binding of the FACT complex (By similarity).SIMILARITY Belongs to the histone H2A family. UniProt Q9BTM1 2 EQUAL 129 EQUAL Reactome Database ID Release 81 8862432 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=8862432 Reactome R-HSA-8862432 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-8862432.2 H2AFV Histone H2A.V H2AV_HUMAN Reactome DB_ID: 8862427 UniProt:Q71UI9 H2AZ2 H2AZ2 H2AFV H2AV FUNCTION Variant histone H2A which replaces conventional H2A in a subset of nucleosomes. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling. May be involved in the formation of constitutive heterochromatin. May be required for chromosome segregation during cell division (By similarity).SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA. H2A or its variant H2AZ2 forms a heterodimer with H2B (By similarity).PTM Monoubiquitination of Lys-122 gives a specific tag for epigenetic transcriptional repression.PTM Acetylated on Lys-5, Lys-8 and Lys-12 during interphase. Acetylation disappears at mitosis (By similarity).MASS SPECTROMETRY Monoisotopic, not modified.SIMILARITY Belongs to the histone H2A family. UniProt Q71UI9 1 EQUAL 128 EQUAL Reactome Database ID Release 81 8862427 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=8862427 Reactome R-HSA-8862427 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-8862427.2 H2AFX Histone H2A.x H2a/x Reactome DB_ID: 56151 UniProt:P16104 H2AX H2AX H2AFX FUNCTION Variant histone H2A which replaces conventional H2A in a subset of nucleosomes. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling. Required for checkpoint-mediated arrest of cell cycle progression in response to low doses of ionizing radiation and for efficient repair of DNA double strand breaks (DSBs) specifically when modified by C-terminal phosphorylation.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA (Probable). Interacts with numerous proteins required for DNA damage signaling and repair when phosphorylated on Ser-140 (PubMed:12419185, PubMed:12607005, PubMed:15201865). These include MDC1, TP53BP1, BRCA1 and the MRN complex, composed of MRE11, RAD50, and NBN (PubMed:12419185, PubMed:12607005, PubMed:15201865). Interaction with the MRN complex is mediated at least in part by NBN (PubMed:12419185). Also interacts with DHX9/NDHII when phosphorylated on Ser-140 and MCPH1 when phosphorylated at Ser-140 or Tyr-143 (PubMed:15613478). Interacts with ARRB2; the interaction is detected in the nucleus upon OR1D2 stimulation (PubMed:16820410). Interacts with WRAP53/TCAB1 (PubMed:26734725, PubMed:27715493). Interacts with HDGFL2 (PubMed:26721387).SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus protein EBNA6.DEVELOPMENTAL STAGE Synthesized in G1 as well as in S-phase.DOMAIN The [ST]-Q motif constitutes a recognition sequence for kinases from the PI3/PI4-kinase family.PTM Phosphorylated on Ser-140 (to form gamma-H2AX or H2AX139ph) in response to DNA double strand breaks (DSBs) generated by exogenous genotoxic agents and by stalled replication forks, and may also occur during meiotic recombination events and immunoglobulin class switching in lymphocytes. Phosphorylation can extend up to several thousand nucleosomes from the actual site of the DSB and may mark the surrounding chromatin for recruitment of proteins required for DNA damage signaling and repair. Widespread phosphorylation may also serve to amplify the damage signal or aid repair of persistent lesions. Phosphorylation of Ser-140 (H2AX139ph) in response to ionizing radiation is mediated by both ATM and PRKDC while defects in DNA replication induce Ser-140 phosphorylation (H2AX139ph) subsequent to activation of ATR and PRKDC. Dephosphorylation of Ser-140 by PP2A is required for DNA DSB repair. In meiosis, Ser-140 phosphorylation (H2AX139ph) may occur at synaptonemal complexes during leptotene as an ATM-dependent response to the formation of programmed DSBs by SPO11. Ser-140 phosphorylation (H2AX139ph) may subsequently occurs at unsynapsed regions of both autosomes and the XY bivalent during zygotene, downstream of ATR and BRCA1 activation. Ser-140 phosphorylation (H2AX139ph) may also be required for transcriptional repression of unsynapsed chromatin and meiotic sex chromosome inactivation (MSCI), whereby the X and Y chromosomes condense in pachytene to form the heterochromatic XY-body. During immunoglobulin class switch recombination in lymphocytes, Ser-140 phosphorylation (H2AX139ph) may occur at sites of DNA-recombination subsequent to activation of the activation-induced cytidine deaminase AICDA. Phosphorylation at Tyr-143 (H2AXY142ph) by BAZ1B/WSTF determines the relative recruitment of either DNA repair or pro-apoptotic factors. Phosphorylation at Tyr-143 (H2AXY142ph) favors the recruitment of APBB1/FE65 and pro-apoptosis factors such as MAPK8/JNK1, triggering apoptosis. In contrast, dephosphorylation of Tyr-143 by EYA proteins (EYA1, EYA2, EYA3 or EYA4) favors the recruitment of MDC1-containing DNA repair complexes to the tail of phosphorylated Ser-140 (H2AX139ph).PTM Monoubiquitination of Lys-120 (H2AXK119ub) by RING1 and RNF2/RING2 complex gives a specific tag for epigenetic transcriptional repression (By similarity). Following DNA double-strand breaks (DSBs), it is ubiquitinated through 'Lys-63' linkage of ubiquitin moieties by the E2 ligase UBE2N and the E3 ligases RNF8 and RNF168, leading to the recruitment of repair proteins to sites of DNA damage. Ubiquitination at Lys-14 and Lys-16 (H2AK13Ub and H2AK15Ub, respectively) in response to DNA damage is initiated by RNF168 that mediates monoubiquitination at these 2 sites, and 'Lys-63'-linked ubiquitin are then conjugated to monoubiquitin; RNF8 is able to extend 'Lys-63'-linked ubiquitin chains in vitro. H2AK119Ub and ionizing radiation-induced 'Lys-63'-linked ubiquitination (H2AK13Ub and H2AK15Ub) are distinct events.PTM Acetylation at Lys-6 (H2AXK5ac) by KAT5 component of the NuA4 histone acetyltransferase complex promotes NBN/NBS1 assembly at the sites of DNA damage (PubMed:17709392, PubMed:26438602). Acetylation at Lys-37 increases in S and G2 phases. This modification has been proposed to play a role in DNA double-strand break repair (By similarity).SIMILARITY Belongs to the histone H2A family. UniProt P16104 2 EQUAL 143 EQUAL Reactome Database ID Release 81 56151 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=56151 Reactome R-HSA-56151 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-56151.1 H2AFZ Histone H2A.z Reactome DB_ID: 181897 UniProt:P0C0S5 H2AZ1 H2AZ1 H2AFZ H2AZ FUNCTION Variant histone H2A which replaces conventional H2A in a subset of nucleosomes. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling. May be involved in the formation of constitutive heterochromatin. May be required for chromosome segregation during cell division.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA. H2A or its variant H2AZ1 forms a heterodimer with H2B. H2AZ1 interacts with INCENP (By similarity). Interacts (via M6 cassette) with ANP32E; leading to removal of H2A.Z/H2AZ1 from the nucleosome. Heterodimer H2BC11 and H2AZ1 interacts with VPS72 (via N-terminal domain) (PubMed:26974126). Interacts with PWWP2A (PubMed:28645917, PubMed:30327463). Interacts with FH (when phosphorylated by PRKDC) (PubMed:26237645).PTM Monoubiquitination of Lys-122 gives a specific tag for epigenetic transcriptional repression.PTM Acetylated on Lys-5, Lys-8, Lys-12 and Lys-14 by KAT2A; KAT2A is recruited by the XPC complex in absence of DNA damage (PubMed:31527837). Acetylated on Lys-5, Lys-8 and Lys-12 during interphase; acetylation disappears at mitosis (By similarity). Acetylation by the NuA4 histone acetyltransferase complex is required for hematopoietic stem cell maintenance (By similarity).PTM Monomethylated on Lys-5 and Lys-8 by SETD6. SETD6 predominantly methylates Lys-8, lys-5 being a possible secondary site.PTM Not phosphorylated.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.MASS SPECTROMETRY Monoisotopic, not modified.SIMILARITY Belongs to the histone H2A family. UniProt P0C0S5 2 EQUAL 128 EQUAL Reactome Database ID Release 81 181897 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=181897 Reactome R-HSA-181897 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-181897.1 Reactome Database ID Release 81 181899 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=181899 Reactome R-HSA-181899 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-181899.2 2 Converted from EntitySet in Reactome H3K9ac AcK10-Histone H3 Reactome DB_ID: 5250644 Histone H3a Ack10-HIST1H3A Histone H3.1 Histone H3b Histone H3c Histone H3d Histone H3f Histone H3h Histone H3i Histone H3j Histone H3k Histone H3l Reactome DB_ID: 4568939 UniProt:P68431 H3C1 H3C1 H3FA HIST1H3A H3C2 H3FL HIST1H3B H3C3 H3FCHIST1H3C H3C4 H3FB HIST1H3D H3C6 H3FD HIST1H3E H3C7 H3FI HIST1H3F H3C8 H3FH HIST1H3G H3C10 H3FK HIST1H3H H3C11 H3FF HIST1H3I H3C12 H3FJ HIST1H3J FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA. Interacts with TONSL; CHAF1A; CHAF1B; MCM2 and DNAJC9 (PubMed:33857403).DEVELOPMENTAL STAGE Expressed during S phase, then expression strongly decreases as cell division slows down during the process of differentiation.PTM Acetylation is generally linked to gene activation. Acetylation on Lys-10 (H3K9ac) impairs methylation at Arg-9 (H3R8me2s). Acetylation on Lys-19 (H3K18ac) and Lys-24 (H3K24ac) favors methylation at Arg-18 (H3R17me). Acetylation at Lys-123 (H3K122ac) by EP300/p300 plays a central role in chromatin structure: localizes at the surface of the histone octamer and stimulates transcription, possibly by promoting nucleosome instability.PTM Citrullination at Arg-9 (H3R8ci) and/or Arg-18 (H3R17ci) by PADI4 impairs methylation and represses transcription.PTM Asymmetric dimethylation at Arg-18 (H3R17me2a) by CARM1 is linked to gene activation. Symmetric dimethylation at Arg-9 (H3R8me2s) by PRMT5 is linked to gene repression. Asymmetric dimethylation at Arg-3 (H3R2me2a) by PRMT6 is linked to gene repression and is mutually exclusive with H3 Lys-5 methylation (H3K4me2 and H3K4me3). H3R2me2a is present at the 3' of genes regardless of their transcription state and is enriched on inactive promoters, while it is absent on active promoters.PTM Methylation at Lys-5 (H3K4me), Lys-37 (H3K36me) and Lys-80 (H3K79me) are linked to gene activation. Methylation at Lys-5 (H3K4me) facilitates subsequent acetylation of H3 and H4. Methylation at Lys-80 (H3K79me) is associated with DNA double-strand break (DSB) responses and is a specific target for TP53BP1. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are linked to gene repression. Methylation at Lys-10 (H3K9me) is a specific target for HP1 proteins (CBX1, CBX3 and CBX5) and prevents subsequent phosphorylation at Ser-11 (H3S10ph) and acetylation of H3 and H4. Methylation at Lys-5 (H3K4me) and Lys-80 (H3K79me) require preliminary monoubiquitination of H2B at 'Lys-120'. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are enriched in inactive X chromosome chromatin. Monomethylation at Lys-57 (H3K56me1) by EHMT2/G9A in G1 phase promotes interaction with PCNA and is required for DNA replication.PTM Phosphorylated at Thr-4 (H3T3ph) by HASPIN during prophase and dephosphorylated during anaphase. Phosphorylation at Ser-11 (H3S10ph) by AURKB is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. In addition phosphorylation at Ser-11 (H3S10ph) by RPS6KA4 and RPS6KA5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or UV irradiation and result in the activation of genes, such as c-fos and c-jun. Phosphorylation at Ser-11 (H3S10ph), which is linked to gene activation, prevents methylation at Lys-10 (H3K9me) but facilitates acetylation of H3 and H4. Phosphorylation at Ser-11 (H3S10ph) by AURKB mediates the dissociation of HP1 proteins (CBX1, CBX3 and CBX5) from heterochromatin. Phosphorylation at Ser-11 (H3S10ph) is also an essential regulatory mechanism for neoplastic cell transformation. Phosphorylated at Ser-29 (H3S28ph) by MAP3K20 isoform 1, RPS6KA5 or AURKB during mitosis or upon ultraviolet B irradiation. Phosphorylation at Thr-7 (H3T6ph) by PRKCB is a specific tag for epigenetic transcriptional activation that prevents demethylation of Lys-5 (H3K4me) by LSD1/KDM1A. At centromeres, specifically phosphorylated at Thr-12 (H3T11ph) from prophase to early anaphase, by DAPK3 and PKN1. Phosphorylation at Thr-12 (H3T11ph) by PKN1 is a specific tag for epigenetic transcriptional activation that promotes demethylation of Lys-10 (H3K9me) by KDM4C/JMJD2C. Phosphorylation at Thr-12 (H3T11ph) by chromatin-associated CHEK1 regulates the transcription of cell cycle regulatory genes by modulating acetylation of Lys-10 (H3K9ac). Phosphorylation at Tyr-42 (H3Y41ph) by JAK2 promotes exclusion of CBX5 (HP1 alpha) from chromatin.PTM Monoubiquitinated by RAG1 in lymphoid cells, monoubiquitination is required for V(D)J recombination (By similarity). Ubiquitinated by the CUL4-DDB-RBX1 complex in response to ultraviolet irradiation. This may weaken the interaction between histones and DNA and facilitate DNA accessibility to repair proteins.PTM Lysine deamination at Lys-5 (H3K4all) to form allysine is mediated by LOXL2. Allysine formation by LOXL2 only takes place on H3K4me3 and results in gene repression.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Butyrylation of histones marks active promoters and competes with histone acetylation. It is present during late spermatogenesis.PTM Succinylation at Lys-80 (H3K79succ) by KAT2A takes place with a maximum frequency around the transcription start sites of genes (PubMed:29211711). It gives a specific tag for epigenetic transcription activation (PubMed:29211711). Desuccinylation at Lys-123 (H3K122succ) by SIRT7 in response to DNA damage promotes chromatin condensation and double-strand breaks (DSBs) repair (PubMed:27436229).PTM Serine ADP-ribosylation constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:30257210). Serine ADP-ribosylation at Ser-11 (H3S10ADPr) is mutually exclusive with phosphorylation at Ser-11 (H3S10ph) and impairs acetylation at Lys-10 (H3K9ac) (PubMed:30257210).PTM Serotonylated by TGM2 at Gln-6 (H3Q5ser) during serotonergic neuron differentiation (PubMed:30867594). H3Q5ser is associated with trimethylation of Lys-5 (H3K4me3) and enhances general transcription factor IID (TFIID) complex-binding to H3K4me3, thereby facilitating transcription (PubMed:30867594).PTM Dopaminylated by TGM2 at Gln-6 (H3Q5dop) in ventral tegmental area (VTA) neurons (PubMed:32273471). H3Q5dop mediates neurotransmission-independent role of nuclear dopamine by regulating relapse-related transcriptional plasticity in the reward system (By similarity).PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.DISEASE HIST1H3B or HIST1H3C mutations affecting residue Lys-37 of histone H3.1 are involved in the pathogenesis of pediatric undifferentiated soft tissue sarcomas. The mechanism through which mutations lead to tumorigenesis involves altered histones methylation with gain of global H3K27 methylation, altered Polycomb repressive complex 1 (PRC1) activity, aberrant epigenetic regulation of gene expression and impaired differentiation of mesenchimal progenitor cells.MISCELLANEOUS This histone is only present in mammals and is enriched in acetylation of Lys-15 and dimethylation of Lys-10 (H3K9me2).SIMILARITY Belongs to the histone H3 family.CAUTION The original paper reporting lysine deamination at Lys-5 by LOXL2 has been retracted due to inappropriate manipulation of figure data (PubMed:22483618, PubMed:27392148). However, this modification was confirmed in a subsequent publication (PubMed:27735137). UniProt P68431 10 EQUAL N6-acetyl-L-lysine MOD MOD:00064 2 EQUAL 136 EQUAL Reactome Database ID Release 81 4568939 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=4568939 Reactome R-HSA-4568939 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-4568939.1 HIST2H3C Ack10-HIST2H3A Histone H3.2 HIST2H3D Reactome DB_ID: 4568924 UniProt:Q71DI3 H3C15 H3C15 HIST2H3A H3C14 H3F2 H3FM HIST2H3C H3C13 HIST2H3D FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA. During nucleosome assembly the chaperone ASF1A interacts with the histone H3-H4 heterodimer. Interacts with DNAJC9, CHAF1A and CHAF1B (PubMed:33857403).DEVELOPMENTAL STAGE Expressed during S phase, then expression strongly decreases as cell division slows down during the process of differentiation.PTM Acetylation is generally linked to gene activation. Acetylation on Lys-10 (H3K9ac) impairs methylation at Arg-9 (H3R8me2s). Acetylation on Lys-19 (H3K18ac) and Lys-24 (H3K24ac) favors methylation at Arg-18 (H3R17me). Acetylation at Lys-123 (H3K122ac) by EP300/p300 plays a central role in chromatin structure: localizes at the surface of the histone octamer and stimulates transcription, possibly by promoting nucleosome instability.PTM Citrullination at Arg-9 (H3R8ci) and/or Arg-18 (H3R17ci) by PADI4 impairs methylation and represses transcription.PTM Asymmetric dimethylation at Arg-18 (H3R17me2a) by CARM1 is linked to gene activation. Symmetric dimethylation at Arg-9 (H3R8me2s) by PRMT5 is linked to gene repression. Asymmetric dimethylation at Arg-3 (H3R2me2a) by PRMT6 is linked to gene repression and is mutually exclusive with H3 Lys-5 methylation (H3K4me2 and H3K4me3). H3R2me2a is present at the 3' of genes regardless of their transcription state and is enriched on inactive promoters, while it is absent on active promoters.PTM Methylation at Lys-5 (H3K4me), Lys-37 (H3K36me) and Lys-80 (H3K79me) are linked to gene activation. Methylation at Lys-5 (H3K4me) facilitates subsequent acetylation of H3 and H4. Methylation at Lys-80 (H3K79me) is associated with DNA double-strand break (DSB) responses and is a specific target for TP53BP1. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are linked to gene repression. Methylation at Lys-10 (H3K9me) is a specific target for HP1 proteins (CBX1, CBX3 and CBX5) and prevents subsequent phosphorylation at Ser-11 (H3S10ph) and acetylation of H3 and H4. Methylation at Lys-5 (H3K4me) and Lys-80 (H3K79me) require preliminary monoubiquitination of H2B at 'Lys-120'. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are enriched in inactive X chromosome chromatin. Monomethylation at Lys-57 (H3K56me1) by EHMT2/G9A in G1 phase promotes interaction with PCNA and is required for DNA replication.PTM Phosphorylated at Thr-4 (H3T3ph) by HASPIN during prophase and dephosphorylated during anaphase. Phosphorylation at Ser-11 (H3S10ph) by AURKB is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. In addition phosphorylation at Ser-11 (H3S10ph) by RPS6KA4 and RPS6KA5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or UV irradiation and result in the activation of genes, such as c-fos and c-jun. Phosphorylation at Ser-11 (H3S10ph), which is linked to gene activation, prevents methylation at Lys-10 (H3K9me) but facilitates acetylation of H3 and H4. Phosphorylation at Ser-11 (H3S10ph) by AURKB mediates the dissociation of HP1 proteins (CBX1, CBX3 and CBX5) from heterochromatin. Phosphorylation at Ser-11 (H3S10ph) is also an essential regulatory mechanism for neoplastic cell transformation. Phosphorylated at Ser-29 (H3S28ph) by MAP3K20 isoform 1, RPS6KA5 or AURKB during mitosis or upon ultraviolet B irradiation. Phosphorylation at Thr-7 (H3T6ph) by PRKCB is a specific tag for epigenetic transcriptional activation that prevents demethylation of Lys-5 (H3K4me) by LSD1/KDM1A. At centromeres, specifically phosphorylated at Thr-12 (H3T11ph) from prophase to early anaphase, by DAPK3 and PKN1. Phosphorylation at Thr-12 (H3T11ph) by PKN1 is a specific tag for epigenetic transcriptional activation that promotes demethylation of Lys-10 (H3K9me) by KDM4C/JMJD2C. Phosphorylation at Tyr-42 (H3Y41ph) by JAK2 promotes exclusion of CBX5 (HP1 alpha) from chromatin.PTM Monoubiquitinated by RAG1 in lymphoid cells, monoubiquitination is required for V(D)J recombination. Ubiquitinated by the CUL4-DDB-RBX1 complex in response to ultraviolet irradiation. This may weaken the interaction between histones and DNA and facilitate DNA accessibility to repair proteins.PTM Lysine deamination at Lys-5 (H3K4all) to form allysine is mediated by LOXL2. Allysine formation by LOXL2 only takes place on H3K4me3 and results in gene repression.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Butyrylation of histones marks active promoters and competes with histone acetylation. It is present during late spermatogenesis.PTM Succinylation at Lys-80 (H3K79succ) by KAT2A takes place with a maximum frequency around the transcription start sites of genes (PubMed:29211711). It gives a specific tag for epigenetic transcription activation (PubMed:29211711). Desuccinylation at Lys-123 (H3K122succ) by SIRT7 in response to DNA damage promotes chromatin condensation and double-strand breaks (DSBs) repair (PubMed:27436229).PTM Serine ADP-ribosylation constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:29480802). Serine ADP-ribosylation at Ser-11 (H3S10ADPr) is mutually exclusive with phosphorylation at Ser-11 (H3S10ph) and impairs acetylation at Lys-10 (H3K9ac) (PubMed:30257210).PTM Serotonylated by TGM2 at Gln-6 (H3Q5ser) during serotonergic neuron differentiation (PubMed:30867594). H3Q5ser is associated with trimethylation of Lys-5 (H3K4me3) and enhances general transcription factor IID (TFIID) complex-binding to H3K4me3, thereby facilitating transcription (PubMed:30867594).PTM Dopaminylated by TGM2 at Gln-6 (H3Q5dop) in ventral tegmental area (VTA) neurons (PubMed:32273471). H3Q5dop mediates neurotransmission-independent role of nuclear dopamine by regulating relapse-related transcriptional plasticity in the reward system (By similarity).PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H3 family.CAUTION The original paper reporting lysine deamination at Lys-5 by LOXL2 has been retracted due to inappropriate manipulation of figure data (PubMed:22483618, PubMed:27392148). However, this modification was confirmed in a subsequent publication (PubMed:27735137). UniProt Q71DI3 13 EQUAL 2 EQUAL 136 EQUAL Reactome Database ID Release 81 4568924 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=4568924 Reactome R-HSA-4568924 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-4568924.1 AcK10-H3F3A Histone H3.3 with acetylated lysine-9 Reactome DB_ID: 5250654 UniProt:P84243 H3-3A H3-3A H3.3A H3F3 H3F3A PP781 H3-3B H3.3B H3F3B FUNCTION Variant histone H3 which replaces conventional H3 in a wide range of nucleosomes in active genes. Constitutes the predominant form of histone H3 in non-dividing cells and is incorporated into chromatin independently of DNA synthesis. Deposited at sites of nucleosomal displacement throughout transcribed genes, suggesting that it represents an epigenetic imprint of transcriptionally active chromatin. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA. Interacts with HIRA, a chaperone required for its incorporation into nucleosomes. Interacts with ZMYND11; when trimethylated at 'Lys-36' (H3.3K36me3). Found in a co-chaperone complex with DNJC9, MCM2 and histone H3.3-H4 dimers (PubMed:33857403). Within the complex, interacts with DNJC9 (via C-terminus); the interaction is direct (PubMed:33857403). Interacts with ASF1A, MCM2, NASP and SPT2 (PubMed:33857403).DEVELOPMENTAL STAGE Expressed throughout the cell cycle independently of DNA synthesis.DOMAIN Specific interaction of trimethylated form at 'Lys-36' (H3.3K36me3) with ZMYND11 is mediated by the encapsulation of Ser-32 residue with a composite pocket formed by the tandem bromo-PWWP domains.PTM Acetylation is generally linked to gene activation. Acetylation on Lys-10 (H3K9ac) impairs methylation at Arg-9 (H3R8me2s). Acetylation on Lys-19 (H3K18ac) and Lys-24 (H3K24ac) favors methylation at Arg-18 (H3R17me). Acetylation at Lys-123 (H3K122ac) by EP300/p300 plays a central role in chromatin structure: localizes at the surface of the histone octamer and stimulates transcription, possibly by promoting nucleosome instability.PTM Citrullination at Arg-9 (H3R8ci) and/or Arg-18 (H3R17ci) by PADI4 impairs methylation and represses transcription.PTM Asymmetric dimethylation at Arg-18 (H3R17me2a) by CARM1 is linked to gene activation. Symmetric dimethylation at Arg-9 (H3R8me2s) by PRMT5 is linked to gene repression. Asymmetric dimethylation at Arg-3 (H3R2me2a) by PRMT6 is linked to gene repression and is mutually exclusive with H3 Lys-5 methylation (H3K4me2 and H3K4me3). H3R2me2a is present at the 3' of genes regardless of their transcription state and is enriched on inactive promoters, while it is absent on active promoters.PTM Specifically enriched in modifications associated with active chromatin such as methylation at Lys-5 (H3K4me), Lys-37 and Lys-80. Methylation at Lys-5 (H3K4me) facilitates subsequent acetylation of H3 and H4. Methylation at Lys-80 (H3K79me) is associated with DNA double-strand break (DSB) responses and is a specific target for TP53BP1. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me), which are linked to gene repression, are underrepresented. Methylation at Lys-10 (H3K9me) is a specific target for HP1 proteins (CBX1, CBX3 and CBX5) and prevents subsequent phosphorylation at Ser-11 (H3S10ph) and acetylation of H3 and H4. Methylation at Lys-5 (H3K4me) and Lys-80 (H3K79me) require preliminary monoubiquitination of H2B at 'Lys-120'. Methylation at Lys-10 (H3K9me) and Lys-28 (H3K27me) are enriched in inactive X chromosome chromatin. Monomethylation at Lys-57 (H3K56me1) by EHMT2/G9A in G1 phase promotes interaction with PCNA and is required for DNA replication.PTM Phosphorylated at Thr-4 (H3T3ph) by HASPIN during prophase and dephosphorylated during anaphase. Phosphorylation at Ser-11 (H3S10ph) by AURKB is crucial for chromosome condensation and cell-cycle progression during mitosis and meiosis. In addition phosphorylation at Ser-11 (H3S10ph) by RPS6KA4 and RPS6KA5 is important during interphase because it enables the transcription of genes following external stimulation, like mitogens, stress, growth factors or UV irradiation and result in the activation of genes, such as c-fos and c-jun. Phosphorylation at Ser-11 (H3S10ph), which is linked to gene activation, prevents methylation at Lys-10 (H3K9me) but facilitates acetylation of H3 and H4. Phosphorylation at Ser-11 (H3S10ph) by AURKB mediates the dissociation of HP1 proteins (CBX1, CBX3 and CBX5) from heterochromatin. Phosphorylation at Ser-11 (H3S10ph) is also an essential regulatory mechanism for neoplastic cell transformation. Phosphorylated at Ser-29 (H3S28ph) by MAP3K20 isoform 1, RPS6KA5 or AURKB during mitosis or upon ultraviolet B irradiation. Phosphorylation at Thr-7 (H3T6ph) by PRKCB is a specific tag for epigenetic transcriptional activation that prevents demethylation of Lys-5 (H3K4me) by LSD1/KDM1A. At centromeres, specifically phosphorylated at Thr-12 (H3T11ph) from prophase to early anaphase, by DAPK3 and PKN1. Phosphorylation at Thr-12 (H3T11ph) by PKN1 is a specific tag for epigenetic transcriptional activation that promotes demethylation of Lys-10 (H3K9me) by KDM4C/JMJD2C. Phosphorylation at Tyr-42 (H3Y41ph) by JAK2 promotes exclusion of CBX5 (HP1 alpha) from chromatin. Phosphorylation on Ser-32 (H3S31ph) is specific to regions bordering centromeres in metaphase chromosomes.PTM Ubiquitinated. Monoubiquitinated by RAG1 in lymphoid cells, monoubiquitination is required for V(D)J recombination (By similarity).PTM Lysine deamination at Lys-5 (H3K4all) to form allysine is mediated by LOXL2. Allysine formation by LOXL2 only takes place on H3K4me3 and results in gene repression.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Butyrylation of histones marks active promoters and competes with histone acetylation. It is present during late spermatogenesis.PTM Succinylation at Lys-80 (H3K79succ) by KAT2A takes place with a maximum frequency around the transcription start sites of genes (PubMed:29211711). It gives a specific tag for epigenetic transcription activation (PubMed:29211711). Desuccinylation at Lys-123 (H3K122succ) by SIRT7 in response to DNA damage promotes chromatin condensation and double-strand breaks (DSBs) repair (PubMed:27436229).PTM Serine ADP-ribosylation constitutes the primary form of ADP-ribosylation of proteins in response to DNA damage (PubMed:29480802). Serine ADP-ribosylation at Ser-11 (H3S10ADPr) is mutually exclusive with phosphorylation at Ser-11 (H3S10ph) and impairs acetylation at Lys-10 (H3K9ac) (PubMed:30257210).PTM Serotonylated by TGM2 at Gln-6 (H3Q5ser) during serotonergic neuron differentiation (PubMed:30867594). H3Q5ser is associated with trimethylation of Lys-5 (H3K4me3) and enhances general transcription factor IID (TFIID) complex-binding to H3K4me3, thereby facilitating transcription (PubMed:30867594).PTM Dopaminylated by TGM2 at Gln-6 (H3Q5dop) in ventral tegmental area (VTA) neurons (PubMed:32273471). H3Q5dop mediates neurotransmission-independent role of nuclear dopamine by regulating relapse-related transcriptional plasticity in the reward system (By similarity).PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.DISEASE H3F3A and H3F3B mutations affecting residues involved in post-translational modifications of histone H3.3 are implicated in the pathogenesis of some bone and cartilage neoplasms. Mutations have been found with high prevalence in chondroblastoma and giant cell tumors of bone, and with low frequency in osteosarcoma, conventional chondrosarcoma and clear cell chondrosarcoma. Chondroblastoma samples frequently carry a H3F3B mutation affecting residue Lys-37 (H3K36), although H3F3A is mutated in some cases. Most giant cell tumors of bone harbor H3F3A mutations affecting residue Gly-35 (H3G34).SIMILARITY Belongs to the histone H3 family.CAUTION The original paper reporting lysine deamination at Lys-5 by LOXL2 has been retracted due to inappropriate manipulation of figure data (PubMed:22483618, PubMed:27392148). However, this modification was confirmed in a subsequent publication (PubMed:27735137). UniProt P84243 10 EQUAL 2 EQUAL 136 EQUAL Reactome Database ID Release 81 5250654 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=5250654 Reactome R-HSA-5250654 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-5250654.1 Reactome Database ID Release 81 5250644 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=5250644 Reactome R-HSA-5250644 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-5250644.1 2 Converted from EntitySet in Reactome Histone H2B Reactome DB_ID: 181911 HIST1H2BK Histone H2B K Reactome DB_ID: 181898 UniProt:O60814 H2BC12 H2BC12 H2BFT HIRIP1 HIST1H2BK FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.FUNCTION Has broad antibacterial activity. May contribute to the formation of the functional antimicrobial barrier of the colonic epithelium, and to the bactericidal activity of amniotic fluid.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H2B family. UniProt O60814 2 EQUAL 126 EQUAL Reactome Database ID Release 81 181898 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=181898 Reactome R-HSA-181898 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-181898.1 HIST3H2BB Histone H2B type 12 Reactome DB_ID: 181923 UniProt:Q8N257 H2BU1 H2BU1 HIST3H2BB FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H2B family. UniProt Q8N257 2 EQUAL 126 EQUAL Reactome Database ID Release 81 181923 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=181923 Reactome R-HSA-181923 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-181923.1 HIST1H2BA Histone H2B, testis Reactome DB_ID: 181916 UniProt:Q96A08 H2BC1 H2BC1 HIST1H2BA TSH2B FUNCTION Variant histone specifically required to direct the transformation of dissociating nucleosomes to protamine in male germ cells (By similarity). Entirely replaces classical histone H2B prior nucleosome to protamine transition and probably acts as a nucleosome dissociating factor that creates a more dynamic chromatin, facilitating the large-scale exchange of histones (By similarity). Core component of nucleosome (By similarity). Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template (By similarity). Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability (By similarity). DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling (By similarity). Also found in fat cells, its function and the presence of post-translational modifications specific to such cells are still unclear (PubMed:21249133).SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers.TISSUE SPECIFICITY Mainly expressed in testis, and the corresponding protein is also present in mature sperm (at protein level). Also found in some fat cells.PTM Monoubiquitination at Lys-36 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-122 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Acetylated during spermatogenesis. Acetylated form is most abundant in spermatogonia compared to spermatocytes and round spermatids (By similarity).PTM Phosphorylated at Thr-117 in spermatogonia, spermatocytes and round spermatids.PTM Methylated at Lys-118 in spermatogonia, spermatocytes and round spermatids.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H2B family. UniProt Q96A08 2 EQUAL 127 EQUAL Reactome Database ID Release 81 181916 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=181916 Reactome R-HSA-181916 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-181916.1 HIST1H2BC Histone H2B type 1-C/E/F/G/I Reactome DB_ID: 181906 UniProt:P62807 H2BC4 H2BC4 H2BFL HIST1H2BC H2BC6 H2BFH HIST1H2BE H2BC7 H2BFG HIST1H2BF H2BC8 H2BFA HIST1H2BG H2BC10 H2BFK HIST1H2BI FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.FUNCTION Has broad antibacterial activity. May contribute to the formation of the functional antimicrobial barrier of the colonic epithelium, and to the bactericidal activity of amniotic fluid.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H2B family. UniProt P62807 2 EQUAL 126 EQUAL Reactome Database ID Release 81 181906 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=181906 Reactome R-HSA-181906 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-181906.1 HIST1H2BD Histone H2B.b Reactome DB_ID: 181912 UniProt:P58876 H2BC5 H2BC5 H2BFB HIRIP2 HIST1H2BD FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM ADP-ribosylated on Ser-7 in response to DNA damage.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.MISCELLANEOUS The mouse orthologous protein seems not to exist.SIMILARITY Belongs to the histone H2B family. UniProt P58876 2 EQUAL 126 EQUAL Reactome Database ID Release 81 181912 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=181912 Reactome R-HSA-181912 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-181912.1 HIST1H2BL Histone H2B.c Reactome DB_ID: 181920 UniProt:Q99880 H2BC13 H2BC13 H2BFC HIST1H2BL FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.PTM ADP-ribosylated on Ser-7 in response to DNA damage.SIMILARITY Belongs to the histone H2B family. UniProt Q99880 2 EQUAL 126 EQUAL Reactome Database ID Release 81 181920 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=181920 Reactome R-HSA-181920 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-181920.1 HIST1H2BN Histone H2B.d Reactome DB_ID: 181907 UniProt:Q99877 H2BC15 H2BC15 H2BFD HIST1H2BN FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H2B family. UniProt Q99877 2 EQUAL 126 EQUAL Reactome Database ID Release 81 181907 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=181907 Reactome R-HSA-181907 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-181907.1 HIST1H2BM Histone H2B.e Reactome DB_ID: 181917 UniProt:Q99879 H2BC14 H2BC14 H2BFE HIST1H2BM FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM ADP-ribosylated on Ser-7 in response to DNA damage.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H2B family. UniProt Q99879 2 EQUAL 126 EQUAL Reactome Database ID Release 81 181917 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=181917 Reactome R-HSA-181917 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-181917.1 HIST1H2BB Histone H2B.f Reactome DB_ID: 181903 UniProt:P33778 H2BC3 H2BC3 H2BFF HIST1H2BB FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H2B family. UniProt P33778 2 EQUAL 126 EQUAL Reactome Database ID Release 81 181903 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=181903 Reactome R-HSA-181903 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-181903.1 HIST1H2BH Histone H2B.j Reactome DB_ID: 181915 UniProt:Q93079 H2BC9 H2BC9 H2BFJ HIST1H2BH FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers (Probable). The octamer wraps approximately 147 bp of DNA (Probable). Found in a complex with PPAR9; DTX3L AND STAT1; the interaction is likely to induce DTX3L-mediated ubiquitination of H2BC9/H2BJ (PubMed:26479788).PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons (PubMed:16627869). Monoubiquitinated by DTX3L upon encephalomyocarditis virus (EMCV)-mediated infection (PubMed:26479788).PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H2B family. UniProt Q93079 2 EQUAL 126 EQUAL Reactome Database ID Release 81 181915 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=181915 Reactome R-HSA-181915 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-181915.1 HIST1H2BO Histone H2B.n Reactome DB_ID: 181910 UniProt:P23527 H2BC17 H2BC17 H2BFH H2BFN HIST1H2BO FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.MISCELLANEOUS The mouse orthologous protein seems not to exist.SIMILARITY Belongs to the histone H2B family. UniProt P23527 2 EQUAL 126 EQUAL Reactome Database ID Release 81 181910 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=181910 Reactome R-HSA-181910 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-181910.1 HIST2H2BE Histone H2B.q Reactome DB_ID: 181908 UniProt:Q16778 H2BC21 H2BC21 H2BFQ HIST2H2BE FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.FUNCTION Has broad antibacterial activity. May contribute to the formation of the functional antimicrobial barrier of the colonic epithelium, and to the bactericidal activity of amniotic fluid.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H2B family. UniProt Q16778 2 EQUAL 126 EQUAL Reactome Database ID Release 81 181908 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=181908 Reactome R-HSA-181908 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-181908.1 HIST1H2BJ Histone H2B.r Reactome DB_ID: 181900 UniProt:P06899 H2BC11 H2BC11 H2BFR HIST1H2BJ FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.FUNCTION Has broad antibacterial activity. May contribute to the formation of the functional antimicrobial barrier of the colonic epithelium, and to the bactericidal activity of amniotic fluid.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA. Heterodimer H2BC11 and H2AZ1 interacts with VPS72 (via N-terminal domain) (PubMed:26974126).PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H2B family. UniProt P06899 2 EQUAL 126 EQUAL Reactome Database ID Release 81 181900 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=181900 Reactome R-HSA-181900 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-181900.1 H2BFS Histone H2B.s Reactome DB_ID: 181904 UniProt:P57053 H2BC12L H2BC12L H2BFS H2BS1 FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.FUNCTION Has broad antibacterial activity. May contribute to the formation of the functional antimicrobial barrier of the colonic epithelium, and to the bactericidal activity of amniotic fluid.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA.PTM Monoubiquitination at Lys-35 (H2BK34Ub) by the MSL1/MSL2 dimer is required for histone H3 'Lys-4' (H3K4me) and 'Lys-79' (H3K79me) methylation and transcription activation at specific gene loci, such as HOXA9 and MEIS1 loci. Similarly, monoubiquitination at Lys-121 (H2BK120Ub) by the RNF20/40 complex gives a specific tag for epigenetic transcriptional activation and is also prerequisite for histone H3 'Lys-4' and 'Lys-79' methylation. It also functions cooperatively with the FACT dimer to stimulate elongation by RNA polymerase II. H2BK120Ub also acts as a regulator of mRNA splicing: deubiquitination by USP49 is required for efficient cotranscriptional splicing of a large set of exons.PTM Phosphorylation at Ser-37 (H2BS36ph) by AMPK in response to stress promotes transcription (By similarity). Phosphorylated on Ser-15 (H2BS14ph) by STK4/MST1 during apoptosis; which facilitates apoptotic chromatin condensation. Also phosphorylated on Ser-15 in response to DNA double strand breaks (DSBs), and in correlation with somatic hypermutation and immunoglobulin class-switch recombination.PTM GlcNAcylation at Ser-113 promotes monoubiquitination of Lys-121. It fluctuates in response to extracellular glucose, and associates with transcribed genes (By similarity).PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.SIMILARITY Belongs to the histone H2B family. UniProt P57053 2 EQUAL 126 EQUAL Reactome Database ID Release 81 181904 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=181904 Reactome R-HSA-181904 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-181904.1 Reactome Database ID Release 81 181911 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=181911 Reactome R-HSA-181911 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-181911.1 2 HIST1H4 Histone H4 HIST1H4A HIST1H4B HIST1H4C HIST1H4D HIST1H4E HIST1H4F HIST1H4H HIST1H4I HIST1H4J HIST1H4K HIST1H4L HIST2H4A HIST2H4B Reactome DB_ID: 181902 UniProt:P62805 H4C1 H4C1 H4/A H4FA HIST1H4A H4C2 H4/I H4FI HIST1H4B H4C3 H4/G H4FG HIST1H4C H4C4 H4/B H4FB HIST1H4D H4C5 H4/J H4FJ HIST1H4E H4C6 H4/C H4FC HIST1H4F H4C8 H4/H H4FH HIST1H4H H4C9 H4/M H4FM HIST1H4I H4C11 H4/E H4FE HIST1H4J H4C12 H4/D H4FD HIST1H4K H4C13 H4/K H4FK HIST1H4L H4C14 H4/N H4F2 H4FN HIST2H4 HIST2H4A H4C15 H4/O H4FO HIST2H4B H4-16 HIST4H4 FUNCTION Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.SUBUNIT The nucleosome is a histone octamer containing two molecules each of H2A, H2B, H3 and H4 assembled in one H3-H4 heterotetramer and two H2A-H2B heterodimers. The octamer wraps approximately 147 bp of DNA (By similarity). Found in a co-chaperone complex with DNJC9, MCM2 and histone H3.3-H4 dimers (PubMed:33857403). Within the complex, interacts with DNJC9 (via C-terminus); the interaction is direct (PubMed:33857403).PTM Acetylation at Lys-6 (H4K5ac), Lys-9 (H4K8ac), Lys-13 (H4K12ac) and Lys-17 (H4K16ac) occurs in coding regions of the genome but not in heterochromatin.PTM Citrullination at Arg-4 (H4R3ci) by PADI4 impairs methylation.PTM Monomethylation and asymmetric dimethylation at Arg-4 (H4R3me1 and H4R3me2a, respectively) by PRMT1 favors acetylation at Lys-9 (H4K8ac) and Lys-13 (H4K12ac). Demethylation is performed by JMJD6. Symmetric dimethylation on Arg-4 (H4R3me2s) by the PRDM1/PRMT5 complex may play a crucial role in the germ-cell lineage.PTM Monomethylated, dimethylated or trimethylated at Lys-21 (H4K20me1, H4K20me2, H4K20me3) (PubMed:12086618, PubMed:15964846, PubMed:17967882). Monomethylation is performed by KMT5A/SET8 (PubMed:15964846). Dimethylation and trimethylation is performed by KMT5B and KMT5C and induces gene silencing (By similarity). Monomethylated at Lys-13 (H4K12me1) by N6AMT1; H4K12me1 modification is present at the promoters of numerous genes encoding cell cycle regulators (PubMed:31061526).PTM Phosphorylated by PAK2 at Ser-48 (H4S47ph). This phosphorylation increases the association of H3.3-H4 with the histone chaperone HIRA, thus promoting nucleosome assembly of H3.3-H4 and inhibiting nucleosome assembly of H3.1-H4.PTM Ubiquitinated by the CUL4-DDB-RBX1 complex in response to ultraviolet irradiation. This may weaken the interaction between histones and DNA and facilitate DNA accessibility to repair proteins. Monoubiquitinated at Lys-92 of histone H4 (H4K91ub1) in response to DNA damage. The exact role of H4K91ub1 in DNA damage response is still unclear but it may function as a licensing signal for additional histone H4 post-translational modifications such as H4 Lys-21 methylation (H4K20me).PTM Ufmylated; monofmylated by UFL1 at Lys-32 (H4K31Ufm1) in response to DNA damage.PTM Sumoylated, which is associated with transcriptional repression.PTM Crotonylation (Kcr) is specifically present in male germ cells and marks testis-specific genes in post-meiotic cells, including X-linked genes that escape sex chromosome inactivation in haploid cells. Crotonylation marks active promoters and enhancers and confers resistance to transcriptional repressors. It is also associated with post-meiotically activated genes on autosomes.PTM Butyrylation of histones marks active promoters and competes with histone acetylation.PTM Glutarylation at Lys-92 (H4K91glu) destabilizes nucleosomes by promoting dissociation of the H2A-H2B dimers from nucleosomes.PTM Lactylated in macrophages by EP300/P300 by using lactoyl-CoA directly derived from endogenous or exogenous lactate, leading to stimulates gene transcription.DISEASE Chromosomal aberrations involving HISTONE H4 is a cause of B-cell non-Hodgkin lymphomas (B-cell NHL). Translocation t(3;6)(q27;p21), with BCL6.SIMILARITY Belongs to the histone H4 family. UniProt P62805 2 EQUAL 103 EQUAL Reactome Database ID Release 81 181902 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=181902 Reactome R-HSA-181902 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-181902.1 2 Reactome Database ID Release 81 5250919 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=5250919 Reactome R-HSA-5250919 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-5250919.1 2 Converted from EntitySet in Reactome NOTCH1 gene,NOTCH4 gene Reactome DB_ID: 9604882 Reactome Database ID Release 81 9604882 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=9604882 Reactome R-HSA-9604882 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-9604882.1 Converted from EntitySet in Reactome SIRT6:Nucleosome(H3K9ac):NOTCH1,NOTCH4 gene Reactome DB_ID: 9604877 SIRT6:Nucleosome(H3K9ac):NOTCH1 gene Reactome DB_ID: 9604881 1 1 1 Reactome Database ID Release 81 9604881 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=9604881 Reactome R-HSA-9604881 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-9604881.1 SIRT6:Nucleosome(H3K9ac):NOTCH4 gene Reactome DB_ID: 9604879 1 1 1 Reactome Database ID Release 81 9604879 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=9604879 Reactome R-HSA-9604879 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-9604879.1 Reactome Database ID Release 81 9604877 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=9604877 Reactome R-HSA-9604877 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-9604877.1 Reactome Database ID Release 81 9604834 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=9604834 Reactome R-HSA-9604834 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-9604834.1 28871079 Pubmed 2017 Sirt6 deficiency exacerbates podocyte injury and proteinuria through targeting Notch signaling Liu, M Liang, Kaili Zhen, Junhui Zhou, Meng Wang, Xiaojie Wang, Ziying Wei, Xinbing Zhang, Y Sun, Yu Zhou, Zhuanli Su, Hua Zhang, Chun Li, Ningjun Gao, Chengjiang Peng, Jun Yi, Fan Nat Commun 8:413 LEFT-TO-RIGHT 3.5.1.98 SIRT6 deacetylates histones at NOTCH1 and NOTCH4 gene promoters Based on studies in mice, SIRT6 deacetylates H3 histones on lysine residue 10 (removing the H3K9Ac epigenetic mark) at promoters of NOTCH1 and NOTCH4 genes (Liu et al. 2017). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 NAD NAD+ NAD(+) Nicotinamide adenine dinucleotide DPN Diphosphopyridine nucleotide Reactome DB_ID: 427523 NAD(1-) [ChEBI:57540] NAD(1-) adenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NAD(+) NAD anion ChEBI CHEBI:57540 Reactome Database ID Release 81 427523 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=427523 Reactome R-ALL-427523 4 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-427523.4 COMPOUND C00003 Converted from EntitySet in Reactome SIRT6:Nucleosome:NOTCH1,NOTCH4 gene Reactome DB_ID: 9604903 SIRT6:Nucleosome:NOTCH1 gene Reactome DB_ID: 9604908 1 1 Nucleosome Nucleosome (Deacetylated) Reactome DB_ID: 427402 2 2 2 Converted from EntitySet in Reactome Histone H3 Reactome DB_ID: 212293 HIST1H3A Histone H3.1 Histone H3a Histone H3b Histone H3c Histone H3d Histone H3f Histone H3h Histone H3i Histone H3j Histone H3k Histone H3l Reactome DB_ID: 212070 2 EQUAL 136 EQUAL Reactome Database ID Release 81 212070 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=212070 Reactome R-HSA-212070 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-212070.1 HIST2H3A Histone H3.2 HIST2H3C HIST2H3D Reactome DB_ID: 212281 2 EQUAL 136 EQUAL Reactome Database ID Release 81 212281 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=212281 Reactome R-HSA-212281 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-212281.1 H3F3A Histone H3.3 Reactome DB_ID: 212295 2 EQUAL 136 EQUAL Reactome Database ID Release 81 212295 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=212295 Reactome R-HSA-212295 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-212295.1 Reactome Database ID Release 81 212293 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=212293 Reactome R-HSA-212293 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-212293.1 2 Reactome Database ID Release 81 427402 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=427402 Reactome R-HSA-427402 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-427402.1 1 Reactome Database ID Release 81 9604908 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=9604908 Reactome R-HSA-9604908 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-9604908.1 SIRT6:Nucleosome:NOTCH4 gene Reactome DB_ID: 9604905 1 1 1 Reactome Database ID Release 81 9604905 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=9604905 Reactome R-HSA-9604905 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-9604905.1 Reactome Database ID Release 81 9604903 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=9604903 Reactome R-HSA-9604903 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-9604903.1 2'-O-acetyl-ADP-ribose 2'-O-acetyl adenosine-5-diphosphoribose 2''-O-acetyl-ADP-D-ribose Reactome DB_ID: 427498 2''-O-acetyl-ADP-D-ribose [ChEBI:76279] 2''-O-acetyl-ADP-D-ribose ChEBI CHEBI:76279 Reactome Database ID Release 81 427498 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=427498 Reactome R-ALL-427498 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-427498.3 ACTIVATION activeUnit: #Protein42 GENE ONTOLOGY GO:0046969 Reactome Database ID Release 81 9604902 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=9604902 Reactome Database ID Release 81 9604829 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=9604829 Reactome R-HSA-9604829 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-9604829.1 LEFT-TO-RIGHT NOTCH1 and NOTCH4 gene transcription is inhibited by SIRT6 Based on studies in mice, SIRT6-mediated deacetylation of lysine residue 10 of H3 histones (removal of H3K9Ac epigenetic mark) at promoters of NOTCH1 and NOTCH4 genes inhibits transcription of NOTCH1 and NOTCH4. SIRT6-mediated downregulation of NOTCH1 and NOTCH4 may protect podocytes, kidney cells involved in blood filtering, from injury. SIRT6 is downregulated in podocytes of patients with podocytopathies, such as proteinuric kidney disease, and SIRT6 levels correlate with glomerular filtration rate (Liu et al. 2017). Authored: Orlic-Milacic, Marija, 2018-04-05 Reviewed: Haw, Robin, 2018-05-01 Edited: Orlic-Milacic, Marija, 2018-05-09 Converted from EntitySet in Reactome NOTCH1 mRNA,NOTCH4 mRNA Reactome DB_ID: 9604923 Reactome Database ID Release 81 9604923 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=9604923 Reactome R-HSA-9604923 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-9604923.2 Reactome Database ID Release 81 9604831 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=9604831 Reactome R-HSA-9604831 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-9604831.1 INHIBITION activeUnit: #Protein42 Reactome Database ID Release 81 9604934 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=9604934 Reactome Database ID Release 81 1912408 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=1912408 Reactome R-HSA-1912408 4 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-1912408.4 1764995 Pubmed 1991 A homolog of Drosophila Notch expressed during mammalian development Weinmaster, G Roberts, VJ Lemke, G Development 113:199-205 10545110 Pubmed 1999 Ca(2+)-ATPase function is required for intracellular trafficking of the Notch receptor in Drosophila Periz, G Fortini, ME EMBO J 18:5983-93 1425352 Pubmed 1992 Expression pattern of Motch, a mouse homolog of Drosophila Notch, suggests an important role in early postimplantation mouse development Del Amo, FF Smith, DE Swiatek, PJ Gendron-Maguire, M Greenspan, RJ McMahon, AP Gridley, T Development 115:737-44 Pre-NOTCH Processing in the Endoplasmic Reticulum In the endoplasmic reticulum, glycosyl transferases modify NOTCH precursors by glycosylating conserved serine and threonine residues in EGF repeats of NOTCH. <br><br> O-fucosyl transferase POFUT1 fucosylates NOTCH serine and threonine residues that conform to the consensus sequence C2-X(4-5)-S/T-C3, where C2 and C3 are the second and third cysteine residue within the EGF repeat, and X(4-5) is four to five amino acid residues of any type (Yao et al. 2011, Stahl et al. 2008, Wang et al. 2001, Shao et al. 2003). <br> <br>O-glucosyl transferase POGLUT1, mammalian homolog of the Drosophila enzyme Rumi, adds a glucosyl group to conserved serine residues within the EGF repeats of NOTCH. The consensus sequence for POGLUT1-mediated glucosylation is C1-X-S-X-P-C2, where C1 and C2 are the first and second cysteine residue in the EGF repeat, respectively, while X represents any amino acid (Acar et al. 2008, Fernandez-Valdivia et al. 2011). Both fucosylation and glucosylation of NOTCH receptor precursors are essential for functionality. Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: D'Eustachio, P, 2012-02-06 LEFT-TO-RIGHT 2.4.1.221 Fucosylation of Pre-NOTCH by POFUT1 In the endoplasmic reticulum, NOTCH receptor precursors are fucosylated on conserved serine and threonine residues in their EGF repeats. The consensus fucosylation site sequence is C2-X(4-5)-S/T-C3, where C2 and C3 are the second and third cysteine residue within the EGF repeat, and X(4-5) is four to five amino acid residues of any type. Only those fucosylation sites that are conserved between human, mouse and rat NOTCH isoforms are annotated. Two additional potential fucosylation sites exist in human NOTCH1, on threonine 194 and threonine 1321, but since they are not conserved between all three species, they are not shown. Fucosylation is performed by the endoplasmic reticulum resident O-fucosyl transferase (POFUT1). Fucosylation by POFUT1 is considered to be essential for NOTCH folding/processing and production of a fully functional receptor. In addition to Notch fucosylation, Drosophila Pofut1 (o-fut1) acts as a Notch chaperone, playing an important role in Notch trafficking (Okajima et al. 2005). The chaperone role of POFUT1 may not be conserved in mammals (Stahl et al. 2008). Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: D'Eustachio, P, 2012-02-06 GDP-Fuc GDP-L-fucose Reactome DB_ID: 1463452 endoplasmic reticulum lumen GENE ONTOLOGY GO:0005788 GDP-L-fucose [ChEBI:17009] GDP-L-fucose ChEBI CHEBI:17009 Reactome Database ID Release 81 1463452 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=1463452 Reactome R-ALL-1463452 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-1463452.3 70 Converted from EntitySet in Reactome Pre-NOTCH NOTCH receptor precursor Reactome DB_ID: 1464801 Reactome Database ID Release 81 1464801 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=1464801 Reactome R-HSA-1464801 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-1464801.1 GDP Guanosine 5'-Diphosphate Guanosine Diphosphate Reactome DB_ID: 1467290 GDP [ChEBI:17552] GDP Guanosine 5'-diphosphate Guanosine diphosphate ChEBI CHEBI:17552 Reactome Database ID Release 81 1467290 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=1467290 Reactome R-ALL-1467290 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-ALL-1467290.2 70 Converted from EntitySet in Reactome Fuc-Pre-NOTCH Fucosylated NOTCH receptor precursor Reactome DB_ID: 1911414 Fuc-Pre-NOTCH1 17xFucT-2xFucS-NOTCH1(19-2555) Fucosylated NOTCH1 receptor precursor Reactome DB_ID: 1467396 73 EQUAL O-fucosyl-L-threonine MOD MOD:00813 116 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 1362 EQUAL 1402 EQUAL 19 EQUAL 2555 EQUAL Reactome Database ID Release 81 1467396 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=1467396 Reactome R-HSA-1467396 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-1467396.1 Fuc-Pre-NOTCH2 18xFucT-FucS-NOTCH2(26-2471) Fucosylated NOTCH2 receptor precursor Reactome DB_ID: 1467363 78 EQUAL 120 EQUAL 158 EQUAL 197 EQUAL 235 EQUAL 314 EQUAL 352 EQUAL 470 EQUAL 696 EQUAL 771 EQUAL 809 EQUAL 925 EQUAL 963 EQUAL 1001 EQUAL 1039 EQUAL 1077 EQUAL 1163 EQUAL 1201 EQUAL 1318 EQUAL 26 EQUAL 2471 EQUAL Reactome Database ID Release 81 1467363 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=1467363 Reactome R-HSA-1467363 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-1467363.1 Fuc-Pre-NOTCH3 10xFucT-4xFucS-NOTCH3(40-2321) Fucosylated NOTCH3 receptor precursor Reactome DB_ID: 1467382 173 EQUAL 211 EQUAL 250 EQUAL 290 EQUAL 328 EQUAL 445 EQUAL 671 EQUAL 748 EQUAL 863 EQUAL 938 EQUAL 1098 EQUAL 1136 EQUAL 1181 EQUAL 1349 EQUAL 40 EQUAL 2321 EQUAL Reactome Database ID Release 81 1467382 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=1467382 Reactome R-HSA-1467382 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-1467382.1 Fuc-Pre-NOTCH4 12xFucT-6xFucS-NOTCH4(24-2003) Fucosylated NOTCH4 receptor precursor Reactome DB_ID: 1467340 40 EQUAL 79 EQUAL 210 EQUAL 248 EQUAL 290 EQUAL 331 EQUAL 369 EQUAL 451 EQUAL 489 EQUAL 603 EQUAL 705 EQUAL 743 EQUAL 781 EQUAL 820 EQUAL 944 EQUAL 982 EQUAL 1060 EQUAL 1145 EQUAL 24 EQUAL 2003 EQUAL Reactome Database ID Release 81 1467340 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=1467340 Reactome R-HSA-1467340 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-1467340.1 Reactome Database ID Release 81 1911414 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=1911414 Reactome R-HSA-1911414 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-1911414.1 ACTIVATION FUT12 POFUT1 GDP-fucose protein O-fucosyltransferase 1 Peptide-O-fucosyltransferase 1 O-FucT-1 KIAA0180 Reactome DB_ID: 1460374 UniProt:Q9H488 POFUT1 POFUT1 FUT12 KIAA0180 FUNCTION Catalyzes the reaction that attaches fucose through an O-glycosidic linkage to a conserved serine or threonine residue found in the consensus sequence C2-X(4,5)-[S/T]-C3 of EGF domains, where C2 and C3 are the second and third conserved cysteines. Specifically uses GDP-fucose as donor substrate and proper disulfide pairing of the substrate EGF domains is required for fucose transfer. Plays a crucial role in NOTCH signaling. Initial fucosylation of NOTCH by POFUT1 generates a substrate for FRINGE/RFNG, an acetylglucosaminyltransferase that can then extend the fucosylation on the NOTCH EGF repeats. This extended fucosylation is required for optimal ligand binding and canonical NOTCH signaling induced by DLL1 or JAGGED1. Fucosylates AGRN and determines its ability to cluster acetylcholine receptors (AChRs).PATHWAY Protein modification; protein glycosylation.TISSUE SPECIFICITY Highly expressed in heart, brain, placenta, lung, liver, skeletal muscle, kidney and pancreas.PTM N-glycosylated.SIMILARITY Belongs to the glycosyltransferase 65 family. UniProt Q9H488 27 EQUAL 388 EQUAL Reactome Database ID Release 81 1460374 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=1460374 Reactome R-HSA-1460374 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-1460374.1 GENE ONTOLOGY GO:0046922 Reactome Database ID Release 81 1464800 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=1464800 Reactome Database ID Release 81 1912349 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=1912349 Reactome R-HSA-1912349 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-1912349.1 21464368 Pubmed 2011 Protein O-fucosyltransferase 1 (Pofut1) regulates lymphoid and myeloid homeostasis through modulation of Notch receptor ligand interactions Yao, D Huang, Y Huang, X Wang, W Yan, Q Wei, L Xin, W Gerson, S Stanley, P Lowe, JB Zhou, L Blood 117:5652-62 12486116 Pubmed 2003 Fringe modifies O-fucose on mouse Notch1 at epidermal growth factor-like repeats within the ligand-binding site and the Abruptex region Shao, L Moloney, DJ Haltiwanger, RS J Biol Chem 278:7775-82 18347015 Pubmed 2008 Roles of Pofut1 and O-fucose in mammalian Notch signaling Stahl, M Uemura, K Ge, C Shi, S Tashima, Y Stanley, P J Biol Chem 283:13638-51 15692013 Pubmed 2005 Chaperone activity of protein O-fucosyltransferase 1 promotes notch receptor folding Okajima, T Xu, A Lei, L Irvine, KD Science 307:1599-603 11524432 Pubmed 2001 Modification of epidermal growth factor-like repeats with O-fucose. Molecular cloning and expression of a novel GDP-fucose protein O-fucosyltransferase Wang, Y Shao, L Shi, S Harris, RJ Spellman, MW Stanley, P Haltiwanger, RS J Biol Chem 276:40338-45 LEFT-TO-RIGHT Glucosylation of Pre-NOTCH by POGLUT1 In addition to fucosylation of NOTCH receptor precursors, glucosylation represents another crucial NOTCH processing reaction, required for full receptor function. Endoplasmic reticulum O-glucosyl transferase, POGLUT1, adds a glucosyl group to conserved serine residues within the EGF repeats of NOTCH. The consensus sequence of POGLUT1 glucosylation sites is C1-X-S-X-P-C2, where C1 and C2 are the first and second cysteine residue in the EGF repeat, respectively, while X represents any amino acid. Only those glucosylation sites that are conserved between human, mouse and rat isoforms are shown. In human NOTCH1, the consensus glucosylation site on serine at position 951 was not annotated since it is not conserved in rat NOTCH1. In human NOTCH4, glucosylation at serine 398 was not annotated because this site is not conserved in rat, and glucosylation at serine 936 was not annotated because this site is not conserved in mouse. Glucosylation of NOTCH4 serine 773 was not annotated because a proline at position 775 is not conserved in either mouse or rat. Authored: Egan, SE, Orlic-Milacic, M, 2011-11-14 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: D'Eustachio, P, 2012-02-06 UDP-Glc UDP-D-glucose(2-) UDP-glucose UDP-D-glucose UDPglucose Reactome DB_ID: 173594 UDP-D-glucose(2-) [ChEBI:58367] UDP-D-glucose(2-) UDP-D-glucose dianion UDP-Glc(2-) ChEBI CHEBI:58367 Reactome Database ID Release 81 173594 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=173594 Reactome R-ALL-173594 4 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-173594.4 COMPOUND C00029 53 UDP uridine 5'-diphosphate Reactome DB_ID: 158602 UDP [ChEBI:17659] UDP ChEBI CHEBI:17659 Reactome Database ID Release 81 158602 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=158602 Reactome R-ALL-158602 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-ALL-158602.2 COMPOUND C00015 53 Converted from EntitySet in Reactome Glc,Fuc-Pre-NOTCH Glucosylated and fucosylated pre-NOTCH Reactome DB_ID: 1911442 Glc,Fuc-Pre-NOTCH1 19xFucT-14xGlcS-2xFucS-NOTCH1(19-2555) Glucosylated and fucosylated NOTCH1 receptor precursor Reactome DB_ID: 1467425 194 EQUAL 1321 EQUAL 146 EQUAL O-glucosyl-L-serine MOD MOD:00804 378 EQUAL 458 EQUAL 496 EQUAL 534 EQUAL 609 EQUAL 647 EQUAL 722 EQUAL 759 EQUAL 797 EQUAL 1027 EQUAL 1065 EQUAL 1189 EQUAL 1273 EQUAL 19 EQUAL 2555 EQUAL Reactome Database ID Release 81 1467425 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=1467425 Reactome R-HSA-1467425 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-1467425.1 Glc,Fuc-Pre-NOTCH2 18xFucT-16xGlcS-FucS-NOTCH2(26-2471) Glucosylated and fucosylated NOTCH2 receptor precursor Reactome DB_ID: 1467379 150 EQUAL 381 EQUAL 462 EQUAL 500 EQUAL 538 EQUAL 613 EQUAL 651 EQUAL 688 EQUAL 726 EQUAL 763 EQUAL 801