Pre-NOTCH Expression and Processing (Homo sapiens)

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1, 10, 11, 13, 17...51, 1075, 14, 19, 13211, 46, 51, 125, 13311620, 51, 12651, 1297730, 436565241081813, 475, 14, 19, 13220, 25, 62, 63, 78...516, 20, 26, 28, 32...20, 94, 119108nucleoplasmGolgi lumenendoplasmic reticulum lumencytosolHIST2H2BE EIF2C3 H2AFJ 18xFucT-16xGlcS-FucS-NOTCH2(26-2471) UDPTNRC6B PRKCIRBPJ NOTCH3 mRNA AGO2 TNRC6C NOTCH4 mRNA CREBBP AcK10-H3F3A MAMLD1 Ack10-HIST2H3A Glc,Gal-GlcNAc-Fuc-Pre-NOTCH2 HIST1H2BH NOTCH2(1582-2471) EIF2C1 SIRT6 CMPGlc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCHE2F1 miR-449A NOTCH4 gene FRINGE-modified NOTCH1 Extracellular Fragment (NECD1) NOTCHmiR-150 Pre-NOTCHTNRC6A TNRC6A EIF2C1 NOTCH1 mRNA:miR-449RISCTNRC6A H2AFX RFNG ST3GAL3/4/6SIRT6 Signaling by NOTCH4NOTCH3 coactivatorcomplexHIST1H2BL NOTCH2 mRNAGlc,GlcNAc-Fuc-Pre-NOTCH3 Glc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCH1 HIST2H2BE TNRC6B HIST1H2BC POFUT1miR-200B EIF2C4 EIF2C4 CCND1 SNW1 MIR34A gene EIF2C1 HIST1H2BH FRINGE-modifiedNOTCHMOV10 NOTCH1 mRNA HIST3H2BB NOTCH4(1337-2003) NOTCH1(1665-2555) H3F3A EIF2C3 miR-34B ATP2A2 HIST1H2BC MOV10 TNRC6A RBPJ TFDP2 Glc,GlcNAc-Fuc-Pre-NOTCHGDPNOTCHMOV10 AGO2 12xFucT-6xFucS-NOTCH4(24-2003) B4GALT1 homodimerMIR34B gene HIST1H2AJ HIST1H2BN NOTCH1 gene 17xFucT-2xFucS-NOTCH1(19-2555) HIST1H4 TFDP2 EIF2C4 NOTCH3(1572-2321) NOTCH1 mRNA AGO2 MAML3 p-S68-ELF3 MAML3 LFNG POGLUT1EIF2C4 miR-181C Glc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCH3 Glc,Fuc-Pre-NOTCHHIST1H2BA E2F3 TNRC6C HIST2H2AC TNRC6A EIF2C4 EIF2C3 NOTCH4 gene HIST1H2BL NOTCH4(1337-2003) NOTCH1 mRNANOTCH2 mRNA KAT2A HIST1H2BO MIR34 genesEIF2C1 CCND1:CREBBP:NOTCH1GeneCMP-Neu5AcEIF2C1 Pre-NOTCH3 miR-34C 18xFucT-16xGlcS-FucS-NOTCH2(26-1581) ATPTNRC6B TNRC6B 14xGlcS-10xFucT-4xFucS-NOTCH3(40-1571) TP53 TetramerTNRC6C TP53 EIF2C1 TNRC6C TNRC6C EIF2C1 Pre-NOTCH2HIST1H2BD HIST1H2BB 14xGlcS-10xFucT-4xFucS-NOTCH3(40-2321) miR-449B H2AFX miR-34A MOV10 12xFucT-11xGlcS-6xFucS-NOTCH4(24-1336) 17xFucT-14xGlcS-2xFucS-NOTCH1(19-2555) FURINmiR-449 RISCGlc,Gal-GlcNAc-Fuc-Pre-NOTCH4 MAML2 HIST1H2BD NOTCH2(1582-2471) H2AFB1 H2AFX HIST1H2AD JUNMIR34A gene EIF2C4 EIF2C3 AGO2 HIST1H2AJ MAML2 Glc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCH4 HIST1H2BJ TFDP1 EIF2C3 NOTCH1 gene AGO2 AGO2 HIST1H2BB AGO2 18xFucT-FucS-NOTCH2(26-2471) NOTCH1 CoactivatorComplexEIF2C4 18xFucT-16xGlcS-FucS-NOTCH2(26-2471) MOV10 MFNG MAMLD1 E2F1 MOV10 CREBBP miR-449B NOTCH4 mRNAmiR-34C HIST2H2AA3 miR-449C HIST2H2AC FRINGE-modified NOTCH4 Extracellular fragment (NECD4) MOV10 TNRC6B NICD1 TNRC6B 19xFucT-14xGlcS-2xFucS-NOTCH1(19-2555) ADPH2AFZ NICD3 H2AFZ MOV10 HIST1H2BC 10xFucT-4xFucS-NOTCH3(40-2321) SIRT6NOTCH4 gene EIF2C3 HIST1H2BN RAB6AFRINGE-modified NOTCH3 Extracellular Fragment (NECD3) Glc,GlcNAc-Fuc-Pre-NOTCH2 HIST2H2AA3 TNRC6A ST3GAL6 H2AFJ miR-200B/C RISCHIST1H3A UDP-GlcNOTCH3(1572-2321) Glc,Gal-GlcNAc-Fuc-Pre-NOTCH1 NOTCH1 mRNA UDPTNRC6B FRINGE-modified NOTCH2 extracellular fragment (NECD2) Nucleosome (H3K9ac)TNRC6C MOV10 NOTCH1 gene p-S68-ELF3Pre-NOTCH2 NOTCH1 mRNA,NOTCH4mRNAMAML2 RUNX1H2AFV AcK10-H3F3A SIRT6:Nucleosome:NOTCH1,NOTCH4 geneNOTCH3 gene TNRC6B TNRC6C Fringe familyNOTCH1 gene HIST1H2AD Ack10-HIST2H3A H2BFS miR-206 SNW1 TNRC6B HIST1H2AC HIST1H2BA NOTCH4(1337-2003) NOTCH2 genePre-NOTCH3miR-150 Ack10-HIST1H3A TNRC6C HIST1H2BJ EIF2C1 NOTCH1(1665-2555) Signaling by NOTCH2TNRC6C HIST1H2BO FRINGE-modified NOTCH1 Extracellular Fragment (NECD1) NOTCH1mRNA:miR-200B/CRISC18xFucT-16xGlcS-FucS-NOTCH2(26-1581) NOTCH4(1337-2003) 12xFucT-8xGlcS-6xFucS-NOTCH4(24-1336) HIST1H2BB HIST1H2AJ TNRC6B B4GALT1 AGO2 NOTCH3 geneNOTCH4 mRNA:miR-181CRISCNOTCH3 gene NOTCH1(1665-2555) Pre-NOTCH1 ATP2A1-3H2BFS NOTCH1 mRNA:miR-34RISCmiR-302A RISCH2AFJ TNRC6C miR-34B Fringe-modifiedNOTCHMAML1 miR-206 TNRC6A NOTCH1 coactivatorcomplex:NOTCH3 geneMOV10 HIST1H2AB HIST1H2AB ST3GAL4 H2AFV E2F1/3:DP1/2:NOTCH1GeneHIST2H3A HIST1H2BJ Pre-NOTCH4NOTCH2(1582-2471) ATP2A3 FRINGE-modified NOTCH2 Extracellular Fragment (NECD2) TNRC6A HIST3H2BB HIST1H2BM UDP-Gal14xGlcS-10xFucT-4xFucS-NOTCH3(40-2321) NOTCH1 mRNA Glc,GlcNAc-Fuc-Pre-NOTCH4 NOTCH3 mRNA AGO2 GDP-FucNOTCH3 mRNA:miR-150RISCmiR-34C MAML1 RUNX1:NOTCH4 geneHIST1H4 EIF2C3 TNRC6A TNRC6B ST3GAL3 FRINGE-modified NOTCH4 Extracellular Fragment (NECD4) MOV10 HIST1H2AB UDP-GlcNAcHIST3H2BB miR-200C HIST1H2BD TP53 EP300 NOTCH1(1665-2555) Signaling by NOTCH1EIF2C4 NOTCH2 mRNA:miR-34RISCHIST1H2BL H2AFB1 TNRC6C Fuc-Pre-NOTCHGlc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCH2 NOTCH3 mRNA:miR-206RISCHIST1H2AC HIST1H2BK EIF2C4 Glc,Gal-GlcNAc-Fuc-Pre-NOTCHHIST1H2BM miR-302A p-S68-ELF3:NOTCH3geneHIST1H2BM ELF3miR-181C RISCPre-NOTCH4 EIF2C1 CREBBP HIST2H2AA3 EP300 HIST1H2AC NOTCH3(1572-2321) AGO2 TNRC6A KAT2A MAMLD1 NOTCH4 geneHIST1H2BK miR-34A HIST1H2AD MOV10 NOTCH4 gene AGO2 MOV10 TMED2EIF2C3 TNRC6A 12xFucT-8xGlcS-6xFucS-NOTCH4(24-2003) miR-206 RISCEIF2C1 TNRC6B miR-200C HIST1H2BA EIF2C4 SEL1LMOV10 NOTCH2(1582-2471) miR-150 RISCTNRC6C miR-449C TNRC6B AGO2 TNRC6C E2F3 H2AFZ 12xFucT-8xGlcS-6xFucS-NOTCH4(24-2003) EIF2C3 Pre-NOTCH1EIF2C3 KAT2B EIF2C1 NOTCH1 gene EIF2C3 EIF2C4 2'-O-acetyl-ADP-riboseATP2A1 MIR34C gene HIST1H4 H2BFS miR-200B MIR34B gene 14xGlcS-10xFucT-4xFucS-NOTCH3(40-1571) HIST1H2BH EIF2C3 EIF2C1 EIF2C4 H2AFV miR-181C NICD1 TNRC6A MAML3 CCND1:CREBBPRBPJ Glc,GlcNAc-Fuc-Pre-NOTCH1 NOTCH3 mRNAAGO2 NOTCH3(1572-2321) EIF2C1 EIF2C1 CCND1 Signaling by NOTCH3NOTCH4 mRNA TNRC6A EIF2C4 TNRC6A TNRC6C miR-302A HIST1H2BO miR-34B miR-34A TP53 Tetramer:MIR34genesHIST1H2BN miR-34 RISCEIF2C1 AGO2 Ack10-HIST1H3A AGO2 NOTCH1 geneE2F1/3:DP1/2KAT2B EIF2C3 EIF2C4 NOTCH4 mRNA EIF2C3 TNRC6B EIF2C4 TNRC6A miR-449A TNRC6B NAD+SIRT6:Nucleosome(H3K9ac):NOTCH1,NOTCH4 geneRUNX1 HIST2H2AC NOTCH1 gene,NOTCH4gene17xFucT-14xGlcS-2xFucS-NOTCH1(19-1664) HIST2H2BE MOV10 MAML1 HIST1H2BK H2AFB1 FRINGE-modified NOTCH3 Extracellular fragment (NECD3) Glc,Fuc-Pre-NOTCHCREBBP EIF2C3 NOTCH4 mRNA:miR-302ARISCTFDP1 Glc,Gal-GlcNAc-Fuc-Pre-NOTCH3 19xFucT-16xGlcS-2xFucS-NOTCH1(19-1664) MIR34C gene UDPTNRC6C 3, 4, 8, 12, 15...65491161081162439, 41, 53, 60, 76...772, 7, 9, 16, 21...5, 14, 19, 13286


Description

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).

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).

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. View original pathway at Reactome.

Comments

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Pathway is converted from Reactome ID: 1912422
Reactome-version 
Reactome version: 75
Reactome Author 
Reactome Author: Egan, SE, Orlic-Milacic, Marija

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  62. Logeat F, Bessia C, Brou C, LeBail O, Jarriault S, Seidah NG, Israël A.; ''The Notch1 receptor is cleaved constitutively by a furin-like convertase.''; PubMed Europe PMC Scholia
  63. Rand MD, Grimm LM, Artavanis-Tsakonas S, Patriub V, Blacklow SC, Sklar J, Aster JC.; ''Calcium depletion dissociates and activates heterodimeric notch receptors.''; PubMed Europe PMC Scholia
  64. Huppert SS, Le A, Schroeter EH, Mumm JS, Saxena MT, Milner LA, Kopan R.; ''Embryonic lethality in mice homozygous for a processing-deficient allele of Notch1.''; PubMed Europe PMC Scholia
  65. Ali SA, Justilien V, Jamieson L, Murray NR, Fields AP.; ''Protein Kinase Cι Drives a NOTCH3-dependent Stem-like Phenotype in Mutant KRAS Lung Adenocarcinoma.''; PubMed Europe PMC Scholia
  66. Song R, Koo BK, Yoon KJ, Yoon MJ, Yoo KW, Kim HT, Oh HJ, Kim YY, Han JK, Kim CH, Kong YY.; ''Neuralized-2 regulates a Notch ligand in cooperation with Mind bomb-1.''; PubMed Europe PMC Scholia
  67. Li L, Krantz ID, Deng Y, Genin A, Banta AB, Collins CC, Qi M, Trask BJ, Kuo WL, Cochran J, Costa T, Pierpont ME, Rand EB, Piccoli DA, Hood L, Spinner NB.; ''Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1.''; PubMed Europe PMC Scholia
  68. Wu G, Lyapina S, Das I, Li J, Gurney M, Pauley A, Chui I, Deshaies RJ, Kitajewski J.; ''SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation.''; PubMed Europe PMC Scholia
  69. Wu L, Aster JC, Blacklow SC, Lake R, Artavanis-Tsakonas S, Griffin JD.; ''MAML1, a human homologue of Drosophila mastermind, is a transcriptional co-activator for NOTCH receptors.''; PubMed Europe PMC Scholia
  70. Jarriault S, Brou C, Logeat F, Schroeter EH, Kopan R, Israel A.; ''Signalling downstream of activated mammalian Notch.''; PubMed Europe PMC Scholia
  71. Weinmaster G, Roberts VJ, Lemke G.; ''Notch2: a second mammalian Notch gene.''; PubMed Europe PMC Scholia
  72. Brou C, Logeat F, Gupta N, Bessia C, LeBail O, Doedens JR, Cumano A, Roux P, Black RA, Israël A.; ''A novel proteolytic cleavage involved in Notch signaling: the role of the disintegrin-metalloprotease TACE.''; PubMed Europe PMC Scholia
  73. Kao HY, Ordentlich P, Koyano-Nakagawa N, Tang Z, Downes M, Kintner CR, Evans RM, Kadesch T.; ''A histone deacetylase corepressor complex regulates the Notch signal transduction pathway.''; PubMed Europe PMC Scholia
  74. Eiraku M, Tohgo A, Ono K, Kaneko M, Fujishima K, Hirano T, Kengaku M.; ''DNER acts as a neuron-specific Notch ligand during Bergmann glial development.''; PubMed Europe PMC Scholia
  75. Chastagner P, Israël A, Brou C.; ''Itch/AIP4 mediates Deltex degradation through the formation of K29-linked polyubiquitin chains.''; PubMed Europe PMC Scholia
  76. Barbarulo A, Grazioli P, Campese AF, Bellavia D, Di Mario G, Pelullo M, Ciuffetta A, Colantoni S, Vacca A, Frati L, Gulino A, Felli MP, Screpanti I.; ''Notch3 and canonical NF-kappaB signaling pathways cooperatively regulate Foxp3 transcription.''; PubMed Europe PMC Scholia
  77. Ohashi S, Natsuizaka M, Yashiro-Ohtani Y, Kalman RA, Nakagawa M, Wu L, Klein-Szanto AJ, Herlyn M, Diehl JA, Katz JP, Pear WS, Seykora JT, Nakagawa H.; ''NOTCH1 and NOTCH3 coordinate esophageal squamous differentiation through a CSL-dependent transcriptional network.''; PubMed Europe PMC Scholia
  78. 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.; ''Effects of S1 cleavage on the structure, surface export, and signaling activity of human Notch1 and Notch2.''; PubMed Europe PMC Scholia
  79. Shimizu K, Chiba S, Saito T, Kumano K, Hamada Y, Hirai H.; ''Functional diversity among Notch1, Notch2, and Notch3 receptors.''; PubMed Europe PMC Scholia
  80. Shimizu K, Chiba S, Hosoya N, Kumano K, Saito T, Kurokawa M, Kanda Y, Hamada Y, Hirai H.; ''Binding of Delta1, Jagged1, and Jagged2 to Notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of Notch2.''; PubMed Europe PMC Scholia
  81. Hubmann R, Schwarzmeier JD, Shehata M, Hilgarth M, Duechler M, Dettke M, Berger R.; ''Notch2 is involved in the overexpression of CD23 in B-cell chronic lymphocytic leukemia.''; PubMed Europe PMC Scholia
  82. Uyttendaele H, Marazzi G, Wu G, Yan Q, Sassoon D, Kitajewski J.; ''Notch4/int-3, a mammary proto-oncogene, is an endothelial cell-specific mammalian Notch gene.''; PubMed Europe PMC Scholia
  83. Kidd S, Lieber T.; ''Furin cleavage is not a requirement for Drosophila Notch function.''; PubMed Europe PMC Scholia
  84. Luo B, Aster JC, Hasserjian RP, Kuo F, Sklar J.; ''Isolation and functional analysis of a cDNA for human Jagged2, a gene encoding a ligand for the Notch1 receptor.''; PubMed Europe PMC Scholia
  85. Tanigaki K, Nogaki F, Takahashi J, Tashiro K, Kurooka H, Honjo T.; ''Notch1 and Notch3 instructively restrict bFGF-responsive multipotent neural progenitor cells to an astroglial fate.''; PubMed Europe PMC Scholia
  86. Leduc R, Molloy SS, Thorne BA, Thomas G.; ''Activation of human furin precursor processing endoprotease occurs by an intramolecular autoproteolytic cleavage.''; PubMed Europe PMC Scholia
  87. Benedito R, Roca C, Sörensen I, Adams S, Gossler A, Fruttiger M, Adams RH.; ''The notch ligands Dll4 and Jagged1 have opposing effects on angiogenesis.''; PubMed Europe PMC Scholia
  88. Nam Y, Sliz P, Song L, Aster JC, Blacklow SC.; ''Structural basis for cooperativity in recruitment of MAML coactivators to Notch transcription complexes.''; PubMed Europe PMC Scholia
  89. Leimeister C, Schumacher N, Steidl C, Gessler M.; ''Analysis of HeyL expression in wild-type and Notch pathway mutant mouse embryos.''; PubMed Europe PMC Scholia
  90. Fryer CJ, White JB, Jones KA.; ''Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover.''; PubMed Europe PMC Scholia
  91. Pan D, Rubin GM.; ''Kuzbanian controls proteolytic processing of Notch and mediates lateral inhibition during Drosophila and vertebrate neurogenesis.''; PubMed Europe PMC Scholia
  92. Yang LT, Nichols JT, Yao C, Manilay JO, Robey EA, Weinmaster G.; ''Fringe glycosyltransferases differentially modulate Notch1 proteolysis induced by Delta1 and Jagged1.''; PubMed Europe PMC Scholia
  93. Sprinzak D, Lakhanpal A, Lebon L, Santat LA, Fontes ME, Anderson GA, Garcia-Ojalvo J, Elowitz MB.; ''Cis-interactions between Notch and Delta generate mutually exclusive signalling states.''; PubMed Europe PMC Scholia
  94. Frisén J, Lendahl U.; ''Oh no, Notch again!''; PubMed Europe PMC Scholia
  95. Mukherjee A, Veraksa A, Bauer A, Rosse C, Camonis J, Artavanis-Tsakonas S.; ''Regulation of Notch signalling by non-visual beta-arrestin.''; PubMed Europe PMC Scholia
  96. Baladrón V, Ruiz-Hidalgo MJ, Nueda ML, Díaz-Guerra MJ, García-Ramírez JJ, Bonvini E, Gubina E, Laborda J.; ''dlk acts as a negative regulator of Notch1 activation through interactions with specific EGF-like repeats.''; PubMed Europe PMC Scholia
  97. Gibb DR, El Shikh M, Kang DJ, Rowe WJ, El Sayed R, Cichy J, Yagita H, Tew JG, Dempsey PJ, Crawford HC, Conrad DH.; ''ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo.''; PubMed Europe PMC Scholia
  98. Yao D, Huang Y, Huang X, Wang W, Yan Q, Wei L, Xin W, Gerson S, Stanley P, Lowe JB, Zhou L.; ''Protein O-fucosyltransferase 1 (Pofut1) regulates lymphoid and myeloid homeostasis through modulation of Notch receptor ligand interactions.''; PubMed Europe PMC Scholia
  99. Zhou S, Fujimuro M, Hsieh JJ, Chen L, Miyamoto A, Weinmaster G, Hayward SD.; ''SKIP, a CBF1-associated protein, interacts with the ankyrin repeat domain of NotchIC To facilitate NotchIC function.''; PubMed Europe PMC Scholia
  100. Arnett KL, Hass M, McArthur DG, Ilagan MX, Aster JC, Kopan R, Blacklow SC.; ''Structural and mechanistic insights into cooperative assembly of dimeric Notch transcription complexes.''; PubMed Europe PMC Scholia
  101. Kopan R, Ilagan MX.; ''The canonical Notch signaling pathway: unfolding the activation mechanism.''; PubMed Europe PMC Scholia
  102. Chastagner P, Israël A, Brou C.; ''AIP4/Itch regulates Notch receptor degradation in the absence of ligand.''; PubMed Europe PMC Scholia
  103. Wang W, Prince CZ, Mou Y, Pollman MJ.; ''Notch3 signaling in vascular smooth muscle cells induces c-FLIP expression via ERK/MAPK activation. Resistance to Fas ligand-induced apoptosis.''; PubMed Europe PMC Scholia
  104. Stahl M, Uemura K, Ge C, Shi S, Tashima Y, Stanley P.; ''Roles of Pofut1 and O-fucose in mammalian Notch signaling.''; PubMed Europe PMC Scholia
  105. D'Souza B, Meloty-Kapella L, Weinmaster G.; ''Canonical and non-canonical Notch ligands.''; PubMed Europe PMC Scholia
  106. Schroeter EH, Kisslinger JA, Kopan R.; ''Notch-1 signalling requires ligand-induced proteolytic release of intracellular domain.''; PubMed Europe PMC Scholia
  107. Chen J, Moloney DJ, Stanley P.; ''Fringe modulation of Jagged1-induced Notch signaling requires the action of beta 4galactosyltransferase-1.''; PubMed Europe PMC Scholia
  108. Li Y, Jin C, Bai H, Gao Y, Sun S, Chen L, Qin L, Liu PP, Cheng L, Wang QF.; ''Human NOTCH4 is a key target of RUNX1 in megakaryocytic differentiation.''; PubMed Europe PMC Scholia
  109. McGill MA, Dho SE, Weinmaster G, McGlade CJ.; ''Numb regulates post-endocytic trafficking and degradation of Notch1.''; PubMed Europe PMC Scholia
  110. Koo BK, Yoon MJ, Yoon KJ, Im SK, Kim YY, Kim CH, Suh PG, Jan YN, Kong YY.; ''An obligatory role of mind bomb-1 in notch signaling of mammalian development.''; PubMed Europe PMC Scholia
  111. Isidor B, Lindenbaum P, Pichon O, Bézieau S, Dina C, Jacquemont S, Martin-Coignard D, Thauvin-Robinet C, Le Merrer M, Mandel JL, David A, Faivre L, Cormier-Daire V, Redon R, Le Caignec C.; ''Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis.''; PubMed Europe PMC Scholia
  112. Bertrand FE, Eckfeldt CE, Lysholm AS, LeBien TW.; ''Notch-1 and Notch-2 exhibit unique patterns of expression in human B-lineage cells.''; PubMed Europe PMC Scholia
  113. Fernandez-Valdivia R, Takeuchi H, Samarghandi A, Lopez M, Leonardi J, Haltiwanger RS, Jafar-Nejad H.; ''Regulation of mammalian Notch signaling and embryonic development by the protein O-glucosyltransferase Rumi.''; PubMed Europe PMC Scholia
  114. Oda T, Elkahloun AG, Pike BL, Okajima K, Krantz ID, Genin A, Piccoli DA, Meltzer PS, Spinner NB, Collins FS, Chandrasekharappa SC.; ''Mutations in the human Jagged1 gene are responsible for Alagille syndrome.''; PubMed Europe PMC Scholia
  115. 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.; ''Control of vertebrate multiciliogenesis by miR-449 through direct repression of the Delta/Notch pathway.''; PubMed Europe PMC Scholia
  116. Bienvenu F, Jirawatnotai S, Elias JE, Meyer CA, Mizeracka K, Marson A, Frampton GM, Cole MF, Odom DT, Odajima J, Geng Y, Zagozdzon A, Jecrois M, Young RA, Liu XS, Cepko CL, Gygi SP, Sicinski P.; ''Transcriptional role of cyclin D1 in development revealed by a genetic-proteomic screen.''; PubMed Europe PMC Scholia
  117. Purcell K, Artavanis-Tsakonas S.; ''The developmental role of warthog, the notch modifier encoding Drab6.''; PubMed Europe PMC Scholia
  118. Lai EC, Deblandre GA, Kintner C, Rubin GM.; ''Drosophila neuralized is a ubiquitin ligase that promotes the internalization and degradation of delta.''; PubMed Europe PMC Scholia
  119. Wen C, Greenwald I.; ''p24 proteins and quality control of LIN-12 and GLP-1 trafficking in Caenorhabditis elegans.''; PubMed Europe PMC Scholia
  120. Shimizu K, Chiba S, Kumano K, Hosoya N, Takahashi T, Kanda Y, Hamada Y, Yazaki Y, Hirai H.; ''Mouse jagged1 physically interacts with notch2 and other notch receptors. Assessment by quantitative methods.''; PubMed Europe PMC Scholia
  121. Yamaguchi N, Oyama T, Ito E, Satoh H, Azuma S, Hayashi M, Shimizu K, Honma R, Yanagisawa Y, Nishikawa A, Kawamura M, Imai J, Ohwada S, Tatsuta K, Inoue J, Semba K, Watanabe S.; ''NOTCH3 signaling pathway plays crucial roles in the proliferation of ErbB2-negative human breast cancer cells.''; PubMed Europe PMC Scholia
  122. Perissi V, Scafoglio C, Zhang J, Ohgi KA, Rose DW, Glass CK, Rosenfeld MG.; ''TBL1 and TBLR1 phosphorylation on regulated gene promoters overcomes dual CtBP and NCoR/SMRT transcriptional repression checkpoints.''; PubMed Europe PMC Scholia
  123. Rhyu MS, Jan LY, Jan YN.; ''Asymmetric distribution of numb protein during division of the sensory organ precursor cell confers distinct fates to daughter cells.''; PubMed Europe PMC Scholia
  124. Grbavec D, Stifani S.; ''Molecular interaction between TLE1 and the carboxyl-terminal domain of HES-1 containing the WRPW motif.''; PubMed Europe PMC Scholia
  125. Yuan JS, Tan JB, Visan I, Matei IR, Urbanellis P, Xu K, Danska JS, Egan SE, Guidos CJ.; ''Lunatic Fringe prolongs Delta/Notch-induced self-renewal of committed αβ T-cell progenitors.''; PubMed Europe PMC Scholia
  126. Teuchert M, Schäfer W, Berghöfer S, Hoflack B, Klenk HD, Garten W.; ''Sorting of furin at the trans-Golgi network. Interaction of the cytoplasmic tail sorting signals with AP-1 Golgi-specific assembly proteins.''; PubMed Europe PMC Scholia
  127. Matsuno K, Eastman D, Mitsiades T, Quinn AM, Carcanciu ML, Ordentlich P, Kadesch T, Artavanis-Tsakonas S.; ''Human deltex is a conserved regulator of Notch signalling.''; PubMed Europe PMC Scholia
  128. Oberg C, Li J, Pauley A, Wolf E, Gurney M, Lendahl U.; ''The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog.''; PubMed Europe PMC Scholia
  129. Harduin-Lepers A, Vallejo-Ruiz V, Krzewinski-Recchi MA, Samyn-Petit B, Julien S, Delannoy P.; ''The human sialyltransferase family.''; PubMed Europe PMC Scholia
  130. 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.; ''Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis.''; PubMed Europe PMC Scholia
  131. Fisher AL, Ohsako S, Caudy M.; ''The WRPW motif of the hairy-related basic helix-loop-helix repressor proteins acts as a 4-amino-acid transcription repression and protein-protein interaction domain.''; PubMed Europe PMC Scholia
  132. Corney DC, Flesken-Nikitin A, Godwin AK, Wang W, Nikitin AY.; ''MicroRNA-34b and MicroRNA-34c are targets of p53 and cooperate in control of cell proliferation and adhesion-independent growth.''; PubMed Europe PMC Scholia
  133. Brückner K, Perez L, Clausen H, Cohen S.; ''Glycosyltransferase activity of Fringe modulates Notch-Delta interactions.''; PubMed Europe PMC Scholia
  134. Welcker M, Clurman BE.; ''FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation.''; PubMed Europe PMC Scholia
  135. Paroush Z, Finley RL, Kidd T, Wainwright SM, Ingham PW, Brent R, Ish-Horowicz D.; ''Groucho is required for Drosophila neurogenesis, segmentation, and sex determination and interacts directly with hairy-related bHLH proteins.''; PubMed Europe PMC Scholia

History

View all...
CompareRevisionActionTimeUserComment
123262view09:01, 9 July 2022EgonwReplaced an old Ensembl identifier
114930view16:44, 25 January 2021ReactomeTeamReactome version 75
113375view11:44, 2 November 2020ReactomeTeamReactome version 74
112580view15:55, 9 October 2020ReactomeTeamReactome version 73
103007view15:10, 31 January 2019Mkutmonupdated outdated Ensembl identifier (MIR34A)
101495view11:36, 1 November 2018ReactomeTeamreactome version 66
101032view21:17, 31 October 2018ReactomeTeamreactome version 65
100565view19:50, 31 October 2018ReactomeTeamreactome version 64
100113view16:35, 31 October 2018ReactomeTeamreactome version 63
99663view15:06, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99262view12:45, 31 October 2018ReactomeTeamreactome version 62
94024view13:52, 16 August 2017ReactomeTeamreactome version 61
93644view11:29, 9 August 2017ReactomeTeamreactome version 61
88114view10:04, 26 July 2016RyanmillerOntology Term : 'Notch signaling pathway' added !
88111view10:01, 26 July 2016RyanmillerOntology Term : 'signaling pathway pertinent to the brain and nervous system' added !
88110view09:58, 26 July 2016RyanmillerOntology Term : 'signaling pathway' added !
86760view09:25, 11 July 2016ReactomeTeamreactome version 56
83418view11:11, 18 November 2015ReactomeTeamVersion54
81617view13:09, 21 August 2015ReactomeTeamVersion53
77076view08:37, 17 July 2014ReactomeTeamFixed remaining interactions
76781view12:14, 16 July 2014ReactomeTeamFixed remaining interactions
76104view10:16, 11 June 2014ReactomeTeamRe-fixing comment source
75816view11:36, 10 June 2014ReactomeTeamReactome 48 Update
75166view14:11, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74813view08:54, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
10xFucT-4xFucS-NOTCH3(40-2321) ProteinQ9UM47 (Uniprot-TrEMBL)
12xFucT-11xGlcS-6xFucS-NOTCH4(24-1336) ProteinQ99466 (Uniprot-TrEMBL)
12xFucT-6xFucS-NOTCH4(24-2003) ProteinQ99466 (Uniprot-TrEMBL)
12xFucT-8xGlcS-6xFucS-NOTCH4(24-1336) ProteinQ99466 (Uniprot-TrEMBL)
12xFucT-8xGlcS-6xFucS-NOTCH4(24-2003) ProteinQ99466 (Uniprot-TrEMBL)
14xGlcS-10xFucT-4xFucS-NOTCH3(40-1571) ProteinQ9UM47 (Uniprot-TrEMBL)
14xGlcS-10xFucT-4xFucS-NOTCH3(40-2321) ProteinQ9UM47 (Uniprot-TrEMBL)
17xFucT-14xGlcS-2xFucS-NOTCH1(19-1664) ProteinP46531 (Uniprot-TrEMBL)
17xFucT-14xGlcS-2xFucS-NOTCH1(19-2555) ProteinP46531 (Uniprot-TrEMBL)
17xFucT-2xFucS-NOTCH1(19-2555) ProteinP46531 (Uniprot-TrEMBL)
18xFucT-16xGlcS-FucS-NOTCH2(26-1581) ProteinQ04721 (Uniprot-TrEMBL)
18xFucT-16xGlcS-FucS-NOTCH2(26-2471) ProteinQ04721 (Uniprot-TrEMBL)
18xFucT-FucS-NOTCH2(26-2471) ProteinQ04721 (Uniprot-TrEMBL)
19xFucT-14xGlcS-2xFucS-NOTCH1(19-2555) ProteinP46531 (Uniprot-TrEMBL)
19xFucT-16xGlcS-2xFucS-NOTCH1(19-1664) ProteinP46531 (Uniprot-TrEMBL)
2'-O-acetyl-ADP-riboseMetaboliteCHEBI:76279 (ChEBI)
ADPMetaboliteCHEBI:456216 (ChEBI)
AGO2 ProteinQ9UKV8 (Uniprot-TrEMBL)
ATP2A1 ProteinO14983 (Uniprot-TrEMBL)
ATP2A1-3ComplexR-HSA-418312 (Reactome)
ATP2A2 ProteinP16615 (Uniprot-TrEMBL)
ATP2A3 ProteinQ93084 (Uniprot-TrEMBL)
ATPMetaboliteCHEBI:30616 (ChEBI)
AcK10-H3F3A ProteinP84243 (Uniprot-TrEMBL)
Ack10-HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
Ack10-HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
B4GALT1 ProteinP15291 (Uniprot-TrEMBL)
B4GALT1 homodimerComplexR-HSA-975900 (Reactome)
CCND1 ProteinP24385 (Uniprot-TrEMBL)
CCND1:CREBBP:NOTCH1 GeneComplexR-HSA-4395224 (Reactome)
CCND1:CREBBPComplexR-HSA-2247939 (Reactome)
CMP-Neu5AcMetaboliteCHEBI:16556 (ChEBI)
CMPMetaboliteCHEBI:17361 (ChEBI)
CREBBP ProteinQ92793 (Uniprot-TrEMBL)
E2F1 ProteinQ01094 (Uniprot-TrEMBL)
E2F1/3:DP1/2:NOTCH1 GeneComplexR-HSA-4395228 (Reactome)
E2F1/3:DP1/2ComplexR-HSA-2248825 (Reactome)
E2F3 ProteinO00716 (Uniprot-TrEMBL)
EIF2C1 ProteinQ9UL18 (Uniprot-TrEMBL)
EIF2C3 ProteinQ9H9G7 (Uniprot-TrEMBL)
EIF2C4 ProteinQ9HCK5 (Uniprot-TrEMBL)
ELF3ProteinP78545 (Uniprot-TrEMBL)
EP300 ProteinQ09472 (Uniprot-TrEMBL)
FRINGE-modified NOTCHComplexR-HSA-1911547 (Reactome)
FRINGE-modified NOTCH1 Extracellular Fragment (NECD1) ProteinP46531 (Uniprot-TrEMBL)
FRINGE-modified NOTCH2 Extracellular Fragment (NECD2) ProteinQ04721 (Uniprot-TrEMBL)
FRINGE-modified NOTCH2 extracellular fragment (NECD2) ProteinQ04721 (Uniprot-TrEMBL)
FRINGE-modified NOTCH3 Extracellular Fragment (NECD3) ProteinQ9UM47 (Uniprot-TrEMBL)
FRINGE-modified NOTCH3 Extracellular fragment (NECD3) ProteinQ9UM47 (Uniprot-TrEMBL)
FRINGE-modified NOTCH4 Extracellular Fragment (NECD4) ProteinQ99466 (Uniprot-TrEMBL)
FRINGE-modified NOTCH4 Extracellular fragment (NECD4) ProteinQ99466 (Uniprot-TrEMBL)
FURINProteinP09958 (Uniprot-TrEMBL)
Fringe familyComplexR-HSA-1464792 (Reactome)
Fringe-modified NOTCHComplexR-HSA-1911550 (Reactome)
Fuc-Pre-NOTCHComplexR-HSA-1911414 (Reactome)
GDP-FucMetaboliteCHEBI:17009 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
Glc,Fuc-Pre-NOTCHComplexR-HSA-1911440 (Reactome)
Glc,Fuc-Pre-NOTCHComplexR-HSA-1911442 (Reactome)
Glc,Gal-GlcNAc-Fuc-Pre-NOTCH1 ProteinP46531 (Uniprot-TrEMBL)
Glc,Gal-GlcNAc-Fuc-Pre-NOTCH2 ProteinQ04721 (Uniprot-TrEMBL)
Glc,Gal-GlcNAc-Fuc-Pre-NOTCH3 ProteinQ9UM47 (Uniprot-TrEMBL)
Glc,Gal-GlcNAc-Fuc-Pre-NOTCH4 ProteinQ99466 (Uniprot-TrEMBL)
Glc,Gal-GlcNAc-Fuc-Pre-NOTCHComplexR-HSA-1911423 (Reactome)
Glc,GlcNAc-Fuc-Pre-NOTCH1 ProteinP46531 (Uniprot-TrEMBL)
Glc,GlcNAc-Fuc-Pre-NOTCH2 ProteinQ04721 (Uniprot-TrEMBL)
Glc,GlcNAc-Fuc-Pre-NOTCH3 ProteinQ9UM47 (Uniprot-TrEMBL)
Glc,GlcNAc-Fuc-Pre-NOTCH4 ProteinQ99466 (Uniprot-TrEMBL)
Glc,GlcNAc-Fuc-Pre-NOTCHComplexR-HSA-1911434 (Reactome)
Glc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCH1 ProteinP46531 (Uniprot-TrEMBL)
Glc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCH2 ProteinQ04721 (Uniprot-TrEMBL)
Glc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCH3 ProteinQ9UM47 (Uniprot-TrEMBL)
Glc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCH4 ProteinQ99466 (Uniprot-TrEMBL)
Glc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCHComplexR-HSA-1911509 (Reactome)
H2AFB1 ProteinP0C5Y9 (Uniprot-TrEMBL)
H2AFJ ProteinQ9BTM1 (Uniprot-TrEMBL)
H2AFV ProteinQ71UI9 (Uniprot-TrEMBL)
H2AFX ProteinP16104 (Uniprot-TrEMBL)
H2AFZ ProteinP0C0S5 (Uniprot-TrEMBL)
H2BFS ProteinP57053 (Uniprot-TrEMBL)
H3F3A ProteinP84243 (Uniprot-TrEMBL)
HIST1H2AB ProteinP04908 (Uniprot-TrEMBL)
HIST1H2AC ProteinQ93077 (Uniprot-TrEMBL)
HIST1H2AD ProteinP20671 (Uniprot-TrEMBL)
HIST1H2AJ ProteinQ99878 (Uniprot-TrEMBL)
HIST1H2BA ProteinQ96A08 (Uniprot-TrEMBL)
HIST1H2BB ProteinP33778 (Uniprot-TrEMBL)
HIST1H2BC ProteinP62807 (Uniprot-TrEMBL)
HIST1H2BD ProteinP58876 (Uniprot-TrEMBL)
HIST1H2BH ProteinQ93079 (Uniprot-TrEMBL)
HIST1H2BJ ProteinP06899 (Uniprot-TrEMBL)
HIST1H2BK ProteinO60814 (Uniprot-TrEMBL)
HIST1H2BL ProteinQ99880 (Uniprot-TrEMBL)
HIST1H2BM ProteinQ99879 (Uniprot-TrEMBL)
HIST1H2BN ProteinQ99877 (Uniprot-TrEMBL)
HIST1H2BO ProteinP23527 (Uniprot-TrEMBL)
HIST1H3A ProteinP68431 (Uniprot-TrEMBL)
HIST1H4 ProteinP62805 (Uniprot-TrEMBL)
HIST2H2AA3 ProteinQ6FI13 (Uniprot-TrEMBL)
HIST2H2AC ProteinQ16777 (Uniprot-TrEMBL)
HIST2H2BE ProteinQ16778 (Uniprot-TrEMBL)
HIST2H3A ProteinQ71DI3 (Uniprot-TrEMBL)
HIST3H2BB ProteinQ8N257 (Uniprot-TrEMBL)
JUNProteinP05412 (Uniprot-TrEMBL)
KAT2A ProteinQ92830 (Uniprot-TrEMBL)
KAT2B ProteinQ92831 (Uniprot-TrEMBL)
LFNG ProteinQ8NES3 (Uniprot-TrEMBL)
MAML1 ProteinQ92585 (Uniprot-TrEMBL)
MAML2 ProteinQ8IZL2 (Uniprot-TrEMBL)
MAML3 ProteinQ96JK9 (Uniprot-TrEMBL)
MAMLD1 ProteinQ13495 (Uniprot-TrEMBL)
MFNG ProteinO00587 (Uniprot-TrEMBL)
MIR34 genesComplexR-HSA-1852586 (Reactome)
MIR34A gene ProteinENSG00000284357 (Ensembl)
MIR34B gene ProteinENSG00000207811 (Ensembl)
MIR34C gene ProteinENSG00000207562 (Ensembl)
MOV10 ProteinQ9HCE1 (Uniprot-TrEMBL)
NAD+MetaboliteCHEBI:57540 (ChEBI)
NICD1 ProteinP46531 (Uniprot-TrEMBL)
NICD3 ProteinQ9UM47 (Uniprot-TrEMBL)
NOTCH1

mRNA:miR-200B/C

RISC
ComplexR-HSA-1911483 (Reactome)
NOTCH1 Coactivator ComplexComplexR-HSA-1604462 (Reactome)
NOTCH1 coactivator complex:NOTCH3 geneComplexR-HSA-9017845 (Reactome)
NOTCH1 gene ProteinENSG00000148400 (Ensembl)
NOTCH1 gene,NOTCH4 geneComplexR-HSA-9604882 (Reactome)
NOTCH1 geneGeneProductENSG00000148400 (Ensembl)
NOTCH1 mRNA ProteinENST00000277541 (Ensembl)
NOTCH1 mRNA,NOTCH4 mRNAComplexR-HSA-9604923 (Reactome)
NOTCH1 mRNA:miR-34 RISCComplexR-HSA-1606698 (Reactome)
NOTCH1 mRNA:miR-449 RISCComplexR-HSA-1606562 (Reactome)
NOTCH1 mRNARnaENST00000277541 (Ensembl)
NOTCH1(1665-2555) ProteinP46531 (Uniprot-TrEMBL)
NOTCH2 geneGeneProductENSG00000134250 (Ensembl)
NOTCH2 mRNA ProteinENST00000256646 (Ensembl)
NOTCH2 mRNA:miR-34 RISCComplexR-HSA-1911490 (Reactome)
NOTCH2 mRNARnaENST00000256646 (Ensembl)
NOTCH2(1582-2471) ProteinQ04721 (Uniprot-TrEMBL)
NOTCH3 coactivator complexComplexR-HSA-2248837 (Reactome)
NOTCH3 gene ProteinENSG00000074181 (Ensembl)
NOTCH3 geneGeneProductENSG00000074181 (Ensembl)
NOTCH3 mRNA ProteinENST00000263388 (Ensembl)
NOTCH3 mRNA:miR-150 RISCComplexR-HSA-1911497 (Reactome)
NOTCH3 mRNA:miR-206 RISCComplexR-HSA-1911498 (Reactome)
NOTCH3 mRNARnaENST00000263388 (Ensembl)
NOTCH3(1572-2321) ProteinQ9UM47 (Uniprot-TrEMBL)
NOTCH4 gene ProteinENSG00000206312 (Ensembl)
NOTCH4 geneGeneProductENSG00000206312 (Ensembl)
NOTCH4 mRNA ProteinENST00000383264 (Ensembl)
NOTCH4 mRNA:miR-181C RISCComplexR-HSA-1911502 (Reactome)
NOTCH4 mRNA:miR-302A RISCComplexR-HSA-1911500 (Reactome)
NOTCH4 mRNARnaENST00000383264 (Ensembl)
NOTCH4(1337-2003) ProteinQ99466 (Uniprot-TrEMBL)
NOTCHComplexR-HSA-1911472 (Reactome)
NOTCHComplexR-HSA-1911474 (Reactome)
Nucleosome (H3K9ac)ComplexR-HSA-5250919 (Reactome)
POFUT1ProteinQ9H488 (Uniprot-TrEMBL)
POGLUT1ProteinQ8NBL1 (Uniprot-TrEMBL)
PRKCIProteinP41743 (Uniprot-TrEMBL)
Pre-NOTCH1 ProteinP46531 (Uniprot-TrEMBL)
Pre-NOTCH1ProteinP46531 (Uniprot-TrEMBL)
Pre-NOTCH2 ProteinQ04721 (Uniprot-TrEMBL)
Pre-NOTCH2ProteinQ04721 (Uniprot-TrEMBL)
Pre-NOTCH3 ProteinQ9UM47 (Uniprot-TrEMBL)
Pre-NOTCH3ProteinQ9UM47 (Uniprot-TrEMBL)
Pre-NOTCH4 ProteinQ99466 (Uniprot-TrEMBL)
Pre-NOTCH4ProteinQ99466 (Uniprot-TrEMBL)
Pre-NOTCHComplexR-HSA-1464801 (Reactome)
RAB6AProteinP20340 (Uniprot-TrEMBL)
RBPJ ProteinQ06330 (Uniprot-TrEMBL)
RFNG ProteinQ9Y644 (Uniprot-TrEMBL)
RUNX1 ProteinQ01196 (Uniprot-TrEMBL)
RUNX1:NOTCH4 geneComplexR-HSA-9604705 (Reactome)
RUNX1ProteinQ01196 (Uniprot-TrEMBL)
SEL1LProteinQ9UBV2 (Uniprot-TrEMBL)
SIRT6 ProteinQ8N6T7 (Uniprot-TrEMBL)
SIRT6:Nucleosome(H3K9ac):NOTCH1,NOTCH4 geneComplexR-HSA-9604877 (Reactome)
SIRT6:Nucleosome:NOTCH1,NOTCH4 geneComplexR-HSA-9604903 (Reactome)
SIRT6ProteinQ8N6T7 (Uniprot-TrEMBL)
SNW1 ProteinQ13573 (Uniprot-TrEMBL)
ST3GAL3 ProteinQ11203 (Uniprot-TrEMBL)
ST3GAL3/4/6ComplexR-HSA-1499957 (Reactome)
ST3GAL4 ProteinQ11206 (Uniprot-TrEMBL)
ST3GAL6 ProteinQ9Y274 (Uniprot-TrEMBL)
Signaling by NOTCH1PathwayR-HSA-1980143 (Reactome) NOTCH1 functions as both a transmembrane receptor presented on the cell surface and as a transcriptional regulator in the nucleus.

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.

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.

Signaling by NOTCH2PathwayR-HSA-1980145 (Reactome) NOTCH2 is activated by binding Delta-like and Jagged ligands (DLL/JAG) expressed in trans on neighboring cells (Shimizu et al. 1999, Shimizu et al. 2000, Hicks et al. 2000, Ji et al. 2004). In trans ligand-receptor binding is followed by ADAM10 mediated (Gibb et al. 2010, Shimizu et al. 2000) and gamma secretase complex mediated cleavage of NOTCH2 (Saxena et al. 2001, De Strooper et al. 1999), resulting in the release of the intracellular domain of NOTCH2, NICD2, into the cytosol. NICD2 traffics to the nucleus where it acts as a transcriptional regulator. For a recent review of the cannonical NOTCH signaling, please refer to Kopan and Ilagan 2009, D'Souza et al. 2010, Kovall and Blacklow 2010. CNTN1 (contactin 1), a protein involved in oligodendrocyte maturation (Hu et al. 2003) and MDK (midkine) (Huang et al. 2008, Gungor et al. 2011), which plays an important role in epithelial-to-mesenchymal transition, can also bind NOTCH2 and activate NOTCH2 signaling.

In the nucleus, NICD2 forms a complex with RBPJ (CBF1, CSL) and MAML (mastermind). The NICD2:RBPJ:MAML complex activates transcription from RBPJ binding promoter elements (RBEs) (Wu et al. 2000). NOTCH2 coactivator complexes directly stimulate transcription of HES1 and HES5 genes (Shimizu et al. 2002), both of which are known NOTCH1 targets. NOTCH2 but not NOTCH1 coactivator complexes, stimulate FCER2 transcription. Overexpression of FCER2 (CD23A) is a hallmark of B-cell chronic lymphocytic leukemia (B-CLL) and correlates with the malfunction of apoptosis, which is thought be an underlying mechanism of B-CLL development (Hubmann et al. 2002). NOTCH2 coactivator complexes together with CREBP1 and EP300 stimulate transcription of GZMB (granzyme B), which is important for the cytotoxic function of CD8+ T cells (Maekawa et al. 2008).

NOTCH2 gene expression is differentially regulated during human B-cell development, with NOTCH2 transcripts appearing at late developmental stages (Bertrand et al. 2000).

NOTCH2 mutations are a rare cause of Alagille syndrome (AGS). AGS is a dominant congenital multisystem disorder characterized mainly by hepatic bile duct abnormalities. Craniofacial, heart and kidney abnormalities are also frequently observed in the Alagille spectrum (Alagille et al. 1975). AGS is predominantly caused by mutations in JAG1, a NOTCH2 ligand (Oda et al. 1997, Li et al. 1997), but it can also be caused by mutations in NOTCH2 (McDaniell et al. 2006).


Hajdu-Cheney syndrome, an autosomal dominant disorder characterized by severe and progressive bone loss, is caused by NOTCH2 mutations that result in premature C-terminal NOTCH2 truncation, probably leading to increased NOTCH2 signaling (Simpson et al. 2011, Isidor et al. 2011, Majewski et al. 2011).
Signaling by NOTCH3PathwayR-HSA-9012852 (Reactome) Similar to NOTCH1, NOTCH3 is activated by delta-like and jagged ligands (DLL/JAG) expressed in trans on a neighboring cell. The activation triggers cleavage of NOTCH3, first by ADAM10 at the S2 cleavage site, then by gamma-secretase at the S3 cleavage site, resulting in the release of the intracellular domain of NOTCH3, NICD3, into the cytosol. NICD3 subsequently traffics to the nucleus where it acts as a transcriptional regulator. NOTCH3 expression pattern is more restricted than the expression patterns of NOTCH1 and NOTCH2, with predominant expression of NOTCH3 in vascular smooth muscle cells, lymphocytes and the nervous system (reviewed by Bellavia et al. 2008). Based on the study of Notch3 knockout mice, Notch3 is not essential for embryonic development or fertility (Krebs et al. 2003).

Germline gain-of-function NOTCH3 mutations are an underlying cause of the CADASIL syndrome - cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. CADASIL is characterized by degeneration and loss of vascular smooth muscle cells from the arterial wall, predisposing affected individuals to an early onset stroke (Storkebaum et al. 2011). NOTCH3 promotes survival of vascular smooth muscle cells at least in part by induction of CFLAR (c FLIP), an inhibitor of FASLG activated death receptor signaling. The mechanism of NOTCH3 mediated upregulation of CFLAR is unknown; it is independent of the NOTCH3 coactivator complex and involves an unelucidated crosstalk with the RAS/RAF/MAPK pathway (Wang et al. 2002).

In rat brain, NOTCH3 and NOTCH1 are expressed at sites of adult neurogenesis, such as the dentate gyrus (Irvin et al. 2001). NOTCH3, similar to NOTCH1, promotes differentiation of the rat adult hippocampus derived multipotent neuronal progenitors into astroglia (Tanigaki et al. 2001). NOTCH1, NOTCH2, NOTCH3, and their ligand DLL1 are expressed in neuroepithelial precursor cells in the neural tube of mouse embryos. Together, they signal to inhibit neuronal differentiation of neuroepithelial precursors. Expression of NOTCH3 in mouse neuroepithelial precursors is stimulated by growth factors BMP2, FGF2, Xenopus TGF beta5 - homologous to TGFB1, LIF, and NTF3 (Faux et al. 2001).

In mouse telencephalon, NOTCH3, similar to NOTCH1, promotes radial glia and neuronal progenitor phenotype. This can, at least in part be attributed to NOTCH mediated activation of RBPJ-dependent and HES5-dependent transcription (Dang et al. 2006).

In mouse spinal cord, Notch3 is involved in neuronal differentiation and maturation. Notch3 knockout mice have a decreased number of mature inhibitory interneurons in the spinal cord, which may be involved in chronic pain conditions (Rusanescu and Mao 2014).

NOTCH3 amplification was reported in breast cancer, where NOTCH3 promotes proliferation and survival of ERBB2 negative breast cancer cells (Yamaguchi et al. 2008), and it has also been reported in ovarian cancer (Park et al. 2006). NOTCH3 signaling is involved in TGF beta (TGFB1) signaling-induced eptihelial to mesenchimal transition (EMT) (Ohashi et al. 2011, Liu et al. 2014)

NOTCH3 indirectly promotes development of regulatory T cells (Tregs). NOTCH3 signaling activates pre-TCR-dependent and PKC-theta (PRKCQ)-dependent NF-kappaB (NFKB) activation, resulting in induction of FOXP3 expression (Barbarulo et al. 2011). Deregulated NOTCH3 and pre-TCR signaling contributes to development of leukemia and lymphoma (Bellavia et al. 2000, Bellavia et al. 2002).

Signaling by NOTCH4PathwayR-HSA-9013694 (Reactome) The NOTCH4 gene locus was discovered as a frequent site of insertion for the proviral genome of the mouse mammary tumor virus (MMTV) (Gallahan and Callahan 1987). MMTV-insertion results in aberrant expression of the mouse mammary tumor gene int-3, which was subsequently discovered to represent the intracellular domain of Notch4 (Robbins et al. 1992, Uyttendaele et al. 1996).

NOTCH4 is prevalently expressed in endothelial cells (Uyttendaele et al. 1996). DLL4 and JAG1 act as ligands for NOTCH4 in human endothelial cells (Shawber et al. 2003, Shawber et al. 2007), but DLL4- and JAG1-mediated activation of NOTCH4 have not been confirmed in all cell types tested (Aste-Amezaga et al. 2010, James et al. 2014). The gamma secretase complex cleaves activated NOTCH4 receptor to release the intracellular domain fragment (NICD4) (Saxena et al. 2001, Das et al. 2004). NICD4 traffics to the nucleus where it acts as a transcription factor and stimulates expression of NOTCH target genes HES1, HES5, HEY1 and HEY2, as well as VEGFR3 and ACTA2 (Lin et al. 2002, Raafat et al.2004, Tsunematsu et al. 2004, Shawber et al. 2007, Tang et al. 2008, Bargo et al. 2010). NOTCH4 signaling can be downregulated by AKT1 phosphorylation-induced cytoplasmic retention (Ramakrishnan et al. 2015) as well as proteasome-dependent degradation upon FBXW7-mediated ubiquitination (Wu et al. 2001, Tsunematsu et al. 2004).

NOTCH4 was reported to inhibit NOTCH1 signaling in-cis, by binding to NOTCH1 and interfering with the S1 cleavage of NOTCH1, thus preventing production of functional NOTCH1 heterodimers at the cell surface (James et al. 2014).

NOTCH4 is involved in development of the vascular system. Overexpression of constitutively active Notch4 in mouse embryonic vasculature results in abnormal vessel structure and patterning (Uyttendaele et al. 2001). NOTCH4 may act to inhibit apoptosis of endothelial cells (MacKenzie et al. 2004).

Expression of int-3 interferes with normal mammary gland development in mice and promotes tumorigenesis. The phenotype of mice expressing int-3 in mammary glands is dependent on the presence of Rbpj (Raafat et al. 2009). JAG1 and NOTCH4 are upregulated in human ER+ breast cancers resistant to anti-estrogen therapy, which correlates with elevated expression of NOTCH target genes HES1, HEY1 and HEY2, and is associated with increased population of breast cancer stem cells and distant metastases (Simoes et al. 2015). Development of int-3-induced mammary tumours in mice depends on Kit and Pdgfra signaling (Raafat et al. 2006) and on int-3-induced activaton of NFKB signaling (Raafat et al. 2017). In head and neck squamous cell carcinoma (HNSCC), high NOTCH4 expression correlates with elevated HEY1 levels, increased cell proliferation and survival, epithelial-to-mesenchymal transition (EMT) phenotype and cisplatin resistance (Fukusumi et al. 2018). In melanoma, however, exogenous NOTCH4 expression correlates with mesenchymal-to-epithelial-like transition and reduced invasiveness (Bonyadi Rad et al. 2016). NOTCH4 is frequently overexpressed in gastric cancer. Increased NOTCH4 levels correlate with activation of WNT signaling and gastric cancer progression (Qian et al. 2015).

NOTCH4 is expressed in adipocytes and may promote adipocyte differentiation (Lai et al. 2013).

During Dengue virus infection, DLL1, DLL4, NOTCH4 and HES1 are upregulated in interferon-beta (INFB) dependent manner (Li et al. 2015). NOTCH4 signaling may be affected by Epstein-Barr virus (EBV) infection, as the EBV protein BARF0 binds to NOTCH4 (Kusano and Raab-Traub 2001).
TFDP1 ProteinQ14186 (Uniprot-TrEMBL)
TFDP2 ProteinQ14188 (Uniprot-TrEMBL)
TMED2ProteinQ15363 (Uniprot-TrEMBL)
TNRC6A ProteinQ8NDV7 (Uniprot-TrEMBL)
TNRC6B ProteinQ9UPQ9 (Uniprot-TrEMBL)
TNRC6C ProteinQ9HCJ0 (Uniprot-TrEMBL)
TP53 ProteinP04637 (Uniprot-TrEMBL)
TP53 Tetramer:MIR34 genesComplexR-HSA-4395237 (Reactome)
TP53 TetramerComplexR-HSA-3209194 (Reactome)
UDP-GalMetaboliteCHEBI:18307 (ChEBI)
UDP-GlcMetaboliteCHEBI:18066 (ChEBI)
UDP-GlcNAcMetaboliteCHEBI:16264 (ChEBI)
UDPMetaboliteCHEBI:17659 (ChEBI)
miR-150 ProteinMI0000479 (miRBase mature sequence)
miR-150 RISCComplexR-HSA-1852612 (Reactome)
miR-181C ProteinMI0000271 (miRBase mature sequence)
miR-181C RISCComplexR-HSA-1852604 (Reactome)
miR-200B ProteinMI0000342 (miRBase mature sequence)
miR-200B/C RISCComplexR-HSA-1614237 (Reactome)
miR-200C ProteinMI0000650 (miRBase mature sequence)
miR-206 ProteinMI0000490 (miRBase mature sequence)
miR-206 RISCComplexR-HSA-1614243 (Reactome)
miR-302A ProteinMI0000738 (miRBase mature sequence)
miR-302A RISCComplexR-HSA-1852598 (Reactome)
miR-34 RISCComplexR-HSA-1606685 (Reactome)
miR-34A ProteinMI0000268 (miRBase mature sequence)
miR-34B ProteinMI0000742 (miRBase mature sequence)
miR-34C ProteinMI0000743 (miRBase mature sequence)
miR-449 RISCComplexR-HSA-1606557 (Reactome)
miR-449A ProteinMI0001648 (miRBase mature sequence)
miR-449B ProteinMI0003673 (miRBase mature sequence)
miR-449C ProteinMI0003823 (miRBase mature sequence)
p-S68-ELF3 ProteinP78545 (Uniprot-TrEMBL)
p-S68-ELF3:NOTCH3 geneComplexR-HSA-9021365 (Reactome)
p-S68-ELF3ProteinP78545 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
2'-O-acetyl-ADP-riboseArrowR-HSA-9604829 (Reactome)
ADPArrowR-HSA-9021357 (Reactome)
ATP2A1-3ArrowR-HSA-1912374 (Reactome)
ATPR-HSA-9021357 (Reactome)
B4GALT1 homodimermim-catalysisR-HSA-1912352 (Reactome)
CCND1:CREBBP:NOTCH1 GeneArrowR-HSA-1912416 (Reactome)
CCND1:CREBBP:NOTCH1 GeneArrowR-HSA-4395227 (Reactome)
CCND1:CREBBPR-HSA-4395227 (Reactome)
CMP-Neu5AcR-HSA-1912378 (Reactome)
CMPArrowR-HSA-1912378 (Reactome)
E2F1/3:DP1/2:NOTCH1 GeneArrowR-HSA-1912416 (Reactome)
E2F1/3:DP1/2:NOTCH1 GeneArrowR-HSA-4395231 (Reactome)
E2F1/3:DP1/2R-HSA-4395231 (Reactome)
ELF3R-HSA-9021357 (Reactome)
FRINGE-modified NOTCHArrowR-HSA-1912372 (Reactome)
FRINGE-modified NOTCHR-HSA-1912379 (Reactome)
FURINmim-catalysisR-HSA-1912369 (Reactome)
FURINmim-catalysisR-HSA-1912372 (Reactome)
Fringe familymim-catalysisR-HSA-1912355 (Reactome)
Fringe-modified NOTCHArrowR-HSA-1912379 (Reactome)
Fuc-Pre-NOTCHArrowR-HSA-1912349 (Reactome)
Fuc-Pre-NOTCHR-HSA-1912353 (Reactome)
GDP-FucR-HSA-1912349 (Reactome)
GDPArrowR-HSA-1912349 (Reactome)
Glc,Fuc-Pre-NOTCHArrowR-HSA-1912353 (Reactome)
Glc,Fuc-Pre-NOTCHArrowR-HSA-1912374 (Reactome)
Glc,Fuc-Pre-NOTCHR-HSA-1912355 (Reactome)
Glc,Fuc-Pre-NOTCHR-HSA-1912369 (Reactome)
Glc,Fuc-Pre-NOTCHR-HSA-1912374 (Reactome)
Glc,Gal-GlcNAc-Fuc-Pre-NOTCHArrowR-HSA-1912352 (Reactome)
Glc,Gal-GlcNAc-Fuc-Pre-NOTCHR-HSA-1912378 (Reactome)
Glc,GlcNAc-Fuc-Pre-NOTCHArrowR-HSA-1912355 (Reactome)
Glc,GlcNAc-Fuc-Pre-NOTCHR-HSA-1912352 (Reactome)
Glc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCHArrowR-HSA-1912378 (Reactome)
Glc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCHR-HSA-1912372 (Reactome)
JUNArrowR-HSA-1912401 (Reactome)
MIR34 genesR-HSA-1912406 (Reactome)
MIR34 genesR-HSA-4395236 (Reactome)
NAD+R-HSA-9604829 (Reactome)
NOTCH1

mRNA:miR-200B/C

RISC
ArrowR-HSA-1912363 (Reactome)
NOTCH1

mRNA:miR-200B/C

RISC
TBarR-HSA-1912412 (Reactome)
NOTCH1 Coactivator ComplexArrowR-HSA-1912416 (Reactome)
NOTCH1 Coactivator ComplexR-HSA-9017835 (Reactome)
NOTCH1 coactivator complex:NOTCH3 geneArrowR-HSA-1912415 (Reactome)
NOTCH1 coactivator complex:NOTCH3 geneArrowR-HSA-9017835 (Reactome)
NOTCH1 gene,NOTCH4 geneR-HSA-9604831 (Reactome)
NOTCH1 gene,NOTCH4 geneR-HSA-9604834 (Reactome)
NOTCH1 geneR-HSA-1912416 (Reactome)
NOTCH1 geneR-HSA-4395227 (Reactome)
NOTCH1 geneR-HSA-4395231 (Reactome)
NOTCH1 mRNA,NOTCH4 mRNAArrowR-HSA-9604831 (Reactome)
NOTCH1 mRNA:miR-34 RISCArrowR-HSA-1606682 (Reactome)
NOTCH1 mRNA:miR-34 RISCTBarR-HSA-1912412 (Reactome)
NOTCH1 mRNA:miR-449 RISCArrowR-HSA-1606561 (Reactome)
NOTCH1 mRNA:miR-449 RISCTBarR-HSA-1912412 (Reactome)
NOTCH1 mRNAArrowR-HSA-1912416 (Reactome)
NOTCH1 mRNAR-HSA-1606561 (Reactome)
NOTCH1 mRNAR-HSA-1606682 (Reactome)
NOTCH1 mRNAR-HSA-1912363 (Reactome)
NOTCH1 mRNAR-HSA-1912412 (Reactome)
NOTCH2 geneR-HSA-1912407 (Reactome)
NOTCH2 mRNA:miR-34 RISCArrowR-HSA-1912367 (Reactome)
NOTCH2 mRNA:miR-34 RISCTBarR-HSA-1912413 (Reactome)
NOTCH2 mRNAArrowR-HSA-1912407 (Reactome)
NOTCH2 mRNAR-HSA-1912367 (Reactome)
NOTCH2 mRNAR-HSA-1912413 (Reactome)
NOTCH3 coactivator complexArrowR-HSA-1912415 (Reactome)
NOTCH3 geneR-HSA-1912415 (Reactome)
NOTCH3 geneR-HSA-9017835 (Reactome)
NOTCH3 geneR-HSA-9021364 (Reactome)
NOTCH3 mRNA:miR-150 RISCArrowR-HSA-1912362 (Reactome)
NOTCH3 mRNA:miR-150 RISCTBarR-HSA-1912409 (Reactome)
NOTCH3 mRNA:miR-206 RISCArrowR-HSA-1912366 (Reactome)
NOTCH3 mRNA:miR-206 RISCTBarR-HSA-1912409 (Reactome)
NOTCH3 mRNAArrowR-HSA-1912415 (Reactome)
NOTCH3 mRNAR-HSA-1912362 (Reactome)
NOTCH3 mRNAR-HSA-1912366 (Reactome)
NOTCH3 mRNAR-HSA-1912409 (Reactome)
NOTCH4 geneR-HSA-1912401 (Reactome)
NOTCH4 geneR-HSA-9604703 (Reactome)
NOTCH4 geneR-HSA-9604719 (Reactome)
NOTCH4 mRNA:miR-181C RISCArrowR-HSA-1912364 (Reactome)
NOTCH4 mRNA:miR-181C RISCTBarR-HSA-1912410 (Reactome)
NOTCH4 mRNA:miR-302A RISCArrowR-HSA-1912368 (Reactome)
NOTCH4 mRNA:miR-302A RISCTBarR-HSA-1912410 (Reactome)
NOTCH4 mRNAArrowR-HSA-1912401 (Reactome)
NOTCH4 mRNAArrowR-HSA-9604719 (Reactome)
NOTCH4 mRNAR-HSA-1912364 (Reactome)
NOTCH4 mRNAR-HSA-1912368 (Reactome)
NOTCH4 mRNAR-HSA-1912410 (Reactome)
NOTCHArrowR-HSA-1912369 (Reactome)
NOTCHArrowR-HSA-1912382 (Reactome)
NOTCHR-HSA-1912382 (Reactome)
Nucleosome (H3K9ac)R-HSA-9604834 (Reactome)
POFUT1mim-catalysisR-HSA-1912349 (Reactome)
POGLUT1mim-catalysisR-HSA-1912353 (Reactome)
PRKCImim-catalysisR-HSA-9021357 (Reactome)
Pre-NOTCH1ArrowR-HSA-1912412 (Reactome)
Pre-NOTCH2ArrowR-HSA-1912413 (Reactome)
Pre-NOTCH3ArrowR-HSA-1912409 (Reactome)
Pre-NOTCH4ArrowR-HSA-1912410 (Reactome)
Pre-NOTCHR-HSA-1912349 (Reactome)
R-HSA-1606561 (Reactome) 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.
R-HSA-1606682 (Reactome) 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.
R-HSA-1912349 (Reactome) 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).
R-HSA-1912352 (Reactome) 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.
R-HSA-1912353 (Reactome) 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.
R-HSA-1912355 (Reactome) 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.
R-HSA-1912362 (Reactome) 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.
R-HSA-1912363 (Reactome) 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.
R-HSA-1912364 (Reactome) miR-181C microRNA inhibits translation of NOTCH4 mRNA by binding to its 3'UTR. miR181c is a candidate tumor suppressor in gastric cancer.
R-HSA-1912366 (Reactome) Translation of NOTCH3 mRNA is inhibited by microRNA miR-206 which binds to the 3'UTR of NOTCH3 mRNA.
R-HSA-1912367 (Reactome) Translation of NOTCH2 mRNA is inhibited by MIR34 microRNAs (MIR34A, MIR34B and MIR34C), which bind to the 3'UTR of NOTCH2 mRNA.
R-HSA-1912368 (Reactome) MicroRNA miR-302A, upregulated in melanoma, binds the 3'UTR of NOTCH4, resulting in inhibition of NOTCH4 mRNA translation.
R-HSA-1912369 (Reactome) 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).
R-HSA-1912372 (Reactome) 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.
R-HSA-1912374 (Reactome) 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.
R-HSA-1912378 (Reactome) 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).
R-HSA-1912379 (Reactome) 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.
R-HSA-1912382 (Reactome) 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.
R-HSA-1912401 (Reactome) 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).

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).
R-HSA-1912406 (Reactome) 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.
R-HSA-1912407 (Reactome) 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.
R-HSA-1912409 (Reactome) 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.
R-HSA-1912410 (Reactome) 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.
R-HSA-1912412 (Reactome) 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.
R-HSA-1912413 (Reactome) 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.
R-HSA-1912415 (Reactome) 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).

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).

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).

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).

R-HSA-1912416 (Reactome) 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).

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).

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).

E2F1 and E2F3 are able to bind to the NOTCH1 promoter and activate NOTCH1 transcription (Viatour et al. 2011).

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).
R-HSA-4395227 (Reactome) 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).
R-HSA-4395231 (Reactome) E2F1 and E2F3 are able to bind to the NOTCH1 promoter and activate NOTCH1 transcription (Viatour et al. 2011).
R-HSA-4395236 (Reactome) 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).
R-HSA-9017835 (Reactome) 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).
R-HSA-9021357 (Reactome) 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).
R-HSA-9021364 (Reactome) 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).
R-HSA-9604703 (Reactome) The transcription factor RUNX1 binds to runx response elements in intron 29 of the NOTCH4 gene (Li et al. 2018).
R-HSA-9604719 (Reactome) 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).
R-HSA-9604829 (Reactome) 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).
R-HSA-9604831 (Reactome) 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).
R-HSA-9604834 (Reactome) 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).
RAB6AArrowR-HSA-1912374 (Reactome)
RUNX1:NOTCH4 geneArrowR-HSA-9604703 (Reactome)
RUNX1:NOTCH4 geneTBarR-HSA-9604719 (Reactome)
RUNX1R-HSA-9604703 (Reactome)
SEL1LTBarR-HSA-1912374 (Reactome)
SIRT6:Nucleosome(H3K9ac):NOTCH1,NOTCH4 geneArrowR-HSA-9604834 (Reactome)
SIRT6:Nucleosome(H3K9ac):NOTCH1,NOTCH4 geneR-HSA-9604829 (Reactome)
SIRT6:Nucleosome(H3K9ac):NOTCH1,NOTCH4 genemim-catalysisR-HSA-9604829 (Reactome)
SIRT6:Nucleosome:NOTCH1,NOTCH4 geneArrowR-HSA-9604829 (Reactome)
SIRT6:Nucleosome:NOTCH1,NOTCH4 geneTBarR-HSA-9604831 (Reactome)
SIRT6R-HSA-9604834 (Reactome)
ST3GAL3/4/6mim-catalysisR-HSA-1912378 (Reactome)
TMED2TBarR-HSA-1912379 (Reactome)
TMED2TBarR-HSA-1912382 (Reactome)
TP53 Tetramer:MIR34 genesArrowR-HSA-1912406 (Reactome)
TP53 Tetramer:MIR34 genesArrowR-HSA-4395236 (Reactome)
TP53 TetramerR-HSA-4395236 (Reactome)
UDP-GalR-HSA-1912352 (Reactome)
UDP-GlcNAcR-HSA-1912355 (Reactome)
UDP-GlcR-HSA-1912353 (Reactome)
UDPArrowR-HSA-1912352 (Reactome)
UDPArrowR-HSA-1912353 (Reactome)
UDPArrowR-HSA-1912355 (Reactome)
miR-150 RISCR-HSA-1912362 (Reactome)
miR-181C RISCR-HSA-1912364 (Reactome)
miR-200B/C RISCR-HSA-1912363 (Reactome)
miR-206 RISCR-HSA-1912366 (Reactome)
miR-302A RISCR-HSA-1912368 (Reactome)
miR-34 RISCArrowR-HSA-1912406 (Reactome)
miR-34 RISCR-HSA-1606682 (Reactome)
miR-34 RISCR-HSA-1912367 (Reactome)
miR-449 RISCR-HSA-1606561 (Reactome)
p-S68-ELF3:NOTCH3 geneArrowR-HSA-1912415 (Reactome)
p-S68-ELF3:NOTCH3 geneArrowR-HSA-9021364 (Reactome)
p-S68-ELF3ArrowR-HSA-9021357 (Reactome)
p-S68-ELF3R-HSA-9021364 (Reactome)
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