BioPAX pathway converted from "Signaling by NOTCH" in the Reactome database. Signaling by NOTCH 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 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 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 CCND1:CREBBP binds NOTCH1 promoter 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 Reactome DB_ID: 1911481 1 nucleoplasm GO 0005654 ENSEMBL:ENSG00000148400 NOTCH1 NOTCH1 Gene NOTCH1 TAN1 Reactome http://www.reactome.org Homo sapiens NCBI Taxonomy 9606 ENSEMBL ENSG00000148400 Reactome DB_ID: 2247939 1 CCND1:CREBBP [nucleoplasm] CCND1:CREBBP Reactome DB_ID: 193545 1 UniProt:Q92793 CREBBP CREBBP CBP CREBBP 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 Chain Coordinates 1 EQUAL 2442 EQUAL Reactome DB_ID: 113832 1 UniProt:P24385 CCND1 CCND1 PRAD1 CCND1 BCL1 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 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 Reactome DB_ID: 4395224 1 CCND1:CREBBP:NOTCH1 Gene [nucleoplasm] CCND1:CREBBP:NOTCH1 Gene Reactome DB_ID: 1911481 1 Reactome DB_ID: 2247939 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 E2F1/3:DP1/2 binds NOTCH1 promoter 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 Reactome DB_ID: 2248825 1 E2F1/3:DP1/2 [nucleoplasm] E2F1/3:DP1/2 Converted from EntitySet in Reactome Reactome DB_ID: 1362227 1 TFDP1,TFDP2 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity TFDP1 [nucleoplasm] TFDP2 [nucleoplasm] UniProt Q14186 UniProt Q14188 Converted from EntitySet in Reactome Reactome DB_ID: 187942 1 E2F1/E2F3 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity E2F1 [nucleoplasm] E2F3 [nucleoplasm] UniProt Q01094 UniProt O00716 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 Reactome DB_ID: 1911481 1 Reactome DB_ID: 4395228 1 E2F1/3:DP1/2:NOTCH1 Gene [nucleoplasm] E2F1/3:DP1/2:NOTCH1 Gene Reactome DB_ID: 2248825 1 Reactome DB_ID: 1911481 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 NOTCH1 gene transcription 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 Reactome DB_ID: 1911481 1 Reactome DB_ID: 1606559 1 cytosol GO 0005829 ENSEMBL:ENST00000277541 NOTCH1 NOTCH1 mRNA NOTCH1 ENSEMBL ENST00000277541 1 EQUAL 9371 EQUAL 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 Reactome DB_ID: 1604462 NOTCH1 Coactivator Complex [nucleoplasm] NOTCH1 Coactivator Complex Reactome DB_ID: 193545 1 1 EQUAL 2442 EQUAL Reactome DB_ID: 1604460 1 NICD1:RBPJ:SNW1 [nucleoplasm] NICD1:RBPJ:SNW1 Reactome DB_ID: 157939 1 UniProt:P46531 NOTCH1 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 DB_ID: 351663 1 UniProt:Q13573 SNW1 SNW1 SNW1 SKIP SKIIP 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 DB_ID: 3008668 1 UniProt:Q06330 RBPJ RBPJ IGKJRB RBPJK RBPSUH IGKJRB1 RBPJ 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 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 Converted from EntitySet in Reactome Reactome DB_ID: 212357 1 MAML [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MAML1 [nucleoplasm] MAML3 [nucleoplasm] MAML2 [nucleoplasm] UniProt Q92585 UniProt Q96JK9 UniProt Q8IZL2 Converted from EntitySet in Reactome Reactome DB_ID: 350078 1 PCAF [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity KAT2B [nucleoplasm] UniProt Q92831 Reactome DB_ID: 381325 1 UniProt:Q09472 EP300 EP300 P300 EP300 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 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 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 Reactome DB_ID: 4395228 ACTIVATION 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 Reactome DB_ID: 4395224 NOTCH2 gene transcription 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 Reactome DB_ID: 1911484 1 ENSEMBL:ENSG00000134250 NOTCH2 NOTCH2 Gene NOTCH2 ENSEMBL ENSG00000134250 Reactome DB_ID: 1911477 1 ENSEMBL:ENST00000256646 NOTCH2 NOTCH2 mRNA NOTCH2 ENSEMBL ENST00000256646 1 EQUAL 11389 EQUAL 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 NOTCH1 coactivator complex binds NOTCH3 gene 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 Reactome DB_ID: 1911492 1 ENSEMBL:ENSG00000074181 NOTCH3 NOTCH3 Gene NOTCH3 ENSEMBL ENSG00000074181 Reactome DB_ID: 1604462 1 Reactome DB_ID: 9017845 1 NOTCH1 coactivator complex:NOTCH3 gene [nucleoplasm] NOTCH1 coactivator complex:NOTCH3 gene Reactome DB_ID: 1911492 1 Reactome DB_ID: 1604462 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 GO 0045747 GO biological process 2.7.11.13 PRKCI phosphorylates ELF3 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 Reactome DB_ID: 29358 1 ATP(4-) [ChEBI:30616] ATP(4-) Adenosine 5'-triphosphate atp ATP ChEBI 30616 Reactome DB_ID: 9021353 1 UniProt:P78545 ELF3 ELF3 JEN ELF3 ERT ESX 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 DB_ID: 9021349 1 O-phospho-L-serine at 68 68 EQUAL O-phospho-L-serine [MOD:00046] 1 EQUAL 371 EQUAL Reactome DB_ID: 113582 1 ADP(3-) [ChEBI:456216] ADP(3-) ADP trianion 5&apos;-O-[(phosphonatooxy)phosphinato]adenosine ADP ChEBI 456216 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 9021345 UniProt:P41743 PRKCI 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 GO 0004697 GO molecular function 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 ELF3 binds NOTCH3 gene promoter 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 Reactome DB_ID: 9021349 1 O-phospho-L-serine at 68 68 EQUAL 1 EQUAL 371 EQUAL Reactome DB_ID: 1911492 1 Reactome DB_ID: 9021365 1 p-S68-ELF3:NOTCH3 gene [nucleoplasm] p-S68-ELF3:NOTCH3 gene Reactome DB_ID: 9021349 1 O-phospho-L-serine at 68 68 EQUAL 1 EQUAL 371 EQUAL Reactome DB_ID: 1911492 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 NOTCH3 gene transcription 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 Reactome DB_ID: 1911492 1 Reactome DB_ID: 1911478 1 ENSEMBL:ENST00000263388 NOTCH3 NOTCH3 mRNA NOTCH3 ENSEMBL ENST00000263388 1 EQUAL 8070 EQUAL 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 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 Reactome DB_ID: 9017845 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 Reactome DB_ID: 2248837 NOTCH3 coactivator complex [nucleoplasm] NOTCH3 coactivator complex Reactome DB_ID: 157928 1 UniProt:Q9UM47 NOTCH3 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 Converted from EntitySet in Reactome Reactome DB_ID: 212357 1 Reactome DB_ID: 3008668 1 1 EQUAL 500 EQUAL 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 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 Reactome DB_ID: 9021365 NOTCH4 gene transcription 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 Reactome DB_ID: 1911501 1 ENSEMBL:ENSG00000206312 NOTCH4 NOTCH4 Gene NOTCH4 ENSEMBL ENSG00000206312 Reactome DB_ID: 1911475 1 ENSEMBL:ENST00000383264 NOTCH4 NOTCH4 mRNA NOTCH4 ENSEMBL ENST00000383264 1 EQUAL 6745 EQUAL 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 GO 0010628 GO biological process 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 Reactome DB_ID: 450250 UniProt:P05412 JUN 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 TP53 binds promoters of MIR34 genes 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 Reactome DB_ID: 3209194 1 TP53 Tetramer [nucleoplasm] TP53 Tetramer Reactome DB_ID: 69488 4 UniProt:P04637 TP53 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 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 Reactome DB_ID: 1852586 1 MIR34 genes [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MIR34C gene [nucleoplasm] MIR34B gene [nucleoplasm] MIR34A gene [nucleoplasm] ENSEMBL ENSG00000207562 ENSEMBL ENSG00000207811 ENSEMBL ENSG00000207865 Reactome DB_ID: 4395237 1 TP53 Tetramer:MIR34 genes [nucleoplasm] TP53 Tetramer:MIR34 genes Reactome DB_ID: 3209194 1 Converted from EntitySet in Reactome Reactome DB_ID: 1852586 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 p53 positively regulates transcription of MIR34 microRNAs 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 Reactome DB_ID: 1852586 1 Converted from EntitySet in Reactome Reactome DB_ID: 1606685 1 miR-34 RISC [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity 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 Reactome DB_ID: 4395237 MIR34 microRNAs bind 3'UTR of NOTCH1 mRNA 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 Reactome DB_ID: 1606559 1 1 EQUAL 9371 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 1606685 1 Reactome DB_ID: 1606698 1 NOTCH1 mRNA:miR-34 RISC [cytosol] NOTCH1 mRNA:miR-34 RISC Reactome DB_ID: 1606559 1 1 EQUAL 9371 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 1606685 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 MIR200B/C microRNAs bind NOTCH1 mRNA 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 Reactome DB_ID: 1606559 1 1 EQUAL 9371 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 1614237 1 miR-200B/C RISC [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 1911483 1 NOTCH1 mRNA:miR-200B/C RISC [cytosol] NOTCH1 mRNA:miR-200B/C RISC Reactome DB_ID: 1606559 1 1 EQUAL 9371 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 1614237 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 MIR449 microRNAs bind 3'UTR of NOTCH1 mRNA 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 Reactome DB_ID: 1606557 1 miR-449 RISC [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 1606559 1 1 EQUAL 9371 EQUAL Reactome DB_ID: 1606562 1 NOTCH1 mRNA:miR-449 RISC [cytosol] NOTCH1 mRNA:miR-449 RISC Converted from EntitySet in Reactome Reactome DB_ID: 1606557 1 Reactome DB_ID: 1606559 1 1 EQUAL 9371 EQUAL 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 MIR34 microRNAs bind 3'UTR of NOTCH2 mRNA 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 Reactome DB_ID: 1911477 1 1 EQUAL 11389 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 1606685 1 Reactome DB_ID: 1911490 1 NOTCH2 mRNA:miR-34 RISC [cytosol] NOTCH2 mRNA:miR-34 RISC Reactome DB_ID: 1911477 1 1 EQUAL 11389 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 1606685 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 MIR150 microRNA binds 3'UTR of NOTCH3 mRNA 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 Reactome DB_ID: 1852612 1 miR-150 RISC [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 1911478 1 1 EQUAL 8070 EQUAL Reactome DB_ID: 1911497 1 NOTCH3 mRNA:miR-150 RISC [cytosol] NOTCH3 mRNA:miR-150 RISC Converted from EntitySet in Reactome Reactome DB_ID: 1852612 1 Reactome DB_ID: 1911478 1 1 EQUAL 8070 EQUAL 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 MIR206 microRNA binds 3'UTR of NOTCH3 mRNA 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 Reactome DB_ID: 1614243 1 miR-206 RISC [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 1911478 1 1 EQUAL 8070 EQUAL Reactome DB_ID: 1911498 1 NOTCH3 mRNA:miR-206 RISC [cytosol] NOTCH3 mRNA:miR-206 RISC Converted from EntitySet in Reactome Reactome DB_ID: 1614243 1 Reactome DB_ID: 1911478 1 1 EQUAL 8070 EQUAL 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 MIR181C microRNA binds 3'UTR of NOTCH4 mRNA 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 Reactome DB_ID: 1911475 1 1 EQUAL 6745 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 1852604 1 miR-181C RISC [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 1911502 1 NOTCH4 mRNA:miR-181C RISC [cytosol] NOTCH4 mRNA:miR-181C RISC Reactome DB_ID: 1911475 1 1 EQUAL 6745 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 1852604 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 GO 0010629 GO biological process MIR302A microRNA binds 3'UTR of NOTCH4 mRNA 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 Reactome DB_ID: 1911475 1 1 EQUAL 6745 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 1852598 1 miR-302A RISC [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 1911500 1 NOTCH4 mRNA:miR-302A RISC [cytosol] NOTCH4 mRNA:miR-302A RISC Reactome DB_ID: 1911475 1 1 EQUAL 6745 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 1852598 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 NOTCH1 mRNA translation controlled by miRNAs 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 Reactome DB_ID: 1606559 1 1 EQUAL 9371 EQUAL Reactome DB_ID: 157024 1 endoplasmic reticulum membrane GO 0005789 19 EQUAL 2555 EQUAL 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 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 Reactome DB_ID: 1911483 INHIBITION 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 Reactome DB_ID: 1606698 INHIBITION 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 Reactome DB_ID: 1606562 NOTCH2 mRNA translation controlled by miRNAs 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 Reactome DB_ID: 1911477 1 1 EQUAL 11389 EQUAL Reactome DB_ID: 157025 1 UniProt:Q04721 NOTCH2 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 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 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 Reactome DB_ID: 1911490 NOTCH3 mRNA translation controlled by miRNAs 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 Reactome DB_ID: 1911478 1 1 EQUAL 8070 EQUAL Reactome DB_ID: 157102 1 40 EQUAL 2321 EQUAL 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 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 Reactome DB_ID: 1911497 INHIBITION 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 Reactome DB_ID: 1911498 NOTCH4 mRNA translation controlled by miRNAs 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 Reactome DB_ID: 1911475 1 1 EQUAL 6745 EQUAL Reactome DB_ID: 157121 1 UniProt:Q99466 NOTCH4 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 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 GO 0035278 GO biological process INHIBITION 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 Reactome DB_ID: 1911500 INHIBITION 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 Reactome DB_ID: 1911502 RUNX1 binds NOTCH4 gene 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 Reactome DB_ID: 8865295 1 UniProt:Q01196 RUNX1 RUNX1 CBFA2 RUNX1 AML1 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 DB_ID: 1911501 1 Reactome DB_ID: 9604705 1 RUNX1:NOTCH4 gene [nucleoplasm] RUNX1:NOTCH4 gene Reactome DB_ID: 8865295 1 1 EQUAL 453 EQUAL Reactome DB_ID: 1911501 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 NOTCH4 gene transcription is inhibited by RUNX1 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 DB_ID: 1911501 1 Reactome DB_ID: 1911475 1 1 EQUAL 6745 EQUAL 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 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 Reactome DB_ID: 9604705 SIRT6 binds to acetylated histones at NOTCH1 and NOTCH4 gene promoters 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 Reactome DB_ID: 5685963 2 UniProt:Q8N6T7 SIRT6 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 DB_ID: 5250919 2 Nucleosome (H3K9ac) [nucleoplasm] Nucleosome (H3K9ac) Converted from EntitySet in Reactome Reactome DB_ID: 181899 2 Histone H2A [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Converted from EntitySet in Reactome Reactome DB_ID: 5250644 2 AcK10-Histone H3 [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity AcK10-H3F3A [nucleoplasm] Ack10-HIST1H3A [nucleoplasm] Ack10-HIST2H3A [nucleoplasm] UniProt P84243 UniProt P68431 UniProt Q71DI3 Converted from EntitySet in Reactome Reactome DB_ID: 181911 2 Histone H2B [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 181902 2 UniProt:P62805 H4C1 H4C1 H4FA H4FC H4FB H4FE H4FD H4FG H4FI H4FH H4FK H4FJ H4FM H4FO H4FN H4C2 H4C1 H4C4 H4C3 H4C6 H4C5 H4-16 H4C15 H4C14 HIST4H4 H4C13 H4C12 HIST2H4 H4C11 H4F2 H4/D H4/C H4/E H4/H H4/G H4/J H4/I H4/K H4/N H4/M H4/O HIST2H4A HIST2H4B H4C8 H4C9 HIST1H4K HIST1H4L HIST1H4A HIST1H4B HIST1H4H HIST1H4I HIST1H4J HIST1H4C HIST1H4D H4/B HIST1H4E H4/A HIST1H4F 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 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 Converted from EntitySet in Reactome Reactome DB_ID: 9604882 1 NOTCH1 gene,NOTCH4 gene [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity NOTCH1 gene [nucleoplasm] NOTCH4 gene [nucleoplasm] Converted from EntitySet in Reactome Reactome DB_ID: 9604877 1 SIRT6:Nucleosome(H3K9ac):NOTCH1,NOTCH4 gene [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity 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 3.5.1.98 SIRT6 deacetylates histones at NOTCH1 and NOTCH4 gene promoters 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 Converted from EntitySet in Reactome Reactome DB_ID: 9604877 1 Reactome DB_ID: 427523 1 NAD(1-) [ChEBI:57540] NAD(1-) NAD(+) adenosine 5'-{3-[1-(3-carbamoylpyridinio)-1,4-anhydro-D-ribitol-5-yl] diphosphate} NAD anion ChEBI 57540 Converted from EntitySet in Reactome Reactome DB_ID: 9604903 1 SIRT6:Nucleosome:NOTCH1,NOTCH4 gene [nucleoplasm] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 427498 1 2''-O-acetyl-ADP-D-ribose [ChEBI:76279] 2''-O-acetyl-ADP-D-ribose ChEBI 76279 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 9604877 GO 0046969 GO molecular function 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 NOTCH1 and NOTCH4 gene transcription is inhibited by SIRT6 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 Reactome DB_ID: 9604882 1 Converted from EntitySet in Reactome Reactome DB_ID: 9604923 1 NOTCH1 mRNA,NOTCH4 mRNA [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity NOTCH4 mRNA [cytosol] NOTCH1 mRNA [cytosol] 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 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 Converted from EntitySet in Reactome Reactome DB_ID: 9604903 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 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 2.4.1.221 Fucosylation of Pre-NOTCH by POFUT1 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 Reactome DB_ID: 1463452 70 endoplasmic reticulum lumen GO 0005788 GDP-L-fucose [ChEBI:17009] GDP-L-fucose ChEBI 17009 Converted from EntitySet in Reactome Reactome DB_ID: 1464801 1 Pre-NOTCH [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Pre-NOTCH3 [endoplasmic reticulum membrane] Pre-NOTCH4 [endoplasmic reticulum membrane] Pre-NOTCH1 [endoplasmic reticulum membrane] Pre-NOTCH2 [endoplasmic reticulum membrane] Reactome DB_ID: 1467290 70 GDP [ChEBI:17552] GDP Guanosine 5'-diphosphate Guanosine diphosphate ChEBI 17552 Converted from EntitySet in Reactome Reactome DB_ID: 1911414 1 Fuc-Pre-NOTCH [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity 17xFucT-2xFucS-NOTCH1(19-2555) [endoplasmic reticulum membrane] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 1460374 UniProt:Q9H488 POFUT1 POFUT1 KIAA0180 FUT12 POFUT1 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 GO 0046922 GO molecular function 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 Glucosylation of Pre-NOTCH by POGLUT1 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 Reactome DB_ID: 173594 53 UDP-D-glucose(2-) [ChEBI:58367] UDP-D-glucose(2-) UDP-D-glucose dianion UDP-Glc(2-) ChEBI 58367 Converted from EntitySet in Reactome Reactome DB_ID: 1911414 1 Reactome DB_ID: 158602 53 UDP [ChEBI:17659] UDP ChEBI 17659 Converted from EntitySet in Reactome Reactome DB_ID: 1911442 1 Glc,Fuc-Pre-NOTCH [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity 19xFucT-14xGlcS-2xFucS-NOTCH1(19-2555) [endoplasmic reticulum membrane] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 1464796 UniProt:Q8NBL1 POGLUT1 POGLUT1 C3orf9 POGLUT1 KTELC1 MDSRP UNQ490/PRO1006 CLP46 MDS010 FUNCTION Dual specificity glycosyltransferase that catalyzes the transfer of glucose and xylose from UDP-glucose and UDP-xylose, respectively, to a serine residue found in the consensus sequence of C-X-S-X-P-C (PubMed:21081508, PubMed:21490058, PubMed:21949356, PubMed:27807076, PubMed:28775322). Specifically targets extracellular EGF repeats of protein such as CRB2, F7, F9 and NOTCH2 (PubMed:21081508, PubMed:21490058, PubMed:21949356, PubMed:27807076, PubMed:28775322). Acts as a positive regulator of Notch signaling by mediating O-glucosylation of Notch, leading to regulate muscle development (PubMed:27807076). Notch glucosylation does not affect Notch ligand binding (PubMed:21490058). Required during early development to promote gastrulation: acts by mediating O-glucosylation of CRB2, which is required for CRB2 localization to the cell membrane (By similarity).PATHWAY Protein modification; protein glycosylation.TISSUE SPECIFICITY Expressed in most adult tissues at different intensities. Abundantly expressed in liver. Expressed also in brain, heart, skeletal muscle, spleen, kidney, placenta, lung and peripheral blood leukocyte. Not detectable in colon, thymus and small intestine. Expressed in the epidermis, especially in the upper parts, stratum spinosum and stratum granulosum (at protein level).SIMILARITY Belongs to the glycosyltransferase 90 family. UniProt Q8NBL1 24 EQUAL 392 EQUAL GO 0035251 GO molecular function Reactome Database ID Release 81 1464797 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1464797 Reactome Database ID Release 81 1912353 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1912353 Reactome R-HSA-1912353 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1912353.1 21490058 Pubmed 2011 Regulation of mammalian Notch signaling and embryonic development by the protein O-glucosyltransferase Rumi Fernandez-Valdivia, R Takeuchi, H Samarghandi, A Lopez, M Leonardi, J Haltiwanger, RS Jafar-Nejad, H Development 138:1925-34 18243100 Pubmed 2008 Rumi is a CAP10 domain glycosyltransferase that modifies Notch and is required for Notch signaling Acar, M Jafar-Nejad, H Takeuchi, H Rajan, A Ibrani, D Rana, NA Pan, H Haltiwanger, RS Bellen, HJ Cell 132:247-58 Reactome Database ID Release 81 1912399 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1912399 Reactome R-HSA-1912399 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-1912399.2 Pre-NOTCH Processing in Golgi Pre-NOTCH Processing in Golgi NOTCH undergoes final posttranslational processing in the Golgi apparatus (Lardelli et al. 1994, Blaumueller et al. 1997, Weinmaster et al. 1991, Weinmaster et al. 1992, Uyttendaele et al. 1996). Movement of NOTCH precursors from the endoplasmic reticulum to Golgi is controlled by SEL1L protein, a homolog of C. elegans sel-1. SEL1L localizes to the endoplasmic reticulum membrane and prevents translocation of misfolded proteins, therefore serving as a quality control check (Li et al. 2010, Sundaram et al. 1993, Francisco et al. 2010). Similarly, C. elegans sel-9 and its mammalian homolog TMED2 are Golgi membrane proteins that participate in quality control of proteins transported from Golgi to the plasma membrane. Translocation of a mutant C. elegans NOTCH homolog lin-12 from the Golgi to the plasma membrane is negatively regulated by sel-9 (Wen et al. 1999). A GTPase RAB6 positively controls NOTCH trafficking through Golgi (Purcell et al. 1999). <br><br> <br>Processing of mammalian NOTCH precursors in the Golgi typically involves the cleavage by FURIN convertase. Pre-NOTCH is a ~300 kDa protein, and cleavage by FURIN produces two fragments with approximate sizes of 110 kDa and 180 kDa. The 110 kDa fragment contains the transmembrane and intracellular domains of NOTCH and is known as NTM or NTMICD. The 189 kDa fragment contains NOTCH extracellular sequence and is known as NEC or NECD. The NTM and NEC fragments heterodimerize (Blaumueller et al. 1997, Logeat et al. 1998, Chan et al. 1998) and are held together by disulfide bonds and calcium ions (Rand et al. 2000, Gordon et al. 2009). <br> <br> <br>An optional step in Pre-NOTCH processing in the Golgi is modification by fringe enzymes. Fringe enzymes are glycosyl transferases that initiate elongation of O-linked fucose on fucosylated peptides by addition of a beta 1,3 N-acetylglucosaminyl group, resulting in formation of disaccharide chains on NOTCH EGF repeats (GlcNAc-bet1,3-fucitol). Three fringe enzymes are known in mammals: LFNG (lunatic fringe), MFNG (manic fringe) and RFNG (radical fringe). LFNG shows the highest catalytic activity in modifying NOTCH (Bruckner et al. 2000, Moloney et al. 2000). Fringe-created disaccharide chains on NOTCH EGF repeats are further extended by B4GALT1 (beta-1,4-galactosyltransferase 1), which adds galactose to the N-acetylglucosaminyl group, resulting in formation of trisaccharide Gal-beta1,4-GlcNAc-beta1,3-fucitol chains (Moloney et al. 2000, Chen et al. 2001). Formation of trisaccharide chains is the minimum requirement for fringe-mediated modulation of NOTCH signaling, although fringe-modified NOTCH expressed on the cell surface predominantly contains tetrasaccharide chains on EGF repeats. The tetrasaccharide chains are formed by sialyltransferase(s) that add sialic acid to galactose, resulting in formation of Sia-alpha2,3-Gal-beta1,4-GlcNAc-beta1,3-fucitol (Moloney et al. 2000). Three known Golgi membrane sialyltransferases could be performing this function: ST3GAL3, ST3GAL4 and ST3GAL6 (Harduin-Lepers et al. 2001). The modification of NOTCH by fringe enzymes modulates NOTCH-signaling by increasing the affinity of NOTCH receptors for delta-like ligands, DLL1 and DLL4, while decreasing affinity for jagged ligands, JAG1 and JAG2. Authored: Jassal, B, 2004-12-15 13:08:03 Reviewed: Joutel, A, 2004-12-15 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: D'Eustachio, P, 2012-02-06 Transport of NOTCH precursor to Golgi Transport of NOTCH precursor to Golgi NOTCH receptor precursors (Pre-NOTCH) traffic from the endoplasmic reticulum to the Golgi. Endoplasmic reticulum calcium ATPases are required for maintenance of high levels of calcium and positively regulate NOTCH trafficking, perhaps by ensuring proper NOTCH folding. Exit of NOTCH precursors from the endoplasmic reticulum is negatively regulated by SEL1L (Li et al. 2010, Sundaram et al. 1993), an endoplasmic reticulum membrane protein that is part of the ERAD (endoplasmic reticulum associated degradation) system, which performs quality control and triggers degradation of misfolded proteins (Francisco et al. 2010). NOTCH trafficking through the Golgi and trans-Golgi network is positively regulated by RAB6, a Golgi membrane GTPase. Endoplasmic reticulum calcium ATPases are required for maintenance of high levels of calcium and positively regulate NOTCH trafficking, perhaps by ensuring proper NOTCH folding. Authored: Jassal, B, 2004-12-15 13:08:03 Reviewed: Joutel, A, 2004-12-15 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 Reactome DB_ID: 1911442 1 Converted from EntitySet in Reactome Reactome DB_ID: 1911440 1 Golgi membrane GO 0000139 Glc,Fuc-Pre-NOTCH [Golgi membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity 17xFucT-14xGlcS-2xFucS-NOTCH1(19-2555) [Golgi membrane] Reactome Database ID Release 81 1912374 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1912374 Reactome R-HSA-1912374 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-1912374.3 1295745 Pubmed 1992 Notch2: a second mammalian Notch gene Weinmaster, G Roberts, VJ Lemke, G Development 116:931-41 20197277 Pubmed 2010 Deficiency of suppressor enhancer Lin12 1 like (SEL1L) in mice leads to systemic endoplasmic reticulum stress and embryonic lethality Francisco, AB Singh, R Li, S Vani, AK Yang, L Munroe, RJ Diaferia, G Cardano, M Biunno, I Qi, L Schimenti, John Long, Q J Biol Chem 285:13694-703 20170518 Pubmed 2010 SEL1L deficiency impairs growth and differentiation of pancreatic epithelial cells Li, S Francisco, AB Munroe, RJ Schimenti, John Long, Q BMC Dev Biol 10:19 7918097 Pubmed 1994 The novel Notch homologue mouse Notch 3 lacks specific epidermal growth factor-repeats and is expressed in proliferating neuroepithelium Lardelli, M Dahlstrand, J Lendahl, U Mech Dev 46:123-36 8681805 Pubmed 1996 Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene Uyttendaele, H Marazzi, G Wu, G Yan, Q Sassoon, D Kitajewski, J Development 122:2251-9 8293978 Pubmed 1993 Suppressors of a lin-12 hypomorph define genes that interact with both lin-12 and glp-1 in Caenorhabditis elegans Sundaram, M Greenwald, I Genetics 135:765-83 10459009 Pubmed 1999 The developmental role of warthog, the notch modifier encoding Drab6 Purcell, K Artavanis-Tsakonas, S J Cell Biol 146:731-40 9244302 Pubmed 1997 Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane Blaumueller, CM Qi, H Zagouras, P Artavanis-Tsakonas, S Cell 90:281-91 INHIBITION Reactome Database ID Release 81 1980101 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1980101 Reactome R-HSA-1980101 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1980101.1 Reactome DB_ID: 1911545 UniProt:Q9UBV2 SEL1L SEL1L TSA305 SEL1L UNQ128/PRO1063 FUNCTION Plays a role in the endoplasmic reticulum quality control (ERQC) system also called ER-associated degradation (ERAD) involved in ubiquitin-dependent degradation of misfolded endoplasmic reticulum proteins (PubMed:16186509, PubMed:29997207). Enhances SYVN1 stability. Plays a role in LPL maturation and secretion. Required for normal differentiation of the pancreas epithelium, and for normal exocrine function and survival of pancreatic cells. May play a role in Notch signaling.SUBUNIT Homodimer and homooligomer (By similarity). May form a complex with ERLEC1, HSPA5, OS9, and SYVN1 (PubMed:18502753, PubMed:18264092). Interacts with FOXRED2 and EDEM1 (PubMed:19524542, PubMed:19706418). Interacts with LPL (PubMed:25066055). Interacts with LMF1; may stabilize the complex formed by LPL and LMF1 and thereby promote the export of LPL dimers (By similarity). Component of the HRD1 complex, which comprises at least SYNV1/HRD1, DERL1/2, FAM8A1, HERPUD1/HERP, OS9, SEL1L and UBE2J1 (PubMed:16186509, PubMed:28827405). SYNV1 assembles with SEL1L and FAM8A1 through its transmembrane domains, but interaction with its cytoplasmic domain is required to confer stability to FAM8A1 and enhance recruitment of HERPUD1 (PubMed:28827405). The interaction with SYNV1/HRD1 is direct (PubMed:26471130).SUBUNIT (Microbial infection) Interacts with human cytomegalovirus protein UL148.TISSUE SPECIFICITY Highly expressed in pancreas.PTM N-glycosylated.SIMILARITY Belongs to the sel-1 family. UniProt Q9UBV2 22 EQUAL 794 EQUAL ACTIVATION Reactome Database ID Release 81 1980104 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1980104 Reactome R-HSA-1980104 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1980104.1 Converted from EntitySet in Reactome Reactome DB_ID: 418312 ATP2A1-3 [endoplasmic reticulum membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity ATP2A3 [endoplasmic reticulum membrane] ATP2A1 [endoplasmic reticulum membrane] ATP2A2 [endoplasmic reticulum membrane] UniProt Q93084 UniProt O14983 UniProt P16615 ACTIVATION Reactome Database ID Release 81 1980098 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1980098 Reactome R-HSA-1980098 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1980098.1 Reactome DB_ID: 1604442 UniProt:P20340 RAB6A RAB6A RAB6 RAB6A FUNCTION Protein transport. Regulator of membrane traffic from the Golgi apparatus towards the endoplasmic reticulum (ER). Has a low GTPase activity. Involved in COPI-independent retrograde transport from the Golgi to the ER (PubMed:25962623).SUBUNIT Interacts with BICDL1; leads to its accumulation in the pericentrosomal region (By similarity). Interacts with SCYL1BP1. Interacts with VSP52 and RABGAP1. Interacts with GCC2 (via its GRIP domain). Interacts with RAB6IP1 (via its RUN 1 domain). Isoform 1 interacts with RAB6KIFL. Isoform 2 does not interact with RAB6KIFL. Isoform 1 interacts with BICD1. Isoform 2 interacts with BICD1. Isoform 1 interacts with BICD2. Isoform 2 interacts with BICD2. Interacts with TMF1. Isoform 1 (GTP-bound) interacts with DYNLRB1; the interaction is direct. Isoform 2 (GDP-bound) interacts with DYNLRB1; the interaction is direct. Interacts with PIFO. Interacts (GTP-bound) with APBA1/MINT1 isoform 2, also called Mint1_826, but not with isoform 1. Interacts with RIC1 and RGP1; the interactions are direct with a preference for RAB6A-GDP.SUBUNIT (Microbial infection) Interacts with human cytomegalovirus protein UL32.TISSUE SPECIFICITY Ubiquitous.PTM Prenylated.SIMILARITY Belongs to the small GTPase superfamily. Rab family. UniProt P20340 2 EQUAL 208 EQUAL 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 NOTCH precursor cleaved to form mature NOTCH NOTCH precursor cleaved to form mature NOTCH The NOTCH receptor is synthesized as a precursor polypeptide (approx. 300 kDa) associated with the endoplasmic reticulum membrane. The mature NOTCH receptor is produced by proteolytic cleavage to form a heterodimer. The enzyme responsible is a furin-like convertase which cleaves the full-length precursor into a transmembrane fragment (NTM) of approximate size 110 kDa and an extracellular fragment (NEC) of approximate size 180 kDa. The mature NOTCH receptor is reassembled as a heterodimer (Blaumueller et al. 1997, Logeat et al. 1998). Both disulfide bonds and calcium-mediated ionic interactions stabilize the heterodimer (Rand et al. 2000, Gordon et al. 2009). This process takes place in the trans-Golgi network . Mammalian NOTCH is predominantly presented as a heterodimer on the cell surface. Although FURIN-mediated cleavage is evolutionarily conserved, it may not be mandatory for Drosophila Notch function (Kidd et al. 2002). Authored: Jassal, B, 2004-12-15 13:08:03 Reviewed: Joutel, A, 2004-12-15 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 Reactome DB_ID: 1911440 1 Converted from EntitySet in Reactome Reactome DB_ID: 1911472 1 NOTCH [Golgi membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 157049 UniProt:P09958 FURIN FURIN FUR PACE FURIN PCSK3 FUNCTION Ubiquitous endoprotease within constitutive secretory pathways capable of cleavage at the RX(K/R)R consensus motif (PubMed:11799113, PubMed:1629222, PubMed:1713771, PubMed:2251280, PubMed:24666235, PubMed:25974265, PubMed:7592877, PubMed:7690548, PubMed:9130696). Mediates processing of TGFB1, an essential step in TGF-beta-1 activation (PubMed:7737999). Converts through proteolytic cleavage the non-functional Brain natriuretic factor prohormone into its active hormone BNP(1-32) (PubMed:20489134, PubMed:21763278). By mediating processing of accessory subunit ATP6AP1/Ac45 of the V-ATPase, regulates the acidification of dense-core secretory granules in islets of Langerhans cells (By similarity).FUNCTION (Microbial infection) Cleaves and activates diphtheria toxin DT.FUNCTION (Microbial infection) Cleaves and activates anthrax toxin protective antigen (PA).FUNCTION (Microbial infection) Required for H7N1 and H5N1 influenza virus infection probably by cleaving hemagglutinin.FUNCTION (Microbial infection) Able to cleave S.pneumoniae serine-rich repeat protein PsrP.FUNCTION (Microbial infection) Facilitates human coronaviruses EMC and SARS-CoV-2 infections by proteolytically cleaving the spike protein at the monobasic S1/S2 cleavage site. This cleavage is essential for spike protein-mediated cell-cell fusion and entry into human lung cells.FUNCTION (Microbial infection) Facilitates mumps virus infection by proteolytically cleaving the viral fusion protein F.ACTIVITY REGULATION Inhibited by the not secondly cleaved propeptide (PubMed:9130696, PubMed:11799113). Inhibited by m-guanidinomethyl-phenylacetyl-Arg-Val-Arg-(amidomethyl)-benzamidine (m-guanidinomethyl-Phac-RVR-Amb) and 4-guanidinomethyl-phenylacetyl-Arg-Tle-Arg-4-amidinobenzylamide (MI-1148) (PubMed:24666235, PubMed:25974265). Inhibited by Decanoyl-Arg-Val-Lys-Arg-chloromethylketone (decanoyl-RVKR-CMK) (PubMed:32362314). Inhibited by heparin/heparan sulfate-binding (PubMed:2408021).SUBUNIT Interacts with FLNA (By similarity). Binds to PACS1 which mediates TGN localization and connection to clathrin adapters (PubMed:11331585). Interacts with LAMP1, LAMP2 and LAMP3 (PubMed:32295904).TISSUE SPECIFICITY Seems to be expressed ubiquitously.DOMAIN Contains a cytoplasmic domain responsible for its TGN localization and recycling from the cell surface.PTM The inhibition peptide, which plays the role of an intramolecular chaperone, is autocatalytically removed in the endoplasmic reticulum (ER) and remains non-covalently bound to furin as a potent autoinhibitor. Following transport to the trans Golgi, a second cleavage within the inhibition propeptide results in propeptide dissociation and furin activation.PTM Phosphorylation is required for TGN localization of the endoprotease. In vivo, exists as di-, mono- and non-phosphorylated forms.SIMILARITY Belongs to the peptidase S8 family. Furin subfamily. UniProt P09958 108 EQUAL 794 EQUAL GO 0004252 GO molecular function Reactome Database ID Release 81 156993 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=156993 Reactome Database ID Release 81 1912369 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1912369 Reactome R-HSA-1912369 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1912369.1 19701457 Pubmed 2009 Effects of S1 cleavage on the structure, surface export, and signaling activity of human Notch1 and Notch2 Gordon, WR Vardar-Ulu, D L'Heureux, S Ashworth, T Malecki, MJ Sanchez-Irizarry, C McArthur, DG Histen, G Mitchell, JL Aster, JC Blacklow, SC PLoS One 4:e6613 9653148 Pubmed 1998 The Notch1 receptor is cleaved constitutively by a furin-like convertase Logeat, F LeBail, O Jarriault, S Seidah, NG Proc Natl Acad Sci U S A 95:8108-12 10669757 Pubmed 2000 Calcium depletion dissociates and activates heterodimeric notch receptors Rand, MD Grimm, LM Artavanis-Tsakonas, S Patriub, V Blacklow, SC Sklar, J Mol Cell Biol 20:1825-35 12049766 Pubmed 2002 Furin cleavage is not a requirement for Drosophila Notch function Kidd, S Lieber, T Mech Dev 115:41-51 9727485 Pubmed 1998 Roles for proteolysis and trafficking in notch maturation and signal transduction Chan, YM Jan, YN Cell 94:423-6 2.4.1.222 Glycosylation of Pre-NOTCH by FRINGE Glycosylation of Pre-NOTCH by FRINGE The Fringe family (CAZy family GT31) of glycosyltransferases in mammals includes LFNG (lunatic fringe; MIM:602576), MFNG (manic fringe; MIM:602577) and RFNG (radical fringe; MIM:602578). Fringe enzymes function in the Golgi apparatus where they initiate the elongation of O-linked fucose on fucosylated peptides by the addition of a beta-1,3-N-acetylglucosaminyl group (GlcNAc) (Moloney et al. 2000). Fringe enzymes elongate conserved O fucosyl residues conjugated to EGF repeats of NOTCH, modulating NOTCH activity (Cohen et al. 1997, Johnston et al. 1997) by decreasing the affinity of NOTCH extracellular domain for JAG ligands (Bruckner et al. 2000). In developing mouse thymocytes, Lfng enhances Notch1 activation by Dll4, resulting in prolonged Notch1 signaling that promotes self-renewal of TCR-beta-expressing progenitors (Yuan et al. 2011). Since the exact preference, if any, of fringe enzymes for NOTCH O-fucose sites is not known, the extension of an O-fucosyl residue at an unknown protein position is shown. 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 Reactome DB_ID: 1911440 1 Reactome DB_ID: 914003 1 Golgi lumen GO 0005796 UDP-N-acetyl-alpha-D-glucosamine(2-) [ChEBI:57705] UDP-N-acetyl-alpha-D-glucosamine(2-) UDP-N-acetyl-alpha-D-glucosamine dianion UDP-N-acetyl-alpha-D-glucosamine uridine 5'-[3-(acetamido-2-deoxy-alpha-D-glucopyranosyl) diphosphate] ChEBI 57705 Reactome DB_ID: 205687 1 UDP(3-) [ChEBI:58223] UDP(3-) UDP 5'-O-[(phosphonatooxy)phosphinato]uridine uridine 5'-diphosphate(3-) uridine 5'-diphosphate trianion uridine 5'-diphosphate UDP trianion ChEBI 58223 Converted from EntitySet in Reactome Reactome DB_ID: 1911434 1 Glc,GlcNAc-Fuc-Pre-NOTCH [Golgi membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Glc,GlcNAc-Fuc-Pre-NOTCH1 [Golgi membrane] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 1464792 Fringe family [Golgi membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity LFNG [Golgi membrane] UniProt Q8NES3 GO 0033829 GO molecular function Reactome Database ID Release 81 1464793 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1464793 Reactome Database ID Release 81 1912355 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1912355 Reactome R-HSA-1912355 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1912355.1 10935626 Pubmed 2000 Fringe is a glycosyltransferase that modifies Notch Moloney, DJ Panin, VM Johnston, SH Chen, J Shao, L Wilson, R Wang, Y Stanley, P Irvine, KD Haltiwanger, RS Vogt, TF Nature 406:369-75 9207795 Pubmed 1997 Fringe boundaries coincide with Notch-dependent patterning centres in mammals and alter Notch-dependent development in Drosophila Cohen, B Bashirullah, A Dagnino, L Campbell, C Fisher, WW Leow, CC Whiting, E Ryan, D Zinyk, D Boulianne, G Hui, CC Gallie, B Phillips, RA Lipshitz, HD Egan, SE Nat Genet 16:283-8 9187150 Pubmed 1997 A family of mammalian Fringe genes implicated in boundary determination and the Notch pathway Johnston, SH Rauskolb, C Wilson, R Prabhakaran, B Irvine, KD Vogt, TF Development 124:2245-54 21097675 Pubmed 2011 Lunatic Fringe prolongs Delta/Notch-induced self-renewal of committed ?? T-cell progenitors Yuan, JS Tan, JB Visan, I Matei, IR Urbanellis, P Xu, K Danska, JS Egan, SE Guidos, CJ Blood 117:1184-95 10935637 Pubmed 2000 Glycosyltransferase activity of Fringe modulates Notch-Delta interactions Brückner, K Perez, L Clausen, H Cohen, S Nature 406:411-5 2.4.1.38 Galactosylation of Pre-NOTCH Galactosylation of Pre-NOTCH Beta-1,4-galactosyltransferase 1 (B4GALT1) is a Golgi membrane enzyme responsible for galactosylation of N-acetylglucosaminyl group added by fringe enzymes to O-linked fucosyl residues on NOTCH. This results in formation of trisaccharide chains on NOTCH (Gal-beta1,4-GlcNAc-beta1,3-fucitol), and is a necessary step for fringe-mediated modulation of NOTCH 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 Reactome DB_ID: 735682 1 UDP-D-galactose(2-) [ChEBI:58439] UDP-D-galactose(2-) uridine 5'-[3-(D-galactopyranosyl) diphosphate] UDP-D-galactose dianion ChEBI 58439 Converted from EntitySet in Reactome Reactome DB_ID: 1911434 1 Reactome DB_ID: 205687 1 Converted from EntitySet in Reactome Reactome DB_ID: 1911423 1 Glc,Gal-GlcNAc-Fuc-Pre-NOTCH [Golgi membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Glc,Gal-GlcNAc-Fuc-Pre-NOTCH1 [Golgi membrane] PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 975900 B4GALT1 homodimer [Golgi membrane] B4GALT1 homodimer Reactome DB_ID: 528072 2 UniProt:P15291 B4GALT1 B4GALT1 B4GALT1 GGTB2 PATHWAY Protein modification; protein glycosylation.SUBUNIT Homodimer; and heterodimer with alpha-lactalbumin to form lactose synthase. Interacts (via N-terminal cytoplasmic domain) with UBE2Q1 (via N-terminus); the interaction is direct (By similarity).TISSUE SPECIFICITY Ubiquitously expressed, but at very low levels in fetal and adult brain.PTM The soluble form derives from the membrane forms by proteolytic processing.SIMILARITY Belongs to the glycosyltransferase 7 family. UniProt P15291 1 EQUAL 398 EQUAL Reactome Database ID Release 81 975900 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=975900 Reactome R-HSA-975900 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-975900.1 GO 0003831 GO molecular function Reactome Database ID Release 81 1499956 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1499956 Reactome Database ID Release 81 1912352 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1912352 Reactome R-HSA-1912352 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1912352.1 11707585 Pubmed 2001 Fringe modulation of Jagged1-induced Notch signaling requires the action of beta 4galactosyltransferase-1 Chen, J Moloney, DJ Stanley, P Proc Natl Acad Sci U S A 98:13716-21 2.4.99.4 Sialylation of Pre-NOTCH Sialylation of Pre-NOTCH Mature fringe-modified NOTCH usually has a tetrasaccharide attached to conserved fucosylated serine and threonine residues in EGF repeats. The chemical structure of these tetrasaccharides is Sia-alpha2,3-Gal-beta1,4-GlcNAc-beta1,3-fucitol (Moloney et al. 2000). The identity of sialyltransferase(s) that add sialic acid to galactose remains unknown in this context. Based on the type of chemical bonds in the tetrasaccharide, there are three known Golgi membrane sialyltransferases that could perform this function: ST3GAL3, ST3GAL4, ST3GAL6 (Harduin-Lepers et al. 2001). 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 Reactome DB_ID: 727815 1 CMP-N-acetyl-beta-neuraminate(2-) [ChEBI:57812] CMP-N-acetyl-beta-neuraminate(2-) cytidine 5'-(5-acetamido-3,5-dideoxy-D-glycero-beta-D-galacto-non-2-ulopyranosylonate monophosphate) CMP-N-acetyl-beta-neuraminate dianion CMP-N-acetyl-beta-neuraminate ChEBI 57812 Converted from EntitySet in Reactome Reactome DB_ID: 1911423 1 Converted from EntitySet in Reactome Reactome DB_ID: 1911509 1 Glc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCH [Golgi membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Glc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCH1 [Golgi membrane] Reactome DB_ID: 727810 1 cytidine 5'-monophosphate(2-) [ChEBI:60377] cytidine 5'-monophosphate(2-) Cytidine-5-monophosphate dianion CMP 5'-O-phosphonatocytidine CMP dianion CMP(2-) ChEBI 60377 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 1499957 ST3GAL3/4/6 [Golgi membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity GO 0003836 GO molecular function Reactome Database ID Release 81 1499958 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1499958 Reactome Database ID Release 81 1912378 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1912378 Reactome R-HSA-1912378 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1912378.1 11530204 Pubmed 2001 The human sialyltransferase family Harduin-Lepers, A Vallejo-Ruiz, V Krzewinski-Recchi, MA Samyn-Petit, B Julien, S Delannoy, P Biochimie 83:727-37 3.4.21.1 3.4.21.92 3.4.21.73 3.4.21.71 3.4.21.93 3.4.21.94 3.4.21.34 3.4.21.78 3.4.21.9 3.4.21.53 3.4.21.6 3.4.21.75 3.4.24.3 3.4.21.10 3.4.21.54 3.4.21.7 3.4.21.4 3.4.21.59 3.4.21.38 3.4.21.5 3.4.21.35 3.4.21.79 3.4.21.36 3.4.19.1 3.4.21.62 3.4.21.41 3.4.21.61 3.4.21.83 3.4.21.22 3.4.21.88 3.4.21.45 3.4.21.89 3.4.21.20 3.4.21.42 3.4.21.21 3.4.21.43 3.4.21.87 3.4.21.26 3.4.21.48 3.4.24.34 3.4.21.27 3.4.21.46 3.4.21.68 3.4.21.47 3.4.21.69 3.4.21.39 3.4.24.7 3.4.21.102 Fringe-modified Pre-NOTCH is cleaved by FURIN Fringe-modified Pre-NOTCH is cleaved by FURIN Cleavage of fringe-modified NOTCH by FURIN has not been examined directly, but since mature, plasma membrane-anchored NOTCH receptors are typically cleaved by FURIN (Blaumueller et al. 1997) and fringe-modified NOTCH functions at the cell surface (Moloney et al. 2000), it is expected that fringe-modified NOTCH is processed by FURIN cleavage. The exact order of fringe-mediated glycosylation and FURIN cleavage has not been experimentally established, but since FURIN localizes to the trans-Golgi network -TGN (Teuchert et al. 1999), while fringe has not been associated with TGN, it is likely that modification of NOTCH by fringe enzymes precedes FURIN-mediated cleavage. 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 Reactome DB_ID: 1911509 1 Converted from EntitySet in Reactome Reactome DB_ID: 1911547 1 FRINGE-modified NOTCH [Golgi membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 157049 108 EQUAL 794 EQUAL Reactome Database ID Release 81 1912372 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1912372 Reactome R-HSA-1912372 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1912372.1 10075724 Pubmed 1999 Sorting of furin at the trans-Golgi network. Interaction of the cytoplasmic tail sorting signals with AP-1 Golgi-specific assembly proteins Teuchert, M Schäfer, W Berghöfer, S Hoflack, B Klenk, HD Garten, W J Biol Chem 274:8199-207 Mature NOTCH heterodimer traffics to the plasma membrane Mature NOTCH heterodimer traffics to the plasma membrane Mature NOTCH translocates from the Golgi to plasma membrane. In Caenorhabditis elegans, a Golgi membrane protein sel-9, a homolog of mammalian TMED2, acts as a quality controller and prevents misfolded lin-12, a NOTCH homolog, to reach the cell surface. Authored: Jassal, B, 2004-12-15 13:08:03 Reviewed: Joutel, A, 2004-12-15 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 Reactome DB_ID: 1911472 1 Converted from EntitySet in Reactome Reactome DB_ID: 1911474 1 plasma membrane GO 0005886 NOTCH [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 81 1912382 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1912382 Reactome R-HSA-1912382 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-1912382.3 11135303 Pubmed 2001 Oh no, Notch again! Frisen, J Lendahl, U Bioessays 23:3-7 10366590 Pubmed 1999 p24 proteins and quality control of LIN-12 and GLP-1 trafficking in Caenorhabditis elegans Wen, C Greenwald, I J Cell Biol 145:1165-75 INHIBITION Reactome Database ID Release 81 2043096 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2043096 Reactome R-HSA-2043096 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2043096.1 Reactome DB_ID: 1911531 endoplasmic reticulum-Golgi intermediate compartment membrane GO 0033116 UniProt:Q15363 TMED2 TMED2 TMED2 RNP24 FUNCTION Involved in vesicular protein trafficking. Mainly functions in the early secretory pathway but also in post-Golgi membranes. Thought to act as cargo receptor at the lumenal side for incorporation of secretory cargo molecules into transport vesicles and to be involved in vesicle coat formation at the cytoplasmic side. In COPII vesicle-mediated anterograde transport involved in the transport of GPI-anchored proteins and proposed to act together with TMED10 as their cargo receptor; the function specifically implies SEC24C and SEC24D of the COPII vesicle coat and lipid raft-like microdomains of the ER. Recognizes GPI anchors structural remodeled in the ER by PGAP1 and MPPE1. In COPI vesicle-mediated retrograde transport inhibits the GTPase-activating activity of ARFGAP1 towards ARF1 thus preventing immature uncoating and allowing cargo selection to take place. Involved in trafficking of G protein-coupled receptors (GPCRs). Regulates F2RL1, OPRM1 and P2RY4 exocytic trafficking from the Golgi to the plasma membrane thus contributing to receptor resensitization. Facilitates CASR maturation and stabilization in the early secretory pathway and increases CASR plasma membrane targeting. Proposed to be involved in organization of intracellular membranes such as the maintenance of the Golgi apparatus. May also play a role in the biosynthesis of secreted cargo such as eventual processing.SUBUNIT Monomer and homodimer in the endoplasmic reticulum, endoplasmic reticulum-Golgi intermediate compartment and Golgi. Probably oligomerizes with other members of the EMP24/GP25L family such as TMED7, TMED9 and TMED10. Interacts (via GOLD domain) with TMED10 (via GOLD domain). Associates with the COPI vesicle coat (coatomer); TMED10:TMED2 heterotetramers are proposed to be involved in coatomer association. Interacts (via C-terminus) with COPG1; the interaction involves dimeric TMED2. Interacts with SEC23A; indicative for an association of TMED2 with the COPII vesicle coat. Interacts with ARF1 and ARFGAP1 (By similarity). Interacts with CD59, SEC24A, SEC24B, SEC24C, SEC24D and ATL1. Interacts with KDELR1; the interaction is decreased by KDEL ligand (By similarity). Interacts with F2RL1; the interaction occurs at the Golgi apparatus. Interacts with CASR (immaturely glycosylated form); the interaction occurs in the endoplasmic reticulum-Golgi intermediate compartment or cis-Golgi. Interacts with F2RL1; the interaction occurs at the Golgi apparatus. Interacts with GORASP1 and GORASP2 (By similarity). Found in a complex composed at least of SURF4, TMED2 and TMED10.MISCELLANEOUS Ectopic expression of TMED2 alone does not result in its proper cis-Golgi network localization. Coexpression of TMED10 is necessary, and coexpression of TMED3 and/or TMED9 is facilitating localization. Down-regulation of TMED10 expression reduces TMED2 protein level.SIMILARITY Belongs to the EMP24/GP25L family. UniProt Q15363 21 EQUAL 201 EQUAL Transport of fringe-modified NOTCH to plasma membrane Transport of fringe-modified NOTCH to plasma membrane Fringe-modified NOTCH functions at the plasma membrane. The transport of fringe-modified NOTCH to the plasma membrane from Golgi has not been studied directly, but is assumed to share properties of transport of mature NOTCH receptors that are not modified by fringe. 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 Reactome DB_ID: 1911547 1 Converted from EntitySet in Reactome Reactome DB_ID: 1911550 1 Fringe-modified NOTCH [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 81 1912379 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1912379 Reactome R-HSA-1912379 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-1912379.3 INHIBITION Reactome Database ID Release 81 2043098 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2043098 Reactome R-HSA-2043098 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2043098.1 Reactome DB_ID: 1911531 21 EQUAL 201 EQUAL Reactome Database ID Release 81 1912420 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1912420 Reactome R-HSA-1912420 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-1912420.2 Reactome Database ID Release 81 1912422 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1912422 Reactome R-HSA-1912422 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1912422.1 Signaling by NOTCH1 Signaling by NOTCH1 NOTCH1 functions as both a transmembrane receptor presented on the cell surface and as a transcriptional regulator in the nucleus.<br><br>NOTCH1 receptor presented on the plasma membrane is activated by a membrane bound ligand expressed in trans on the surface of a neighboring cell. In trans, ligand binding triggers proteolytic cleavage of NOTCH1 and results in release of the NOTCH1 intracellular domain, NICD1, into the cytosol.<br><br>NICD1 translocates to the nucleus where it associates with RBPJ (also known as CSL or CBF) and mastermind-like (MAML) proteins (MAML1, MAML2 or MAML3; possibly also MAMLD1) to form NOTCH1 coactivator complex. NOTCH1 coactivator complex activates transcription of genes that possess RBPJ binding sites in their promoters. <br><br> 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 Activated NOTCH1 Transmits Signal to the Nucleus Activated NOTCH1 Transmits Signal to the Nucleus Mature NOTCH1 heterodimer on the cell surface is activated by one of its ligands: DLL1 (Cordle et al. 2008, Jarriault et al. 1998), DLL4 (Benedito et al. 2009), JAG1 (Li et al. 1998, Benedito et al. 2009) or JAG2 (Luo et al. 1997, Shimizu et al. 2000), expressed in trans on a neighboring cell. Thus, a ligand-expressing cell is a signal-sending cell, while the NOTCH1 expressing cell is a signal-receiving cell. If NOTCH1 has undergone Fringe modification in the Golgi, it is preferentially activated by Delta ligands (Yang et al. 2005), DLL1 and DLL4. <br><br><br>Upon binding to NOTCH1 on a neighboring cell, NOTCH ligands are ubiquitinated by Mindbomb (MIB1 and MIB2) and/or Neuralized (NEURL and NEURL1B) E3 ubiquitin ligases and endocytosed (Koo et al. 2007, Koo et al. 2005, Itoh et al. 2003, Lai et al. 2001, Koutelou et al. 2008, Song et al. 2006). Endocytosis of ubiquitinated ligands is thought to mechanically stretch the bound NOTCH1 receptor, exposing a cleavage site S2 that is recognized by ADAM10 and/or ADAM17 metalloprotease (van Tetering et al. 2009, Brou et al. 2000, Hartmann et al. 2002, Pan et al. 1997). S2 cleavage of NOTCH1 produces the NEXT1 fragment which is further cleaved at an S3 cleavage site by the gamma-secretase complex, resulting in release of the NOTCH1 intracellular domain (NICD1) into the cytosol (de Strooper et al. 1999, Schroeter et al. 1998, Huppert et al. 2000). NICD1 produced by activation of NOTCH1 in response to in trans presented Delta and Jagged ligands (DLL/JAG) traffics to the nucleus where it acts as a transcription regulator.<br><br><br>NOTCH1 signaling can also be activated by ligands other than DLL1, DLL4, JAG1 and JAG2. CNTN1 (Contactin-1), transiently expressed during central and peripheral nervous system development, activates NOTCH1 and NOTCH2 in trans, promoting oligodendrocyte maturation and myelination (Hu et al. 2003). DNER (Delta and Notch-like epidermal growth factor-related receptor) is a transmembrane protein specifically expressed in dendrites and cell bodies of postmitotic neurons. Activation of NOTCH1 by DNER in trans may play an important role in development of the central nervous system by influencing differentiation of astrocytes (Eiraku et al. 2005). Activation of NOTCH1 by both CNTN1 and DNER is Deltex (DTX)-dependent and results in gamma-secretase mediated release of NICD1. Three members of the Deltex protein family: DTX1, DTX2 and DTX4 possess a domain involved in binding cdc10/ankyrin repeats of NOTCH. DTX proteins are considered as positive regulators of NOTCH signaling, although the exact mechanism has not been elucidated (Matsuno et al. 1998, Kishi et al. 2001).In addition, DTX can mediate downregulation of NOTCH signaling by recruiting non-visual beta-arrestins to NOTCH (Mukherjee et al. 2005), thereby trigerring NOTCH ubiquitination. DTX proteins are negatively regulated by ITCH (AIP4) ubiquitin ligase (Chastagner et al. 2006).<br><br>NOTCH1 signaling in the signal-receiving cell can be turned off in cis by expression of NOTCH ligands DLL/JAG (Cordle et al. 2008, Sprinzak et al. 2010), as well as DLK1 (Baladron et al. 2005, Bray et al. 2008). Formation of NOTCH1:ligand complexes in cis prevents interaction of NOTCH1 with ligands expressed in trans, resulting in the inhibition of NOTCH signaling. In the signal-sending cell, NOTCH signaling can be negatively regulated by the protein NUMB, which is asymmetrically distributed during cell division (Rhyu et al. 1994). NUMB recruits ITCH ubiquitin ligase to NOTCH1 and promotes sorting of NOTCH1 through late endosomes for degradation (McGill et al. 2009, Chastagner 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 NOTCH1 binds DLL1 NOTCH1 binds DLL1 The NOTCH1 receptor is activated by binding Delta-like 1 ligand (DLL1), presented on the plasma membrane of a neighboring cell (Jarriault et al. 1998). EGF repeat 12 (EGF12) in the extracellular domain of NOTCH1 appears to be particularly important for interaction of NOTCH1 with DLL1 (Cordle et al. 2008). The affinity of NOTCH1 for DLL1 is increased when NOTCH1 is glycosylated by fringe enzymes (Yang et al 2005). Authored: Jassal, B, 2004-12-15 13:08:03 Reviewed: Joutel, A, 2004-12-15 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: D'Eustachio, P, 2012-02-06 Reactome DB_ID: 157089 1 UniProt:O00548 DLL1 DLL1 UNQ146/PRO172 DLL1 FUNCTION Transmembrane ligand protein of NOTCH1, NOTCH2 and NOTCH3 receptors that binds the extracellular domain (ECD) of Notch receptor in a cis and trans fashion manner (PubMed:11006133). Following transinteraction, ligand cells produce mechanical force that depends of a clathrin-mediated endocytosis, requiring ligand ubiquitination, EPN1 interaction, and actin polymerisation; these events promote Notch receptor extracellular domain (NECD) transendocytosis and triggers Notch signaling through induction of cleavage, hyperphosphorylation, and nuclear accumulation of the intracellular domain of Notch receptors (NICD) (By similarity). Is required for embryonic development and maintenance of adult stem cells in many different tissues and immune systeme; the DLL1-induced Notch signaling is mediated through an intercellular communication that regulates cell lineage, cell specification, cell patterning and morphogenesis through effects on differentiation and proliferation (PubMed:11581320). Plays a role in brain development at different level, namely by regulating neuronal differentiation of neural precursor cells via cell-cell interaction, most likely through the lateral inhibitory system in an endogenous level dependent-manner. During neocortex development, Dll1-Notch signaling transmission is mediated by dynamic interactions between intermediate neurogenic progenitors and radial glia; the cell-cell interactions are mediated via dynamic and transient elongation processes, likely to reactivate/maintain Notch activity in neighboring progenitors, and coordinate progenitor cell division and differentiation across radial and zonal boundaries. During cerebellar development, regulates Bergmann glial monolayer formation and its morphological maturation through a Notch signaling pathway. At the retina and spinal cord level, regulates neurogenesis by preventing the premature differentiation of neural progenitors and also by maintaining progenitors in spinal cord through Notch signaling pathway. Also controls neurogenesis of the neural tube in a progenitor domain-specific fashion along the dorsoventral axis. Maintains quiescence of neural stem cells and plays a role as a fate determinant that segregates asymmetrically to one daughter cell during neural stem cells mitosis, resulting in neuronal differentiation in Dll1-inheriting cell. Plays a role in immune systeme development, namely the development of all T-cells and marginal zone (MZ) B-cells (By similarity). Blocks the differentiation of progenitor cells into the B-cell lineage while promoting the emergence of a population of cells with the characteristics of a T-cell/NK-cell precursor (PubMed:11581320). Also plays a role during muscle development. During early development, inhibits myoblasts differentiation from the medial dermomyotomal lip and later regulates progenitor cell differentiation. Directly modulates cell adhesion and basal lamina formation in satellite cells through Notch signaling. Maintains myogenic progenitors pool by suppressing differentiation through down-regulation of MYOD1 and is required for satellite cell homing and PAX7 expression. During craniofacial and trunk myogenesis suppresses differentiation of cranial mesoderm-derived and somite-derived muscle via MYOD1 regulation but in cranial mesoderm-derived progenitors, is neither required for satellite cell homing nor for PAX7 expression. Also plays a role during pancreatic cell development. During type B pancreatic cell development, may be involved in the initiation of proximodistal patterning in the early pancreatic epithelium. Stimulates multipotent pancreatic progenitor cells proliferation and pancreatic growth by maintaining HES1 expression and PTF1A protein levels. During fetal stages of development, is required to maintain arterial identity and the responsiveness of arterial endothelial cells for VEGFA through regulation of KDR activation and NRP1 expression. Controls sprouting angiogenesis and subsequent vertical branch formation througth regulation on tip cell differentiation. Negatively regulates goblet cell differentiation in intestine and controls secretory fat commitment through lateral inhibition in small intestine. Plays a role during inner ear development; negatively regulates auditory hair cell differentiation. Plays a role during nephron development through Notch signaling pathway. Regulates growth, blood pressure and energy homeostasis (By similarity).SUBUNIT Homodimer. Interacts with TJP1. Interacts with MAGI1 (via PDZ domain); forms a complex with CTNNB1 and CDH2 and promotes recruitment to the adherens junction and stabilization on the cell surface. Interacts with PSEN1; undergoes a presenilin-dependent gamma-secretase cleavage that releases a Dll1-intracellular form. Interacts with MFAP5. Interacts with MIB1. Interacts with NEURL1B; leads to ubiquitination. Interacts with NEURL1 (By similarity). Interacts with SYNJ2BP; enhances DLL1 protein stability, and promotes Notch signaling in endothelial cells (PubMed:24025447). Interacts with MAGI1, MAGI2, MAGI3 and MPDZ (PubMed:15509766). Interacts (via ubiquitin) with EPN1 (via IUM domain); binding with NOTCH1 attached to neighboring cell, promotes ligand ubiquitination and EPN1 interaction, leading to NECD transendocytosis and Notch signaling. Interacts with NOTCH1 (By similarity) (PubMed:15509766, PubMed:24025447). Interacts with NOTCH2NLB; leading to promote Notch signaling pathway in a cell-autonomous manner through inhibition of cis DLL1-NOTCH2 interactions (PubMed:29856955).TISSUE SPECIFICITY Expressed in heart and pancreas, with lower expression in brain and muscle and almost no expression in placenta, lung, liver and kidney.PTM Ubiquitinated by MIB (MIB1 or MIB2), leading to its endocytosis and subsequent degradation (By similarity). Ubiquitinated; promotes recycling back to the plasma membrane and confers a strong affinity for NOTCH1. Multi-ubiquitination of LYS-613 by MIB1 promotes both cis and trans-interaction with NOTCH1, as well as activation of Notch signaling. Ubiquitinated by NEURL1B (By similarity).PTM Phosphorylated in a membrane association-dependent manner. Phosphorylation at Ser-697 requires the presence of Ser-694, whereas phosphorylation at Ser-694 occurs independently of the other site. Phosphorylation is required for full ligand activity in vitro and affects surface presentation, ectodomain shedding, and endocytosis.PTM O-fucosylated. Can be elongated to a disaccharide by MFNG. UniProt O00548 18 EQUAL 723 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 1911555 1 NOTCH1/Fringe-modified NOTCH1 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome DB_ID: 1911557 1 DLL1:NOTCH1 [plasma membrane] DLL1:NOTCH1 Reactome DB_ID: 157089 1 18 EQUAL 723 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 1911555 1 Reactome Database ID Release 81 1911557 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1911557 Reactome R-HSA-1911557 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1911557.1 Reactome Database ID Release 81 1980039 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1980039 Reactome R-HSA-1980039 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1980039.1 15574878 Pubmed 2005 Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1 Yang, LT Nichols, JT Yao, C Manilay, JO Robey, EA Weinmaster, G Mol Biol Cell 16:927-42 18296446 Pubmed 2008 Localization of the delta-like-1-binding site in human Notch-1 and its modulation by calcium affinity Cordle, J Redfield, C Stacey, M van der Merwe, PA Willis, AC Champion, BR Hambleton, S Handford, Penny A J Biol Chem 283:11785-93 9819428 Pubmed 1998 Delta-1 activation of notch-1 signaling results in HES-1 transactivation Jarriault, S Le, Bail O Hirsinger, E Pourquie, O Logeat, F Strong, CF Brou, C Seidah, NG Isra, l A Mol Cell Biol 18:7423-31 NOTCH1 binds DLL4 NOTCH1 binds DLL4 NOTCH1 is activated by DLL4 ligand expressed on a neighboring cell. The interaction of NOTCH1 and DLL4 is enhanced when NOTCH1 is glycosylated by fringe-enzymes. Based on mouse studies, activation of NOTCH1 by DLL4 may be important in angiogenesis (Benedito et al. 2009). DLL4 may also be involved in T-cell development. Mouse Dll4 is expressed on thymic epithelial cells and its interaction with Notch1 expressed on hematopoietic progenitors is necessary for T-cell lineage commitment (Koch et al. 2008, Hozumi et al. 2008). Authored: Jassal, B, 2004-12-15 13:08:03 Reviewed: Joutel, A, 2004-12-15 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: D'Eustachio, P, 2012-02-06 Reactome DB_ID: 158437 1 UniProt:Q9NR61 DLL4 DLL4 DLL4 UNQ1895/PRO4341 FUNCTION Involved in the Notch signaling pathway as Notch ligand (PubMed:11134954). Activates NOTCH1 and NOTCH4. Involved in angiogenesis; negatively regulates endothelial cell proliferation and migration and angiogenic sprouting (PubMed:20616313). Essential for retinal progenitor proliferation. Required for suppressing rod fates in late retinal progenitors as well as for proper generation of other retinal cell types (By similarity). During spinal cord neurogenesis, inhibits V2a interneuron fate (PubMed:17728344).SUBUNIT Interacts with NOTCH4. Interacts (via N-terminal DSL and MNNL domains) with NOTCH1 (via EGF-like domains).TISSUE SPECIFICITY Expressed in vascular endothelium.DOMAIN The Delta-Serrate-Lag2 (DSL) domain is required for binding to the Notch receptor. UniProt Q9NR61 27 EQUAL 685 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 1911555 1 Reactome DB_ID: 1911559 1 DLL4:NOTCH1 [plasma membrane] DLL4:NOTCH1 Reactome DB_ID: 158437 1 27 EQUAL 685 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 1911555 1 Reactome Database ID Release 81 1911559 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1911559 Reactome R-HSA-1911559 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1911559.1 Reactome Database ID Release 81 1980041 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1980041 Reactome R-HSA-1980041 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1980041.1 18824585 Pubmed 2008 Delta-like 4 is the essential, nonredundant ligand for Notch1 during thymic T cell lineage commitment Koch, U Fiorini, E Benedito, R Besseyrias, V Schuster-Gossler, K Pierres, M Manley, NR Duarte, A MacDonald, HR Radtke, F J Exp Med 205:2515-23 18824583 Pubmed 2008 Delta-like 4 is indispensable in thymic environment specific for T cell development Hozumi, K Mailhos, C Negishi, N Hirano, K Yahata, T Ando, K Zuklys, S Holländer, GA Shima, DT Habu, S J Exp Med 205:2507-13 19524514 Pubmed 2009 The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis Benedito, R Roca, C Sörensen, I Adams, S Gossler, A Fruttiger, M Adams, Ralf H Cell 137:1124-35 NOTCH1 binds JAG1 NOTCH1 binds JAG1 NOTCH1 is activated by JAG1 ligand expressed on a neighboring cell. Based on mouse studies, activation of NOTCH1 by JAG1 may be important in angiogenesis (Benedito et al. 2009). In addition, human JAG1 was shown to inhibit granulocytic differentiation of 32D mouse myeloid progenitors expressing Notch1 (Li et al. 1998). Authored: Jassal, B, 2004-12-15 13:08:03 Reviewed: Joutel, A, 2004-12-15 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: D'Eustachio, P, 2012-02-06 Reactome DB_ID: 157098 1 UniProt:P78504 JAG1 JAG1 JAG1 JAGL1 FUNCTION Ligand for multiple Notch receptors and involved in the mediation of Notch signaling (PubMed:18660822, PubMed:20437614). May be involved in cell-fate decisions during hematopoiesis (PubMed:9462510). Seems to be involved in early and late stages of mammalian cardiovascular development. Inhibits myoblast differentiation (By similarity). Enhances fibroblast growth factor-induced angiogenesis (in vitro).SUBUNIT Interacts with NOTCH2 and NOTCH3 (By similarity). Interacts with NOTCH1 (in the presence of calcium ions) (PubMed:18660822).TISSUE SPECIFICITY Widely expressed in adult and fetal tissues. In cervix epithelium expressed in undifferentiated subcolumnar reserve cells and squamous metaplasia. Expression is up-regulated in cervical squamous cell carcinoma. Expressed in bone marrow cell line HS-27a which supports the long-term maintenance of immature progenitor cells.DEVELOPMENTAL STAGE Expressed in 32-52 days embryos in the distal cardiac outflow tract and pulmonary artery, major arteries, portal vein, optic vesicle, otocyst, branchial arches, metanephros, pancreas, mesocardium, around the major bronchial branches, and in the neural tube.DOMAIN The second EGF-like domain is atypical. UniProt P78504 34 EQUAL 1218 EQUAL Reactome DB_ID: 157027 1 NOTCH1 [plasma membrane] NOTCH1 NTM-NEC 1 heterodimer Reactome DB_ID: 157239 1 1665 EQUAL 2555 EQUAL Reactome DB_ID: 1983670 1 extracellular region GO 0005576 O-fucosyl-L-threonine at 73 73 EQUAL O-fucosyl-L-threonine O-fucosyl-L-threonine at 116 116 EQUAL O-fucosyl-L-threonine at 194 194 EQUAL O-fucosyl-L-threonine at 232 232 EQUAL O-fucosyl-L-threonine at 311 311 EQUAL O-fucosyl-L-threonine at 349 349 EQUAL O-fucosyl-L-threonine at 466 466 EQUAL O-fucosyl-L-threonine at 617 617 EQUAL O-fucosyl-L-threonine at 692 692 EQUAL O-fucosyl-L-threonine at 767 767 EQUAL O-fucosyl-L-threonine at 805 805 EQUAL O-fucosyl-L-serine at 883 883 EQUAL O-fucosyl-L-serine O-fucosyl-L-serine at 921 921 EQUAL O-fucosyl-L-threonine at 997 997 EQUAL O-fucosyl-L-threonine at 1035 1035 EQUAL O-fucosyl-L-threonine at 1159 1159 EQUAL O-fucosyl-L-threonine at 1197 1197 EQUAL O-fucosyl-L-threonine at 1243 1243 EQUAL O-fucosyl-L-threonine at 1321 1321 EQUAL O-fucosyl-L-threonine at 1362 1362 EQUAL O-fucosyl-L-threonine at 1402 1402 EQUAL O-glucosyl-L-serine at 65 65 EQUAL O-glucosyl-L-serine O-glucosyl-L-serine at 146 146 EQUAL O-glucosyl-L-serine at 378 378 EQUAL O-glucosyl-L-serine at 458 458 EQUAL O-glucosyl-L-serine at 496 496 EQUAL O-glucosyl-L-serine at 534 534 EQUAL O-glucosyl-L-serine at 609 609 EQUAL O-glucosyl-L-serine at 647 647 EQUAL O-glucosyl-L-serine at 722 722 EQUAL O-glucosyl-L-serine at 759 759 EQUAL O-glucosyl-L-serine at 797 797 EQUAL O-glucosyl-L-serine at 951 951 EQUAL O-glucosyl-L-serine at 1027 1027 EQUAL O-glucosyl-L-serine at 1065 1065 EQUAL O-glucosyl-L-serine at 1189 1189 EQUAL O-glucosyl-L-serine at 1273 1273 EQUAL 19 EQUAL 1664 EQUAL Reactome Database ID Release 81 157027 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157027 Reactome R-HSA-157027 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157027.1 Reactome DB_ID: 157008 1 JAG1:NOTCH1 [plasma membrane] JAG1:NOTCH1 Reactome DB_ID: 157098 1 34 EQUAL 1218 EQUAL Reactome DB_ID: 157027 1 Reactome Database ID Release 81 157008 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157008 Reactome R-HSA-157008 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157008.1 Reactome Database ID Release 81 1980042 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1980042 Reactome R-HSA-1980042 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1980042.1 9462510 Pubmed 1998 The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1 Li, L Milner, LA Deng, Y Iwata, M Banta, AB Graf, L Marcovina, S Friedman, C Trask, BJ Hood, L Torok-Storb, B Immunity 8:43-55 NOTCH1 binds JAG2 NOTCH1 binds JAG2 NOTCH1 is activated by JAG2 ligand expressed on a neighboring cell. When the mouse myoblast cell line C2C12 expressing exogenous human NOTCH1 is grown with NIH3T3 cells expressing exogenous human JAG2, myogenic differentiation is inhibited and a NOTCH1 polypeptide that corresponds to the NOTCH intracellular domain appears (Luo et al. 1997). Authored: Jassal, B, 2004-12-15 13:08:03 Reviewed: Joutel, A, 2004-12-15 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: D'Eustachio, P, 2012-02-06 Reactome DB_ID: 157120 1 UniProt:Q9Y219 JAG2 JAG2 JAG2 FUNCTION Putative Notch ligand involved in the mediation of Notch signaling. Involved in limb development (By similarity).TISSUE SPECIFICITY Expressed in heart, placenta and skeletal muscle and to a lesser extent in pancreas. Very low expression in brain, lung, liver and kidney. UniProt Q9Y219 24 EQUAL 1238 EQUAL Reactome DB_ID: 157027 1 Reactome DB_ID: 157140 1 JAG2:NOTCH1 [plasma membrane] JAG2:NOTCH1 NTM-NEC1-Jagged2 complex Reactome DB_ID: 157120 1 24 EQUAL 1238 EQUAL Reactome DB_ID: 157027 1 Reactome Database ID Release 81 157140 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157140 Reactome R-HSA-157140 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157140.1 Reactome Database ID Release 81 1980044 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1980044 Reactome R-HSA-1980044 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-1980044.2 11006133 Pubmed 2000 Physical interaction of Delta1, Jagged1, and Jagged2 with Notch1 and Notch3 receptors Shimizu, K Chiba, S Saito, T Kumano, K Hirai, H Biochem Biophys Res Commun 276:385-9 9315665 Pubmed 1997 Isolation and functional analysis of a cDNA for human Jagged2, a gene encoding a ligand for the Notch1 receptor Luo, B Aster, JC Hasserjian, RP Kuo, F Sklar, J Mol Cell Biol 17:6057-67 6.3.2.19 Ubiquitination of DLL/JAG ligands upon binding to NOTCH1 Ubiquitination of DLL/JAG ligands upon binding to NOTCH1 NOTCH ligands DLL1, DLL4, JAG1 and JAG2 undergo ubiquitination and endocytosis after binding NOTCH1 in trans. In Drosophila, ubiquitination of Delta and Serrate ligands is performed by either Mindbomb or Neuralized ubiquitin ligase. In mammals, there are two Mindbomb homologues, MIB1 and MIB2 and two Neuralized homologues, NEURL (also known as NEUR1) and NEURL1B (also known as NEUR2). Although both Mib1 and Mib2 ubiquitinate Delta (Koo et al. 2005), only Mib1 was shown to be essential for normal development in mice, with Mib1 deficient mice exhibiting typical Notch deficiency phenotypes (Koo et al. 2007). This could be due to different expression patterns of Mib1 and Mib2. While Mib1 is abundantly expressed in embryos and adult tissues, Mib2 expression is limited to adult tissues only (Koo et al. 2005). Mouse Neurl was directly shown to ubiquitinate Jag1 but not other Notch ligands in vitro. N-terminal myristoylation targets Neurl to the plasma membrane and this is a prerequisite for Jag1 internalization (Koutelou et al. 2008). Mouse Neurl1b was shown to directly bind and ubiquitinate recombinant Xenopus Delta and to cooperate with Mib1 in Delta endocytosis (Song et al. 2006). Ubiquitination of NOTCH ligands by MIB and NEURL ubiquitin ligases triggers ligand endocytosis. Drosophila Neuralized needs to interact with membrane phosphoinositides through its phosphoinositide-binding motif to trigger endocytosis of ubiquitinated Delta (Skwarek et al. 2007). Endocytosis of ubiquitinated Notch ligands is thought to mechanically stretch the ligand-bound Notch receptor, exposing the S2 cleavage site and resulting in Notch receptor cleavage by ADAM10 and/or ADAM17 metalloproteases (Itoh et al. 2003). 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 Reactome DB_ID: 157655 1 DLL/JAG:NOTCH1 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Converted from EntitySet in Reactome Reactome DB_ID: 113595 1 Ub [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity UBC(1-76) [cytosol] UBB(153-228) [cytosol] UBC(457-532) [cytosol] UBB(1-76) [cytosol] UBC(305-380) [cytosol] UBC(609-684) [cytosol] UBC(153-228) [cytosol] UBC(381-456) [cytosol] RPS27A(1-76) [cytosol] UBA52(1-76) [cytosol] UBC(77-152) [cytosol] UBC(533-608) [cytosol] UBB(77-152) [cytosol] UBC(229-304) [cytosol] UniProt P0CG48 UniProt P0CG47 UniProt P62979 UniProt P62987 Reactome DB_ID: 1911537 1 Ub-DLL/JAG:NOTCH1 [plasma membrane] Ub-DLL/JAG:NOTCH1 NOTCH1:Ub-DSL Converted from EntitySet in Reactome Reactome DB_ID: 157655 1 Converted from EntitySet in Reactome Reactome DB_ID: 113595 1 Reactome Database ID Release 81 1911537 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1911537 Reactome R-HSA-1911537 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1911537.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Converted from EntitySet in Reactome Reactome DB_ID: 1911464 MIB/NEURL [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity MIB1 [cytosol] UniProt Q86YT6 GO 0004842 GO molecular function Reactome Database ID Release 81 1980072 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1980072 Reactome Database ID Release 81 1980074 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1980074 Reactome R-HSA-1980074 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1980074.1 11740940 Pubmed 2001 Drosophila neuralized is a ubiquitin ligase that promotes the internalization and degradation of delta Lai, EC Deblandre, GA Kintner, C Rubin, GM Dev Cell 1:783-94 15760269 Pubmed 2005 Two distinct E3 ubiquitin ligases have complementary functions in the regulation of delta and serrate signaling in Drosophila Le Borgne, R Remaud, S Hamel, S Schweisguth, F PLoS Biol 3:e96 18077452 Pubmed 2008 Neuralized-like 1 (Neurl1) targeted to the plasma membrane by N-myristoylation regulates the Notch ligand Jagged1 Koutelou, E Sato, S Tomomori-Sato, C Florens, Laurence A Swanson, SK Washburn, MP Kokkinaki, M Conaway, Ron C Conaway, Joan W Moschonas, NK J Biol Chem 283:3846-53 16093323 Pubmed 2005 The interplay between DSL proteins and ubiquitin ligases in Notch signaling Pitsouli, C Delidakis, C Development 132:4041-50 12530964 Pubmed 2003 Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta Itoh, M Kim, CH Palardy, G Oda, T Jiang, YJ Maust, D Yeo, SY Lorick, K Wright, GJ Ariza-McNaughton, L Weissman, AM Lewis, J Chandrasekharappa, SC Chitnis, AB Dev Cell 4:67-82 18043734 Pubmed 2007 An obligatory role of mind bomb-1 in notch signaling of mammalian development Koo, BK Yoon, MJ Yoon, KJ Im, SK Kim, YY Kim, CH Suh, PG Jan, YN Kong, YY PLoS One 2:e1221 15829515 Pubmed 2005 The ubiquitin ligase Drosophila Mind bomb promotes Notch signaling by regulating the localization and activity of Serrate and Delta Lai, EC Roegiers, F Qin, X Jan, YN Rubin, GM Development 132:2319-32 17003037 Pubmed 2006 Neuralized-2 regulates a Notch ligand in cooperation with Mind bomb-1 Song, R Koo, BK Yoon, KJ Yoon, MJ Yoo, KW Kim, HT Oh, HJ Kim, YY Han, JK Kim, CH Kong, YY J Biol Chem 281:36391-400 15824097 Pubmed 2005 Mind bomb-2 is an E3 ligase for Notch ligand Koo, BK Yoon, KJ Yoo, KW Lim, HS Song, R So, JH Kim, CH Kong, YY J Biol Chem 280:22335-42 Complex of NOTCH1 with its ligand is cleaved to produce NEXT1 Complex of NOTCH1 with its ligand is cleaved to produce NEXT1 Ligand binding induces a conformational change in NOTCH1, probably through mechanical stretching of NOTCH1 triggered by endocytosis of the ligand attached to the receptor. This conformational change exposes the S2 site in the extracellular region of NOTCH1 and results in cleavage of NOTCH1 by ADAM10 metalloprotease, the mammalian homolog of Kuzbanian (Pan and Rubin, 1997), generating the membrane-anchored NOTCH1 fragment NEXT1.This model is supported by the crystal structure of human NOTCH2 negative regulatory region, showing that NOTCH adopts an autoinhibited conformation where extensive interdomain interactions within the negative regulatory region bury S2. A substantial conformational movement, triggered by ligand binding in trans, is needed to expose S2 (Gordon et al. 2007). After S2 cleavage, the extracellular NOTCH1 portion remains attached to the ligand presented on the plasma membrane of a neighboring cell. ADAM17 is able to perform cleavage at the S2 site in vitro (Brou et al. 2000), but ADAM10 was shown to be necessary in studies done on mouse cell lines deficient in different ADAM enzymes (van Tetering et al. 2009). Adam10 knockout mice die at embryonic day 9.5 with multiple defects in the developing central nervous system, somites and cardiovascular system and exhibit decreased expression of the Notch target Hes5 in the neural tube (Hartmann et al. 2002). Authored: Jassal, B, 2004-12-15 13:08:03 Reviewed: Joutel, A, 2004-12-15 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: D'Eustachio, P, 2012-02-06 Reactome DB_ID: 1911537 1 Reactome DB_ID: 1911540 1 Ub-DLL/JAG:NOTCH1 fragment [plasma membrane] Ub-DLL/JAG:NOTCH1 fragment NOTCH1 fragment:Ub-DSL Reactome DB_ID: 157658 1 NOTCH1 fragment:DLL/JAG [plasma membrane] NOTCH1 fragment:DLL/JAG NOTCH1 fragment:DSL Reactome DB_ID: 2193050 1 NOTCH1 fragment [plasma membrane] NOTCH1 fragment Reactome DB_ID: 157654 1 1665 EQUAL 1720 EQUAL Reactome DB_ID: 1983670 1 O-fucosyl-L-threonine at 73 73 EQUAL O-fucosyl-L-threonine at 116 116 EQUAL O-fucosyl-L-threonine at 194 194 EQUAL O-fucosyl-L-threonine at 232 232 EQUAL O-fucosyl-L-threonine at 311 311 EQUAL O-fucosyl-L-threonine at 349 349 EQUAL O-fucosyl-L-threonine at 466 466 EQUAL O-fucosyl-L-threonine at 617 617 EQUAL O-fucosyl-L-threonine at 692 692 EQUAL O-fucosyl-L-threonine at 767 767 EQUAL O-fucosyl-L-threonine at 805 805 EQUAL O-fucosyl-L-serine at 883 883 EQUAL O-fucosyl-L-serine at 921 921 EQUAL O-fucosyl-L-threonine at 997 997 EQUAL O-fucosyl-L-threonine at 1035 1035 EQUAL O-fucosyl-L-threonine at 1159 1159 EQUAL O-fucosyl-L-threonine at 1197 1197 EQUAL O-fucosyl-L-threonine at 1243 1243 EQUAL O-fucosyl-L-threonine at 1321 1321 EQUAL O-fucosyl-L-threonine at 1362 1362 EQUAL O-fucosyl-L-threonine at 1402 1402 EQUAL O-glucosyl-L-serine at 65 65 EQUAL O-glucosyl-L-serine at 146 146 EQUAL O-glucosyl-L-serine at 378 378 EQUAL O-glucosyl-L-serine at 458 458 EQUAL O-glucosyl-L-serine at 496 496 EQUAL O-glucosyl-L-serine at 534 534 EQUAL O-glucosyl-L-serine at 609 609 EQUAL O-glucosyl-L-serine at 647 647 EQUAL O-glucosyl-L-serine at 722 722 EQUAL O-glucosyl-L-serine at 759 759 EQUAL O-glucosyl-L-serine at 797 797 EQUAL O-glucosyl-L-serine at 951 951 EQUAL O-glucosyl-L-serine at 1027 1027 EQUAL O-glucosyl-L-serine at 1065 1065 EQUAL O-glucosyl-L-serine at 1189 1189 EQUAL O-glucosyl-L-serine at 1273 1273 EQUAL 19 EQUAL 1664 EQUAL Reactome Database ID Release 81 2193050 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2193050 Reactome R-HSA-2193050 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-2193050.1 Converted from EntitySet in Reactome Reactome DB_ID: 157643 1 DLL/JAG [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity DLL4 [plasma membrane] JAG2 [plasma membrane] DLL1 [plasma membrane] JAG1 [plasma membrane] Reactome Database ID Release 81 157658 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157658 Reactome R-HSA-157658 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157658.1 Converted from EntitySet in Reactome Reactome DB_ID: 113595 1 Reactome Database ID Release 81 1911540 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1911540 Reactome R-HSA-1911540 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1911540.1 Reactome DB_ID: 157200 1 1721 EQUAL 2555 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 1852620 ADAM10/17:Zn2+ [plasma membrane] ADAM10/17:Zn2+ Converted from EntitySet in Reactome Reactome DB_ID: 1852617 1 ADAM10/17 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity ADAM10 [plasma membrane] UniProt O14672 Reactome DB_ID: 109265 1 zinc(2+) [ChEBI:29105] zinc(2+) ChEBI 29105 Reactome Database ID Release 81 1852620 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1852620 Reactome R-HSA-1852620 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1852620.1 GO 0008237 GO molecular function Reactome Database ID Release 81 1852619 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1852619 Reactome Database ID Release 81 157632 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157632 Reactome R-HSA-157632 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157632.1 10882063 Pubmed 2000 A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE Brou, C Logeat, F Gupta, N Bessia, C LeBail, O Doedens, JR Cumano, A Roux, P Black, RA Israel, A Mol Cell 5:207-16 9244301 Pubmed 1997 Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis Pan, D Rubin, GM Cell 90:271-80 19726682 Pubmed 2009 Metalloprotease ADAM10 is required for Notch1 site 2 cleavage van Tetering, G van Diest, P Verlaan, I van der Wall, E Kopan, R Vooijs, M J Biol Chem 284:31018-27 12354787 Pubmed 2002 The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts Hartmann, D De Strooper, B Serneels, L Craessaerts, K Herreman, A Annaert, W Umans, L Lübke, T Lena Illert, A von Figura, K Saftig, P Hum Mol Genet 11:2615-24 17401372 Pubmed 2007 Structural basis for autoinhibition of Notch Gordon, WR Vardar-Ulu, D Histen, G Sanchez-Irizarry, C Aster, JC Blacklow, SC Nat Struct Mol Biol 14:295-300 3.4.23.32 3.4.23.43 3.4.23.20 3.4.23.25 3.4.23.36 3.4.23.35 3.4.23.34 3.4.23.4 3.4.23.5 3.4.23.1 3.4.23.15 NEXT1 is cleaved to produce NICD1 NEXT1 is cleaved to produce NICD1 NEXT1 fragment of NOTCH1 is further cleaved at S3 by the presenilin-1 (PSEN1) containing gamma-secretase complex, which releases the intracellular domain NICD1 into the cytosol (Schroeter et al. 1998, De Strooper et al. 1999, Huppert et al. 2000, Fortini et al. 2002). PIN1, a prolyl isomerase, was recently found to bind phosphorylated Ser/Thr-Pro motifs in the cytoplasmic domain of NOTCH1 and potentiate NEXT1 cleavage by gamma-secretase. This generates a positive loop in NOTCH1 signaling since PIN1 is a transcriptional target of NICD1 (Rustighi et al. 2009). Authored: Jassal, B, 2004-12-15 13:08:03 Reviewed: Joutel, A, 2004-12-15 Reviewed: Haw, R, 2012-02-06 Edited: Orlic-Milacic, M, 2012-02-10 Edited: D'Eustachio, P, 2012-02-06 Reactome DB_ID: 157200 1 1721 EQUAL 2555 EQUAL Reactome DB_ID: 157634 1 1754 EQUAL 2555 EQUAL Reactome DB_ID: 157656 1 1721 EQUAL 1753 EQUAL PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 157343 gamma-secretase complex [plasma membrane] gamma-secretase complex Reactome DB_ID: 2534241 1 UniProt:Q92542 NCSTN NCSTN NCSTN KIAA0253 UNQ1874/PRO4317 FUNCTION Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:10993067, PubMed:12679784, PubMed:25043039, PubMed:26280335, PubMed:30598546, PubMed:30630874). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels.SUBUNIT Component of the gamma-secretase complex (PubMed:10993067, PubMed:30598546, PubMed:30630874). The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PSENEN/PEN2 (PubMed:12740439, PubMed:25043039, PubMed:26623517, PubMed:26280335, PubMed:25918421, PubMed:30598546, PubMed:30630874). Binds to proteolytic processed C-terminal fragments C83 and C99 of the amyloid precursor protein (APP) (PubMed:10993067, PubMed:30630874). Interacts with PSEN1 and PSEN2 (PubMed:10993067).TISSUE SPECIFICITY Detected in brain (at protein level) (PubMed:10993067). Widely expressed (PubMed:11396676).INDUCTION Constitutively expressed in neural cells.PTM N-glycosylated.SIMILARITY Belongs to the nicastrin family. UniProt Q92542 34 EQUAL 709 EQUAL Reactome DB_ID: 157331 1 UniProt:Q9NZ42 PSENEN PSENEN PSENEN PEN2 MDS033 FUNCTION Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:12522139, PubMed:12763021, PubMed:12740439, PubMed:12679784, PubMed:24941111, PubMed:30598546, PubMed:30630874). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (Probable). PSENEN modulates both endoproteolysis of presenilin and gamma-secretase activity (PubMed:12522139, PubMed:12763021, PubMed:12740439, PubMed:12679784, PubMed:24941111).SUBUNIT The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PSENEN.TISSUE SPECIFICITY Widely expressed. Expressed in leukocytes, lung, placenta, small intestine, liver, kidney, spleen thymus, skeletal muscle, heart and brain.SIMILARITY Belongs to the PEN-2 family.CAUTION The high-resolution electron microscopy structures indicate that the N-terminus is cytoplasmic, followed by two short helices that dip into the membrane, but do not cross it (PubMed:26280335). In contrast, results based on mutagenesis to create N-glycosylation sites indicate that the N-terminus is lumenal (PubMed:12639958, PubMed:30598546, PubMed:30630874). Both studies indicate that the C-terminus is lumenal (PubMed:12639958, PubMed:26280335). UniProt Q9NZ42 1 EQUAL 101 EQUAL Converted from EntitySet in Reactome Reactome DB_ID: 157341 1 APH-1 [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity APH1A [plasma membrane] APH1B [plasma membrane] UniProt Q96BI3 UniProt Q8WW43 Converted from EntitySet in Reactome Reactome DB_ID: 9013333 1 Presenilin [plasma membrane] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity Reactome Database ID Release 81 157343 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157343 Reactome R-HSA-157343 2 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157343.2 GO 0004190 GO molecular function Reactome Database ID Release 81 157355 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157355 Reactome Database ID Release 81 157353 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157353 Reactome R-HSA-157353 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157353.1 12209127 Pubmed 2002 Gamma-secretase-mediated proteolysis in cell-surface-receptor signalling Fortini, ME Nat Rev Mol Cell Biol 3:673-84 19151708 Pubmed 2009 The prolyl-isomerase Pin1 is a Notch1 target that enhances Notch1 activation in cancer Rustighi, A Tiberi, L Soldano, A Napoli, M Nuciforo, P Rosato, A Kaplan, F Capobianco, A Pece, S Di Fiore, PP Del Sal, G Nat Cell Biol 11:133-42 10206645 Pubmed 1999 A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain De Strooper, B Annaert, W Cupers, P Saftig, P Craessaerts, K Mumm, JS Schroeter, EH Schrijvers, V Wolfe, MS Ray, WJ Goate, A Kopan, R Nature 398:518-22 9620803 Pubmed 1998 Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain Schroeter, EH Kisslinger, JA Kopan, R Nature 393:382-6 10879540 Pubmed 2000 Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1 Huppert, SS Le, A Schroeter, EH Mumm, JS Saxena, MT Milner, LA Kopan, R Nature 405:966-70 NICD1 traffics to nucleus NICD1 traffics to nucleus Cytosolic NICD1 translocates to the nucleus. Authored: Ferrer, J, Tello-Ruiz, MK, 2008-05-23 Reviewed: Jensen, J, 2008-05-12 21:46:53 Edited: D'Eustachio, P, 2008-05-12 21:43:33 Reactome DB_ID: 157634 1 1754 EQUAL 2555 EQUAL Reactome DB_ID: 157939 1 1754 EQUAL 2555 EQUAL Reactome Database ID Release 81 157926 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=157926 Reactome R-HSA-157926 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-157926.1 9604939 Pubmed 1998 Nuclear access and action of notch in vivo Struhl, G Adachi, A Cell 93:649-60 9651681 Pubmed 1998 Indirect evidence for Delta-dependent intracellular processing of notch in Drosophila embryos Lecourtois, M Schweisguth, F Curr Biol 8:771-4 DTX binds NOTCH1 DTX binds NOTCH1 Deltex (DTX) protein family in mammals includes four proteins: DTX1, DTX2, DTX3 and DTX4. Human DTX1 interacts with cdc10/ankyrin repeats of the intracellular domain of NOTCH1 and NOTCH2, similar to the interaction of Drosophila deltex and notch proteins (Matsuno et al. 1998). Studies on mouse deltex proteins showed that the N-terminal region of Dtx1, homologous to the Drosophila deltex domain I, is necessary and sufficient to bind the ankyrin repeats of Notch. Besides Dtx1, this Notch-interacting region is conserved in Dtx2 and Dtx4. Dtx3 lacks most of the N-terminal sequence homologous to Drosophila deltex domain I and cannot bind ankyrin repeats of mouse Notch1, while Dtx1, Dtx2 and Dtx4 bind to it strongly. Dtx3 also has a different class of RING finger domain than the other three deltex proteins (Kishi et al. 2001). While deltex colocalizes with Notch at the plasma membrane and in the cytosol, there is no colocalization between NICD and deltex in the nucleus, suggesting that DTX does not mediate NOTCH signaling by direct interaction with nuclear NICD (Matsuno et al. 1998). Recent studies in Drosophila indicate that Deltex, acting as an E3 ubiquitin ligase, may activate ligand independent Notch proteolysis and signaling by shunting Notch into an endocytic pathway that involves HOPS and AP-3 complexes (Wiklin 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 Converted from EntitySet in Reactome Reactome DB_ID: 1604454 1 DTX [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity DTX1 [cytosol] UniProt Q86Y01 Reactome DB_ID: 157027 1 Reactome DB_ID: 1852570 1 NOTCH1:DTX [plasma membrane] NOTCH1:DTX Converted from EntitySet in Reactome Reactome DB_ID: 1604454 1 Reactome DB_ID: 157027 1 Reactome Database ID Release 81 1852570 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1852570 Reactome R-HSA-1852570 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1852570.1 Reactome Database ID Release 81 1980122 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1980122 Reactome R-HSA-1980122 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1980122.1 19000840 Pubmed 2008 Drosophila HOPS and AP-3 complex genes are required for a Deltex-regulated activation of notch in the endosomal trafficking pathway Wilkin, M Tongngok, P Gensch, N Clemence, S Motoki, M Yamada, K Hori, K Taniguchi-Kanai, M Franklin, E Matsuno, K Baron, M Dev Cell 15:762-72 11226752 Pubmed 2001 Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis Kishi, N Tang, Z Maeda, Y Hirai, A Mo, R Ito, M Suzuki, S Nakao, K Kinoshita, T Kadesch, T Hui, C Artavanis-Tsakonas, S Okano, H Matsuno, K Int J Dev Neurosci 19:21-35 9590294 Pubmed 1998 Human deltex is a conserved regulator of Notch signalling Matsuno, K Eastman, D Mitsiades, T Quinn, AM Carcanciu, ML Ordentlich, P Kadesch, T Artavanis-Tsakonas, S Nat Genet 19:74-8 Contactin-1 (CNTN1) binds NOTCH1 Contactin-1 (CNTN1) binds NOTCH1 Contactin-1 (CNTN1) is composed of six Ig domains followed by four FNIII repeats and is anchored to the membrane via a glycosyl-phosphatidylinositol (GPI) tail. It is expressed transiently during CNS and PNS development both as GPI-anchored and soluble forms. CNTN1 is a physiological ligand of NOTCH, shown to bind and activate NOTCH1 and NOTCH2 in trans. The activation of NOTCH signaling by CNTN1 is Deltex (DTX)-dependent and promotes oligodendrocyte maturation and myelination. 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 Reactome DB_ID: 373622 1 UniProt:Q12860 CNTN1 CNTN1 CNTN1 FUNCTION Contactins mediate cell surface interactions during nervous system development. Involved in the formation of paranodal axo-glial junctions in myelinated peripheral nerves and in the signaling between axons and myelinating glial cells via its association with CNTNAP1. Participates in oligodendrocytes generation by acting as a ligand of NOTCH1. Its association with NOTCH1 promotes NOTCH1 activation through the released notch intracellular domain (NICD) and subsequent translocation to the nucleus. Interaction with TNR induces a repulsion of neurons and an inhibition of neurite outgrowth (By similarity).SUBUNIT Monomer (PubMed:2026173). Interacts with CNTNAP1 in cis form (By similarity). Binds to the carbonic-anhydrase like domain of PTPRZ1 (PubMed:20133774). Interacts with NOTCH1 and TNR. Detected in a complex with NRCAM and PTPRB (By similarity). Interacts with TASOR (By similarity).TISSUE SPECIFICITY Strongly expressed in brain and in neuroblastoma and retinoblastoma cell lines. Lower levels of expression in lung, pancreas, kidney and skeletal muscle.SIMILARITY Belongs to the immunoglobulin superfamily. Contactin family. UniProt Q12860 21 EQUAL 993 EQUAL Reactome DB_ID: 1852570 1 Reactome DB_ID: 373658 1 CNTN1:NOTCH1:DTX [plasma membrane] CNTN1:NOTCH1:DTX Contactin-1:Notch1 complex Reactome DB_ID: 373622 1 21 EQUAL 993 EQUAL Reactome DB_ID: 1852570 1 Reactome Database ID Release 81 373658 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=373658 Reactome R-HSA-373658 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-373658.1 Reactome Database ID Release 81 373706 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=373706 Reactome R-HSA-373706 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-373706.1 14567914 Pubmed 2003 F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation Hu, QD Ang, BT Karsak, M Hu, WP Cui, XY Duka, T Takeda, Y Chia, W Sankar, N Ng, YK Ling, EA Maciag, T Small, D Trifonova, R Kopan, R Okano, H Nakafuku, M Chiba, S Hirai, H Aster, JC Schachner, M Pallen, CJ Watanabe, K Xiao, ZC Cell 115:163-75 Cleavage of CNTN1:NOTCH1 complex releases NICD1 Cleavage of CNTN1:NOTCH1 complex releases NICD1 Binding of NOTCH1 to CNTN1 (contactin-1) is followed by gamma-secretase mediated cleavage of NOTCH1 at the S3 cleavage site and accumulation of NICD1 in the nucleus. Cleavage of NOTCH1 by ADAM10/17 at the S2 cleavage site, which should precede the S3 cleavage by gamma-secretase, has not been studied in the context of NOTCH1 activation by CNTN1. NOTCH activation by CNTN1 is deltex-dependent, but the exact mechanism for action of the NOTCH:DTX complex has not yet been elucidated. 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 Reactome DB_ID: 373658 1 Reactome DB_ID: 1911468 1 NICD1:DTX [cytosol] NICD1:DTX Converted from EntitySet in Reactome Reactome DB_ID: 1604454 1 Reactome DB_ID: 157634 1 1754 EQUAL 2555 EQUAL Reactome Database ID Release 81 1911468 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1911468 Reactome R-HSA-1911468 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1911468.1 Reactome Database ID Release 81 1980109 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1980109 Reactome R-HSA-1980109 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-1980109.3 ACTIVATION Reactome Database ID Release 81 1980110 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1980110 Reactome R-HSA-1980110 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1980110.1 Reactome DB_ID: 157343 NOTCH1 binds DNER NOTCH1 binds DNER DNER is a transmembrane protein specifically expressed in dendrites and cell bodies of postmitotic neurons. DNER has ten extracellular EGF repeats highly homologous to EGF repeats of Notch and Delta proteins, but does not contain a typical DSL domain. DNER binds NOTCH1 and this interaction involves the first and second EGF repeat of DNER. Activation of NOTCH1 signaling by DNER requires the presence of deltex (DTX1, DTX2 and/or DTX4). The interaction of DNER and NOTCH may be playing an important role in the development of the central nervous system by influencing the differentiation of astrocytes, based on mouse studies. 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 Reactome DB_ID: 1604557 1 UniProt:Q8NFT8 DNER DNER BET DNER UNQ262/PRO299 FUNCTION Activator of the NOTCH1 pathway. May mediate neuron-glia interaction during astrocytogenesis (By similarity).SUBUNIT Interacts with AP1G1. Interacts with NOTCH1 (By similarity).TISSUE SPECIFICITY Expressed in brain, spinal cord and adrenal gland. UniProt Q8NFT8 35 EQUAL 737 EQUAL Reactome DB_ID: 1852570 1 Reactome DB_ID: 1911551 1 DNER:NOTCH1:DTX [plasma membrane] DNER:NOTCH1:DTX Reactome DB_ID: 1604557 1 35 EQUAL 737 EQUAL Reactome DB_ID: 1852570 1 Reactome Database ID Release 81 1911551 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1911551 Reactome R-HSA-1911551 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1911551.1 Reactome Database ID Release 81 1912398 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1912398 Reactome R-HSA-1912398 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1912398.1 15965470 Pubmed 2005 DNER acts as a neuron-specific Notch ligand during Bergmann glial development Eiraku, M Tohgo, A Ono, K Kaneko, M Fujishima, K Hirano, T Kengaku, M Nat Neurosci 8:873-80 Cleavage of DNER:NOTCH1 complex releases NICD1 Cleavage of DNER:NOTCH1 complex releases NICD1 Binding of DNER to NOTCH1 induces gamma-secretase dependent cleavage of NOTCH1 at the S3 cleavage site and releases NOTCH1 intracellular domain into the cytosol. Cleavage of NOTCH1 at the S2 cleavage site by ADAM10/17, which should precede cleavage at the S3 site, has not been studied in the context of DNER-mediated NOTCH1 activation. 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 Reactome DB_ID: 1911551 1 Reactome DB_ID: 1911468 1 Reactome Database ID Release 81 1980112 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1980112 Reactome R-HSA-1980112 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-1980112.3 ACTIVATION Reactome Database ID Release 81 1980114 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1980114 Reactome R-HSA-1980114 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1980114.1 Reactome DB_ID: 157343 DTX recruits beta-arrestin (ARRB) to NOTCH DTX recruits beta-arrestin (ARRB) to NOTCH Formation of a complex involving NOTCH, Deltex (DTX) and non-visual beta-arrestin (ARRB) has not been directly studied in mammalian cells. The mammalian non-visual beta-arrestins ARRB1 and ARRB2 play a major role in desensitization and endocytosis of G-protein-coupled receptors (GPCRs), and their interaction with GPCRs involves N-terminal beta-arrestin sequences that are homologous to the Deltex-binding N-terminus of Drosophila Kurtz (Mukherjee et al. 2005). Shrub, a core component of the ESCRT-III complex, was recently identified as an important modulator of non-visual beta-arrestin-mediated downregulation of Notch in Drosophila (Hori et al. 2011). 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 Reactome DB_ID: 1911410 1 ARRB [cytosol] Converted from EntitySet in Reactome. Each synonym is a name of a PhysicalEntity, and each XREF points to one PhysicalEntity ARRB1 [cytosol] ARRB2 [cytosol] UniProt P49407 UniProt P32121 Reactome DB_ID: 1852570 1 Reactome DB_ID: 1911487 1 NOTCH1:DTX:ARRB [plasma membrane] NOTCH1:DTX:ARRB Converted from EntitySet in Reactome Reactome DB_ID: 1911410 1 Reactome DB_ID: 1852570 1 Reactome Database ID Release 81 1911487 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1911487 Reactome R-HSA-1911487 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1911487.1 Reactome Database ID Release 81 1980123 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1980123 Reactome R-HSA-1980123 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1980123.1 16284625 Pubmed 2005 Regulation of Notch signalling by non-visual beta-arrestin Mukherjee, A Veraksa, A Bauer, A Rosse, C Camonis, J Artavanis-Tsakonas, S Nat Cell Biol 7:1191-201 22162134 Pubmed 2011 Synergy between the ESCRT-III complex and Deltex defines a ligand-independent Notch signal Hori, K Sen, A Kirchhausen, T Artavanis-Tsakonas, S J Cell Biol 195:1005-15 6.3.2.19 ARRB mediates NOTCH1 ubiquitination ARRB mediates NOTCH1 ubiquitination Ubiquitination of NOTCH1 mediated by DTX-recruited beta-arrestins (ARRB) has not been directly studied in mammals. Non-visual beta arrestins ARRB1 and ARRB2 are known to facilitate ubiquitination and downregulation of GPCRs and IGF1R. 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 Reactome DB_ID: 113595 1 Reactome DB_ID: 1911487 1 Reactome DB_ID: 1911542 1 Ub-NOTCH1:DTX:ARRB [plasma membrane] Ub-NOTCH1:DTX:ARRB Converted from EntitySet in Reactome Reactome DB_ID: 113595 1 Reactome DB_ID: 1911487 1 Reactome Database ID Release 81 1911542 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1911542 Reactome R-HSA-1911542 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1911542.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 69593 Ubiquitin ligase [cytosol] Ubiquitin ligase Reactome Database ID Release 81 69594 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=69594 Reactome Database ID Release 81 1980118 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1980118 Reactome R-HSA-1980118 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1980118.1 ITCH binds DTX ITCH binds DTX Genetic studies in Drosophila identified deltex as a positive regulator of Notch signaling, while the Drosophila homologue of ITCH (AIP4) was identified as a negative regulator of Notch signaling and named suppressor of deltex. ITCH and DTX1 interact and form a complex, as determined by co-immunoprecipitaion experiments in human embryonic kidney cell line HEK293 in which tagged recombinant human DTX1 and ITCH were expressed. It is not known whether this complex involves other proteins, but its formation is NOTCH-independent. Both DTX1 and ITCH are ubiquitin ligases. DTX1 is a RING-type ubiquitin ligase, while ITCH is a HECT-type ubiquitin ligase. The ubiquitin ligase activity of either protein is not needed for the formation of the DTX1:ITCH complex, and the inactive ITCH mutant co-immunoprecipitates more DTX1 than the wild-type ITCH, implicating the ubiquitin ligase activity of ITCH in DTX1 degradation. 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 Reactome DB_ID: 1604454 1 Reactome DB_ID: 975995 1 UniProt:Q96J02 ITCH ITCH ITCH FUNCTION Acts as an E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates (PubMed:14602072, PubMed:17028573, PubMed:16387660, PubMed:18718448, PubMed:18718449, PubMed:11046148, PubMed:19592251, PubMed:19116316, PubMed:19881509, PubMed:20491914, PubMed:20392206, PubMed:20068034, PubMed:23146885, PubMed:24790097, PubMed:25631046). Catalyzes 'Lys-29'-, 'Lys-48'- and 'Lys-63'-linked ubiquitin conjugation (PubMed:17028573, PubMed:18718448, PubMed:19131965, PubMed:19881509). Involved in the control of inflammatory signaling pathways (PubMed:19131965). Essential component of a ubiquitin-editing protein complex, comprising also TNFAIP3, TAX1BP1 and RNF11, that ensures the transient nature of inflammatory signaling pathways (PubMed:19131965). Promotes the association of the complex after TNF stimulation (PubMed:19131965). Once the complex is formed, TNFAIP3 deubiquitinates 'Lys-63' polyubiquitin chains on RIPK1 and catalyzes the formation of 'Lys-48'-polyubiquitin chains (PubMed:19131965). This leads to RIPK1 proteasomal degradation and consequently termination of the TNF- or LPS-mediated activation of NFKB1 (PubMed:19131965). Ubiquitinates RIPK2 by 'Lys-63'-linked conjugation and influences NOD2-dependent signal transduction pathways (PubMed:19592251). Regulates the transcriptional activity of several transcription factors, and probably plays an important role in the regulation of immune response (PubMed:18718448, PubMed:20491914). Ubiquitinates NFE2 by 'Lys-63' linkages and is implicated in the control of the development of hematopoietic lineages (PubMed:18718448). Mediates JUN ubiquitination and degradation (By similarity). Mediates JUNB ubiquitination and degradation (PubMed:16387660). Critical regulator of type 2 helper T (Th2) cell cytokine production by inducing JUNB ubiquitination and degradation (By similarity). Involved in the negative regulation of MAVS-dependent cellular antiviral responses (PubMed:19881509). Ubiquitinates MAVS through 'Lys-48'-linked conjugation resulting in MAVS proteasomal degradation (PubMed:19881509). Following ligand stimulation, regulates sorting of Wnt receptor FZD4 to the degradative endocytic pathway probably by modulating PI42KA activity (PubMed:23146885). Ubiquitinates PI4K2A and negatively regulates its catalytic activity (PubMed:23146885). Ubiquitinates chemokine receptor CXCR4 and regulates sorting of CXCR4 to the degradative endocytic pathway following ligand stimulation by ubiquitinating endosomal sorting complex required for transport ESCRT-0 components HGS and STAM (PubMed:14602072, PubMed:23146885). Targets DTX1 for lysosomal degradation and controls NOTCH1 degradation, in the absence of ligand, through 'Lys-29'-linked polyubiquitination (PubMed:17028573, PubMed:18628966, PubMed:23886940). Ubiquitinates SNX9 (PubMed:20491914). Ubiquitinates MAP3K7 through 'Lys-48'-linked conjugation (By similarity). Involved in the regulation of apoptosis and reactive oxygen species levels through the ubiquitination and proteasomal degradation of TXNIP (PubMed:20068034). Mediates the antiapoptotic activity of epidermal growth factor through the ubiquitination and proteasomal degradation of p15 BID (PubMed:20392206). Ubiquitinates BRAT1 and this ubiquitination is enhanced in the presence of NDFIP1 (PubMed:25631046). Inhibits the replication of influenza A virus (IAV) via ubiquitination of IAV matrix protein 1 (M1) through 'Lys-48'-linked conjugation resulting in M1 proteasomal degradation (PubMed:30328013).ACTIVITY REGULATION Activated by NDFIP1- and NDFIP2-binding (PubMed:25631046). Activated by PI4K2A-binding (PubMed:23146885). Inhibited by DTX3L-binding (PubMed:24790097). Inhibited by N4BP1 binding (By similarity).PATHWAY Protein modification; protein ubiquitination.SUBUNIT Monomer. Interacts (via WW domains) with OCNL (By similarity). Interacts (via WW domains) with NOTCH1 (By similarity). Interacts (via WW domains) with JUN (By similarity). Interacts with JUNB; the interaction promotes ITCH-mediated ubiquitination and degradation of JUNB (PubMed:16387660). Interacts with FYN; the interaction phosphorylates ITCH on Tyr-420 decreasing binding of JUNB (PubMed:16387660). Interacts (via WW domain 2) with N4BP1; the interaction inhibits the E3 ubiquitin-protein ligase activity (By similarity). Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase and may induce its recruitment to exosomes (By similarity). Interacts with ARHGEF7 (PubMed:17652093). Interacts with RNF11 (PubMed:14559117, PubMed:19131965). Interacts (via the WW 1 domain) with NFE2 (via the PXY motif 1); the interaction promotes 'Lys-63'-linked ubiquitination of NFE2, retains it in the cytoplasm and prevents its transactivation activity (PubMed:11318614, PubMed:18718448). Interacts (via WW domains) with CXCR4 (via C-terminus); the interaction depends on CXCR4 phosphorylation (PubMed:19116316). Found in a complex with E3 ligase DTX3L and ESCRT-0 components HGS and STAM (PubMed:24790097). Interacts with DTX3L (via C-terminus); the interaction is increased upon CXCL12 stimulation and inhibits ITCH catalytic activity (the interaction is direct) (PubMed:24790097). Interacts with HGS (PubMed:14602072). Interacts (via WW domains) with PCBP2 within a complex containing ITCH, MAVS and PCBP2 (PubMed:19881509). Interacts (via WW domains) with TXNIP (via C-terminus) (PubMed:20068034). Interacts with p15 BID (PubMed:20392206). Interacts with ERBB4 (PubMed:20858735). Interacts with DTX1 (PubMed:17028573). Interacts with SPART (PubMed:19580544). Interacts with SNX9 and SNX18 (PubMed:20491914). Interacts (via its WW domains) with ATN1 (PubMed:9647693). Interacts (via WW domains) with SGK3 (PubMed:16888620). Interacts with CBLC (PubMed:12226085). Interacts with OTUD7B (PubMed:22179831). Interacts (via WW domain 1,2 and 3) with PI4K2A; the interaction inhibits PI4K2A catalytic activity and promotes ITCH catalytic activity (PubMed:23146885). Interacts with ARRDC4 (PubMed:23236378). Part of a complex containing ITCH, NDFIP1 and MAP3K7 (By similarity). Interacts with UBE2L3; the interaction is mediated by NDFIP1 (PubMed:25632008). Interacts with MAPK8/JNK1 (By similarity). Interacts (via WW domains) with ARRDC1 (via PPxY motifs); the interaction is direct and participates in the recruitment of the ubiquitin-protein ligase ITCH to the NOTCH1 receptor (PubMed:21191027, PubMed:23886940). Interacts (via WW domains) with ARRDC2 (PubMed:21191027). Interacts (via WW domains) with ARRDC3 (PubMed:21191027, PubMed:23886940). Interacts directly with LDLRAD3; this interaction promotes ITCH auto-ubiquitination leading to its degradation (PubMed:26854353).SUBUNIT (Microbial infection) Interacts with Epstein-Barr virus LMP2A.SUBUNIT (Microbial infection) Interacts with Human cytomegalovirus (HCMV) protein UL42; this interaction induces ubiquitination and degradation of ITCH.SUBUNIT (Microbial infection) Interacts with herpesvirus 1 (HHV-1) UL56 protein; this interaction induces ubiquitination and probably degradation of ITCH.SUBUNIT (Microbial infection) Interacts with herpesvirus 2 (HHV-2) UL56 protein.SUBUNIT (Microbial infection) Interacts with varicella-zoster virus (VZV) Orf0 protein.SUBUNIT (Microbial infection) Interacts with herpesvirus 6A (HHV-6A) U24 protein.SUBUNIT (Microbial infection) Interacts with ebola virus protein VP40; this interaction is required for efficient viral egress from the infected cell.SUBUNIT (Microbial infection) Interacts with influenza A virus matrix protein 1.TISSUE SPECIFICITY Widely expressed.DOMAIN The WW domains mediate interaction with PPxY motif-containing proteins.PTM On T-cell activation, phosphorylation by the JNK cascade on serine and threonine residues surrounding the PRR domain accelerates the ubiquitination and degradation of JUN and JUNB. The increased ITCH catalytic activity due to phosphorylation by JNK1 may occur due to a conformational change disrupting the interaction between the PRR/WW motifs domain and the HECT domain and, thus exposing the HECT domain (By similarity). Phosphorylation by FYN reduces interaction with JUNB and negatively controls JUN ubiquitination and degradation.PTM Monoubiquitinated (PubMed:19116316). Autopolyubiquitinated with 'Lys-63' linkages which does not lead to protein degradation (PubMed:18718449, PubMed:23146885, PubMed:24790097). UniProt Q96J02 1 EQUAL 903 EQUAL Reactome DB_ID: 1604453 1 DTX:ITCH [cytosol] DTX:ITCH Converted from EntitySet in Reactome Reactome DB_ID: 1604454 1 Reactome DB_ID: 975995 1 1 EQUAL 903 EQUAL Reactome Database ID Release 81 1604453 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1604453 Reactome R-HSA-1604453 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1604453.1 Reactome Database ID Release 81 1980125 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1980125 Reactome R-HSA-1980125 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1980125.1 17028573 Pubmed 2006 Itch/AIP4 mediates Deltex degradation through the formation of K29-linked polyubiquitin chains Chastagner, P Israel, A Brou, C EMBO Rep 7:1147-53 6.3.2.19 ITCH ubiquitinates DTX ITCH ubiquitinates DTX ITCH ubiquitinates DTX, targeting it for degradation. 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 Reactome DB_ID: 1604453 1 Converted from EntitySet in Reactome Reactome DB_ID: 113595 1 Reactome DB_ID: 1911536 1 Ub-DTX:ITCH [cytosol] Ub-DTX:ITCH Converted from EntitySet in Reactome Reactome DB_ID: 1604454 1 Converted from EntitySet in Reactome Reactome DB_ID: 113595 1 Reactome DB_ID: 975995 1 1 EQUAL 903 EQUAL Reactome Database ID Release 81 1911536 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1911536 Reactome R-HSA-1911536 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1911536.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 1604453 Reactome Database ID Release 81 1604455 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1604455 Reactome Database ID Release 81 1912357 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1912357 Reactome R-HSA-1912357 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-1912357.2 NOTCH1 binds DLL/JAG ligand in cis NOTCH1 binds DLL/JAG ligand in cis Binding of NOTCH1 to DLL/JAG ligands expressed in the same cells (in cis) blocks NOTCH1 activation by DLL/JAG ligands expressed on neighboring cells (in trans). Cis-inhibiton of NOTCH signaling can amplify small differences in NOTCH and DLL/JAG levels between neighboring cells. 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 Reactome DB_ID: 157027 1 Converted from EntitySet in Reactome Reactome DB_ID: 157643 1 Reactome DB_ID: 1980055 1 NOTCH1:DLL/JAG [plasma membrane] NOTCH1:DLL/JAG Reactome DB_ID: 157027 1 Converted from EntitySet in Reactome Reactome DB_ID: 157643 1 Reactome Database ID Release 81 1980055 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1980055 Reactome R-HSA-1980055 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1980055.1 Reactome Database ID Release 81 1980138 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1980138 Reactome R-HSA-1980138 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1980138.1 20418862 Pubmed 2010 Cis-interactions between Notch and Delta generate mutually exclusive signalling states Sprinzak, D Lakhanpal, A LeBon, L Santat, LA Fontes, ME Anderson, GA Garcia-Ojalvo, J Elowitz, MB Nature 465:86-90 18660822 Pubmed 2008 A conserved face of the Jagged/Serrate DSL domain is involved in Notch trans-activation and cis-inhibition Cordle, J Johnson, S Tay, JZ Roversi, P Wilkin, MB Hernandez de Madrid Diaz, B Shimizu, H Jensen, S Whiteman, P Jin, B Redfield, C Baron, M Lea, SM Handford, Penny A Nat Struct Mol Biol 15:849-57 NOTCH1 binds DLK1 NOTCH1 binds DLK1 DLK1 is a Delta-like transmembrane protein with six extracellular EGF repeats and a short intracellular tail. DLK1 is encoded by a paternally imprinted gene and, based on mouse studies, is implicated in many developmental processes, such as adipogenesis, hematopoiesis, differentiation of adrenal gland and other neuroendocrine cells, as well as development of the central nervous system. Mice lacking Dlk1 exhibit growth retardation and obesity. Based on studies done in mice and flies, NOTCH1 and DLK1 interact to form a complex, most likely in cis, which results in the inhibition of NOTCH1 signaling by preventing NOTCH1 interaction with DLL and JAG ligands (Baladron et al. 2005, Bray et al. 2008). Besides its inhibitory role, DLK1 may function as a coactivator for NOTCH receptors. DLK1 possesses a Delta and OSM-11 motif (DOS), which has been found in C. elegans proteins that facilitate Notch activation in trans by DSL family ligands. The mammalian DLK1 can substitute for OSM-11 protein in C. elegans development (Komatsu 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 Reactome DB_ID: 1604447 1 UniProt:P80370 DLK1 DLK1 DLK DLK1 FUNCTION May have a role in neuroendocrine differentiation.SUBUNIT Monomer. Interacts with SH3RF2 (By similarity).TISSUE SPECIFICITY Found within the stromal cells in close contact to the vascular structure of placental villi, yolk sac, fetal liver, adrenal cortex and pancreas and in the beta cells of the islets of Langerhans in the adult pancreas. Found also in some forms of neuroendocrine lung tumor tissue.PTM N- and O-glycosylated. O-glycosylated with core 1 or possibly core 8 glycans. UniProt P80370 24 EQUAL 383 EQUAL Reactome DB_ID: 157027 1 Reactome DB_ID: 1911561 1 NOTCH1:DLK1 [plasma membrane] NOTCH1:DLK1 Reactome DB_ID: 1604447 1 24 EQUAL 383 EQUAL Reactome DB_ID: 157027 1 Reactome Database ID Release 81 1911561 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1911561 Reactome R-HSA-1911561 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1911561.1 Reactome Database ID Release 81 1980130 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1980130 Reactome R-HSA-1980130 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1980130.1 18237417 Pubmed 2008 The atypical mammalian ligand Delta-like homologue 1 (Dlk1) can regulate Notch signalling in Drosophila Bray, SJ Takada, S Harrison, E Shen, SC Ferguson-Smith, AC BMC Dev Biol 8:11 15652348 Pubmed 2005 dlk acts as a negative regulator of Notch1 activation through interactions with specific EGF-like repeats Baladrón, V Ruiz-Hidalgo, MJ Nueda, ML Díaz-Guerra, MJM García-Ramírez, JJ Bonvini, E Gubina, E Laborda, J Exp Cell Res 303:343-59 18700817 Pubmed 2008 OSM-11 facilitates LIN-12 Notch signaling during Caenorhabditis elegans vulval development Komatsu, H Chao, MY Larkins-Ford, J Corkins, ME Somers, GA Tucey, T Dionne, HM White, JQ Wani, K Boxem, M Hart, AC PLoS Biol 6:e196 NOTCH1 associates with negative regulators NUMB and ITCH NOTCH1 associates with negative regulators NUMB and ITCH Genetic studies in Drosophila have identified Numb as an inhibitor of Notch signaling during development of the peripheral and central nervous systems as well as muscle cell differentiation. Both Drosophila and mammalian Numb are asymmetrically localized in dividing precursor cells, ensuring that cells adopt distinct cell fates through suppression of Notch signaling in one daughter cell (Rhyu et al. 1994). NUMB recruits E3 ubiquitin ligase ITCH (AIP4) to NOTCH1 and promotes sorting of NOTCH1 through late endosomes for degradation (McGill et al. 2009). 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 Reactome DB_ID: 443595 1 UniProt:P49757 NUMB NUMB C14orf41 NUMB FUNCTION Regulates clathrin-mediated receptor endocytosis (PubMed:18657069). Plays a role in the process of neurogenesis (By similarity). Required throughout embryonic neurogenesis to maintain neural progenitor cells, also called radial glial cells (RGCs), by allowing their daughter cells to choose progenitor over neuronal cell fate (By similarity). Not required for the proliferation of neural progenitor cells before the onset of neurogenesis. Also involved postnatally in the subventricular zone (SVZ) neurogenesis by regulating SVZ neuroblasts survival and ependymal wall integrity (By similarity). May also mediate local repair of brain ventricular wall damage (By similarity).SUBUNIT Interacts with SIAH1 (PubMed:11752454). Interacts with LNX (By similarity). Interacts with CDH1 (By similarity). Interacts with TFAP2A and TFAP2B (By similarity). Interacts with RALBP1 in a complex also containing EPN1 and TFAP2A during interphase and mitosis (PubMed:12775724). Interacts with AAK1 (PubMed:18657069). May interact with DUOXA1 (PubMed:14670962).PTM Phosphorylated on Ser-276 and Ser-295 by CaMK1.PTM Isoform 1 and isoform 2 are ubiquitinated by LNX leading to their subsequent proteasomal degradation (By similarity). Ubiquitinated; mediated by SIAH1 and leading to its subsequent proteasomal degradation. UniProt P49757 1 EQUAL 651 EQUAL Reactome DB_ID: 157027 1 Reactome DB_ID: 975995 1 1 EQUAL 903 EQUAL Reactome DB_ID: 1604458 1 NOTCH1:NUMB:ITCH [plasma membrane] NOTCH1:NUMB:ITCH Reactome DB_ID: 443595 1 1 EQUAL 651 EQUAL Reactome DB_ID: 157027 1 Reactome DB_ID: 975995 1 1 EQUAL 903 EQUAL Reactome Database ID Release 81 1604458 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1604458 Reactome R-HSA-1604458 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1604458.1 Reactome Database ID Release 81 1980128 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1980128 Reactome R-HSA-1980128 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1980128.1 19567869 Pubmed 2009 Numb regulates post-endocytic trafficking and degradation of Notch1 McGill, MA Dho, SE Weinmaster, G McGlade, CJ J Biol Chem 284:26427-38 8313469 Pubmed 1994 Asymmetric distribution of numb protein during division of the sensory organ precursor cell confers distinct fates to daughter cells Rhyu, MS Jan, LY Jan, YN Cell 76:477-91 6.3.2.19 Ubiquitination of NOTCH1 by ITCH in the absence of ligand Ubiquitination of NOTCH1 by ITCH in the absence of ligand ITCH, recruited to NOTCH1 indirectly through association with NUMB, ubiquitinates NOTCH1 and targets it for degradation. 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 Reactome DB_ID: 113595 1 Reactome DB_ID: 1604458 1 Reactome DB_ID: 1911544 1 Ub-NOTCH1:NUMB:ITCH [plasma membrane] Ub-NOTCH1:NUMB:ITCH Reactome DB_ID: 1911534 1 Ub-NOTCH1 [plasma membrane] Ub-NOTCH1 Converted from EntitySet in Reactome Reactome DB_ID: 113595 1 Reactome DB_ID: 157027 1 Reactome Database ID Release 81 1911534 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1911534 Reactome R-HSA-1911534 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1911534.1 Reactome DB_ID: 443595 1 1 EQUAL 651 EQUAL Reactome DB_ID: 975995 1 1 EQUAL 903 EQUAL Reactome Database ID Release 81 1911544 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1911544 Reactome R-HSA-1911544 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1911544.1 PHYSIOL-LEFT-TO-RIGHT ACTIVATION Reactome DB_ID: 1604458 Reactome Database ID Release 81 1604459 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1604459 Reactome Database ID Release 81 1912386 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=1912386 Reactome R-HSA-1912386 1 Reactome stable identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser_st_id?ST_ID=R-HSA-1912386.1 18628966 Pubmed 2008 AIP4/Itch regulates Notch receptor degradation in the absence of ligand Chastagner, P Israel, A Brou, C PLoS One 3:e2735 Reactome Database ID Release 81 2122948 Database identifier. Use this URL to connect to the web page of this instance in Reactome: http://www.reactome.org/cgi-bin/eventbrowser?DB=gk_current&ID=2122948 Reactome R-HSA-2122948 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-2122948.3 GO 0007219 GO biological process