Pre-NOTCH Expression and Processing (Homo sapiens)

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2, 13, 18, 20, 29...56, 11840, 1051, 6, 9, 10, 23...3237, 80, 111, 112, 129...20, 29, 89, 91, 1232, 18, 38, 97, 1228210513, 3245, 88, 1128820, 82, 91, 13028, 76, 1165, 86, 89, 12370, 75, 88, 109, 11954, 11565, 102, 1121302015, 4212, 21, 33, 48, 57...20134088, 10488, 108miR-302A Nonendonucleolytic RISC NOTCH2 miR-181C Endonucleolytic Minimal RISC miR-200B/C Nonendonucleolytic RISC miR-302A Endonucleolytic RISC TNRC6 TNRC6 miR-302A Nonendonucleolytic RISC miR-34 RISC NOTCH1 mRNAmiR-200B/C RISC cytosolmiR-200B/C Nonendonucleolytic Minimal RISC Nonendonucleolytic Argonaute NOTCH3 TNRC6 Golgi lumenmiR-206 RISC miR-150 Endonucleolytic RISC NOTCH4 mRNAmiR-302A RISC miR-449 Endonucleolytic Minimal RISC miR-200B/C RISC miR-449 Endonucleolytic Minimal RISC miR-181C RISC miR-150 Endonucleolytic Minimal RISC miR-34 Nonendonucleolytic Minimal RISC NOTCH miR-200B/C Endonucleolytic RISC miR-34 Nonendonucleolytic RISC miR-302A Nonendonucleolytic Minimal RISC miR-206 Nonendonucleolytic Minimal RISC miR-206 Nonendonucleolytic RISC Nonendonucleolytic Argonaute DP1/2 miR-449 Nonendonucleolytic RISC miR-302A Nonendonucleolytic Minimal RISC miR-302A Endonucleolytic Minimal RISC TNRC6 miR-206 RISC miR-200B/C miR-150 Endonucleolytic RISC miR-302A Endonucleolytic Minimal RISC NOTCH1 mRNAmiR-449 RISC NOTCH3 Nonendonucleolytic Argonaute miR-150 Endonucleolytic Minimal RISC miR-206 Nonendonucleolytic Minimal RISC endoplasmic reticulum lumenmiR-449 Nonendonucleolytic RISC NOTCH1 NOTCH1 mRNAmiR-34 RISC miR-181C Nonendonucleolytic RISC miR-34 Endonucleolytic Minimal RISC miR-200B/C Nonendonucleolytic RISC NOTCH1 Coactivator Complex NOTCH2 miR-449 Nonendonucleolytic Minimal RISC Nonendonucleolytic Argonaute Nonendonucleolytic Argonaute miR-34 RISC miR-34 Endonucleolytic Minimal RISC miR-449 Nonendonucleolytic Minimal RISC Nonendonucleolytic Argonaute miR-181C Nonendonucleolytic RISC NOTCH NOTCH4 TNRC6 miR-34 RISC TNRC6 miR-449 Endonucleolytic RISC miR-150 Nonendonucleolytic Minimal RISC miR-200B/C Nonendonucleolytic Minimal RISC Nonendonucleolytic Argonaute miR-34 Nonendonucleolytic RISC TNRC6 NOTCH2 mRNAmiR-34 RISC miR-34 Nonendonucleolytic Minimal RISC B4GALT1 homodimer Nonendonucleolytic Argonaute CCND1CREBBP miR-200B/C miR-206 Endonucleolytic RISC miR-449 RISC miR-181C RISC miR-181C Nonendonucleolytic Minimal RISC miR-206 Endonucleolytic Minimal RISC miR-200B/C Endonucleolytic Minimal RISC Nonendonucleolytic Argonaute miR-34 Endonucleolytic RISC E2F1/3DP1/2 miR-200B/C RISC NOTCH3 mRNAmiR-206 RISC NOTCH3 mRNAmiR-150 RISC miR-206 Endonucleolytic RISC miR-302A RISC TNRC6 miR-34 Endonucleolytic Minimal RISC miR-150 RISC miR-206 Nonendonucleolytic RISC TNRC6 miR-150 RISC NOTCH1 Nonendonucleolytic Argonaute nucleoplasmTNRC6 Nonendonucleolytic Argonaute miR-302A Endonucleolytic RISC miR-150 Nonendonucleolytic Minimal RISC miR-449 Endonucleolytic RISC miR-150 Nonendonucleolytic RISC miR-181C Nonendonucleolytic Minimal RISC TNRC6 miR-181C Endonucleolytic Minimal RISC miR-34 Nonendonucleolytic Minimal RISC Nonendonucleolytic Argonaute NICD1RBPJSNW1 Nonendonucleolytic Argonaute NOTCH4 TNRC6 TNRC6 Nonendonucleolytic Argonaute miR-34 Endonucleolytic RISC miR-200B/C Endonucleolytic RISC miR-34 Endonucleolytic RISC miR-34 Nonendonucleolytic RISC TNRC6 miR-200B/C Endonucleolytic Minimal RISC TNRC6 miR-150 Nonendonucleolytic RISC miR-206 Endonucleolytic Minimal RISC miR-181C Endonucleolytic RISC E2F1/E2F3 miR-181C Endonucleolytic RISC Nonendonucleolytic Argonaute NOTCH4 mRNAmiR-181C RISC NOTCH3 Coactivator Complex miR-302A RISC miR-449 RISC TNRC6A TNRC6C EIF2C4 EIF2C1 EIF2C3 EIF2C1 18xFucT-16xGlcS-FucS-NOTCH2TNRC6A NOTCH1 geneEIF2C4 MOV10 JUNNOTCH3NICD1 TNRC6B NOTCH4 mRNAmiR-302A RISCEIF2C4 Fringe familyEIF2C2 UDPTNRC6A EP300MOV10 miR-181C 12xFucT-11xGlcS-6xFucS-NOTCH4TNRC6C miR-302A RISCMOV10 NOTCH2TMED214xGlcS-10xFucT-4xFucS-NOTCH3NOTCH4 mRNA TNRC6C EIF2C2 EIF2C4 TNRC6C MOV10 MOV10 miR-206 EIF2C1 miR-302A NOTCH1miR-206 TNRC6B TNRC6B POGLUT1TNRC6C miR-302A E2F3 Signaling by NOTCH4EIF2C3 miR-150 RISCNOTCH1 mRNAmiR-34 RISCCREBBPTNRC6B TFDP1EIF2C2 Glc,GlcNAc-Fuc-Pre-NOTCHEIF2C4 EIF2C3 NOTCH4EIF2C3 TNRC6A TNRC6B 19xFucT-16xGlcS-2xFucS-NOTCH1TNRC6C EIF2C4 Signaling by NOTCH1NOTCH3 mRNA TNRC6C CMPTNRC6B Glc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCHEIF2C1 SEL1LEIF2C1 EIF2C4 NOTCH1NOTCHNOTCH1TNRC6A NOTCH2EIF2C4 EIF2C3 NOTCH3 mRNA UDPPOFUT1E2F1 miR-181C ATP2A1-3NOTCH4miR-200C NOTCHTNRC6A NOTCH1 mRNA TNRC6B TNRC6C EIF2C1 TNRC6A MOV10 NOTCH1 mRNAmiR-200B/C RISCmiR-200B EIF2C3 miR-206 RISCNOTCH2 mRNAmiR-34 RISCEIF2C4 GDP-FucGlc,Gal-GlcNAc-Fuc-Pre-NOTCHB4GALT1 homodimerTNRC6B EIF2C2 Signaling by NOTCH2TFDP2 EIF2C1 EIF2C3 EIF2C4 TNRC6A EIF2C2 NOTCH2 mRNA SNW1 NOTCH3NOTCH3 mRNAmiR-206 RISCEIF2C1 NOTCH1 mRNA EIF2C3 TNRC6A EIF2C2 NICD3 TNRC6A TNRC6C EIF2C2 miR-200B/C RISCTNRC6C Fuc-Pre-NOTCHNOTCH1 mRNAmiR-449 RISCNOTCH3 mRNATNRC6C NOTCH4 mRNAMOV10 18xFucT-16xGlcS-FucS-NOTCH2FURINTNRC6A EIF2C2 NOTCH3 mRNAmiR-150 RISCTNRC6A EIF2C1 NOTCH4 mRNAmiR-181C RISCNOTCH1 mRNATNRC6B EIF2C1 12xFucT-8xGlcS-6xFucS-NOTCH4UDPEIF2C4 EIF2C2 MOV10 TNRC6A miR-200C EIF2C4 EIF2C3 EIF2C3 Glc,Fuc-Pre-NOTCHTNRC6C NOTCH2 mRNATNRC6B EIF2C3 EIF2C3 TNRC6B MOV10 Pre-NOTCHEIF2C4 17xFucT-14xGlcS-2xFucS-NOTCH1MOV10 EIF2C1 UDP-GlcNAcNOTCH1 mRNA miR-34 RISCCMP-SAEIF2C3 TNRC6C E2F1/3DP1/2RBPJ MOV10 MOV10 miR-181C RISCMIR34 genesCCND1CREBBPNOTCH4 mRNA CCND1 MOV10 EIF2C1 NOTCH4EIF2C2 TNRC6B RAB6ATNRC6A UDP-GalEIF2C4 NOTCH3 geneEIF2C2 EIF2C2 MOV10 ST3GAL3/4/6RBPJ EIF2C3 Glc,Fuc-Pre-NOTCHNOTCH4 geneUDP-GlcCREBBPTNRC6C TNRC6B MOV10 TNRC6C 14xGlcS-10xFucT-4xFucS-NOTCH3NOTCH3GDPEIF2C2 NOTCH1 Coactivator ComplexSignaling by NOTCH3EIF2C1 miR-150 B4GALT1 miR-200B miR-449 RISCNOTCH3 Coactivator ComplexNOTCH2 geneTP53FRINGE-modified NOTCHEIF2C1 miR-150 NOTCH2EIF2C2 EIF2C4 EIF2C1 TNRC6A TNRC6B EIF2C3 Fringe-modified NOTCHTNRC6B EIF2C2 7, 8, 14, 25, 26, 28...49923, 4, 11, 16, 17, 19...


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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.

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  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
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  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
12xFucT-11xGlcS-6xFucS-NOTCH4ProteinQ99466 (Uniprot-TrEMBL)
12xFucT-8xGlcS-6xFucS-NOTCH4ProteinQ99466 (Uniprot-TrEMBL)
14xGlcS-10xFucT-4xFucS-NOTCH3ProteinQ9UM47 (Uniprot-TrEMBL)
17xFucT-14xGlcS-2xFucS-NOTCH1ProteinP46531 (Uniprot-TrEMBL)
18xFucT-16xGlcS-FucS-NOTCH2ProteinQ04721 (Uniprot-TrEMBL)
19xFucT-16xGlcS-2xFucS-NOTCH1ProteinP46531 (Uniprot-TrEMBL)
ATP2A1-3ProteinREACT_26227 (Reactome)
B4GALT1 ProteinP15291 (Uniprot-TrEMBL)
B4GALT1 homodimerComplexREACT_26670 (Reactome)
CCND1 CREBBPComplexREACT_124278 (Reactome)
CCND1 ProteinP24385 (Uniprot-TrEMBL)
CMP-SAMetaboliteCHEBI:16556 (ChEBI)
CMPMetaboliteCHEBI:17361 (ChEBI)
CREBBPProteinQ92793 (Uniprot-TrEMBL)
E2F1 ProteinQ01094 (Uniprot-TrEMBL)
E2F1/3 DP1/2ComplexREACT_124495 (Reactome)
E2F3 ProteinO00716 (Uniprot-TrEMBL)
EIF2C1 ProteinQ9UL18 (Uniprot-TrEMBL)
EIF2C2 ProteinQ9UKV8 (Uniprot-TrEMBL)
EIF2C3 ProteinQ9H9G7 (Uniprot-TrEMBL)
EIF2C4 ProteinQ9HCK5 (Uniprot-TrEMBL)
EP300ProteinQ09472 (Uniprot-TrEMBL)
FRINGE-modified NOTCHComplexREACT_118888 (Reactome)
FURINProteinP09958 (Uniprot-TrEMBL)
Fringe familyProteinREACT_119986 (Reactome)
Fringe-modified NOTCHComplexREACT_120243 (Reactome)
Fuc-Pre-NOTCHProteinREACT_120233 (Reactome)
GDP-FucMetaboliteCHEBI:17009 (ChEBI)
GDPMetaboliteCHEBI:17552 (ChEBI)
Glc,Fuc-Pre-NOTCHProteinREACT_119436 (Reactome)
Glc,Fuc-Pre-NOTCHProteinREACT_119529 (Reactome)
Glc,Gal-GlcNAc-Fuc-Pre-NOTCHProteinREACT_119453 (Reactome)
Glc,GlcNAc-Fuc-Pre-NOTCHProteinREACT_119767 (Reactome)
Glc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCHProteinREACT_119543 (Reactome)
JUNProteinP05412 (Uniprot-TrEMBL)
MIR34 genesREACT_119280 (Reactome)
MOV10 ProteinQ9HCE1 (Uniprot-TrEMBL)
NICD1 ProteinP46531 (Uniprot-TrEMBL)
NICD3 ProteinQ9UM47 (Uniprot-TrEMBL)
NOTCH1 Coactivator ComplexComplexREACT_119935 (Reactome)
NOTCH1 geneENSG00000148400 (ENSEMBL)
NOTCH1 mRNA miR-200B/C RISCComplexREACT_119797 (Reactome)
NOTCH1 mRNA miR-34 RISCComplexREACT_119152 (Reactome)
NOTCH1 mRNA miR-449 RISCComplexREACT_119337 (Reactome)
NOTCH1 mRNA ProteinENST00000277541 (ENSEMBL)
NOTCH1 mRNARnaENST00000277541 (ENSEMBL)
NOTCH1ProteinP46531 (Uniprot-TrEMBL)
NOTCH2 geneENSG00000134250 (ENSEMBL)
NOTCH2 mRNA miR-34 RISCComplexREACT_120101 (Reactome)
NOTCH2 mRNA ProteinENST00000256646 (ENSEMBL)
NOTCH2 mRNARnaENST00000256646 (ENSEMBL)
NOTCH2ProteinQ04721 (Uniprot-TrEMBL)
NOTCH3 Coactivator ComplexComplexREACT_121818 (Reactome)
NOTCH3 geneENSG00000074181 (ENSEMBL)
NOTCH3 mRNA miR-150 RISCComplexREACT_119485 (Reactome)
NOTCH3 mRNA miR-206 RISCComplexREACT_120083 (Reactome)
NOTCH3 mRNA ProteinENST00000263388 (ENSEMBL)
NOTCH3 mRNARnaENST00000263388 (ENSEMBL)
NOTCH3ProteinQ9UM47 (Uniprot-TrEMBL)
NOTCH4 geneENSG00000206312 (ENSEMBL)
NOTCH4 mRNA miR-181C RISCComplexREACT_119872 (Reactome)
NOTCH4 mRNA miR-302A RISCComplexREACT_118905 (Reactome)
NOTCH4 mRNA ProteinENST00000383264 (ENSEMBL)
NOTCH4 mRNARnaENST00000383264 (ENSEMBL)
NOTCH4ProteinQ99466 (Uniprot-TrEMBL)
NOTCHComplexREACT_119110 (Reactome)
NOTCHComplexREACT_119526 (Reactome)
POFUT1ProteinQ9H488 (Uniprot-TrEMBL)
POGLUT1ProteinQ8NBL1 (Uniprot-TrEMBL)
Pre-NOTCHProteinREACT_118931 (Reactome)
RAB6AProteinP20340 (Uniprot-TrEMBL)
RBPJ ProteinQ06330 (Uniprot-TrEMBL)
SEL1LProteinQ9UBV2 (Uniprot-TrEMBL)
SNW1 ProteinQ13573 (Uniprot-TrEMBL)
ST3GAL3/4/6ProteinREACT_118994 (Reactome)
Signaling by NOTCH1PathwayWP2720 (WikiPathways) 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, MAML3 or MAMLD1) to form NOTCH1 coactivator complex. NOTCH1 coactivator complex activates transcription of genes that possess RBPJ binding sites in their promoters.

Signaling by NOTCH2PathwayWP2718 (WikiPathways) 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 NOTCH3PathwayWP2722 (WikiPathways) 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.
Signaling by NOTCH4PathwayWP2721 (WikiPathways) Similar to NOTCH1, NOTCH4 is activated by delta-like and jagged ligands (DLL/JAG) expressed in trans on a neighboring cell. The activation triggers cleavage of NOTCH4, 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 NOTCH4, NICD4, into the cytosol. NICD4 subsequently traffics to the nucleus where it acts as a transcriptional regulator.
TFDP1ProteinQ14186 (Uniprot-TrEMBL)
TFDP2 ProteinQ14188 (Uniprot-TrEMBL)
TMED2ProteinQ15363 (Uniprot-TrEMBL)
TNRC6A ProteinQ8NDV7 (Uniprot-TrEMBL)
TNRC6B ProteinQ9UPQ9 (Uniprot-TrEMBL)
TNRC6C ProteinQ9HCJ0 (Uniprot-TrEMBL)
TP53ProteinP04637 (Uniprot-TrEMBL)
UDP-GalMetaboliteCHEBI:18307 (ChEBI)
UDP-GlcMetaboliteCHEBI:18066 (ChEBI)
UDP-GlcNAcMetaboliteCHEBI:16264 (ChEBI)
UDPMetaboliteCHEBI:17659 (ChEBI)
miR-150 ProteinMI0000479 (miRBase)
miR-150 RISCComplexREACT_119440 (Reactome)
miR-181C ProteinMI0000271 (miRBase)
miR-181C RISCComplexREACT_119531 (Reactome)
miR-200B ProteinMI0000342 (miRBase)
miR-200B/C RISCComplexREACT_119264 (Reactome)
miR-200C ProteinMI0000650 (miRBase)
miR-206 ProteinMI0000490 (miRBase)
miR-206 RISCComplexREACT_120082 (Reactome)
miR-302A ProteinMI0000738 (miRBase)
miR-302A RISCComplexREACT_120131 (Reactome)
miR-34 RISCComplexREACT_118950 (Reactome)
miR-449 RISCComplexREACT_120304 (Reactome)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ATP2A1-3ArrowREACT_118577 (Reactome)
B4GALT1 homodimerREACT_118855 (Reactome)
CCND1 CREBBPArrowREACT_118626 (Reactome)
CMP-SAREACT_118739 (Reactome)
CMPArrowREACT_118739 (Reactome)
E2F1/3 DP1/2ArrowREACT_118626 (Reactome)
FURINREACT_118767 (Reactome)
FURINREACT_118833 (Reactome)
Fringe familyREACT_118594 (Reactome)
Fuc-Pre-NOTCHArrowREACT_118694 (Reactome)
Fuc-Pre-NOTCHREACT_118657 (Reactome)
GDP-FucREACT_118694 (Reactome)
GDPArrowREACT_118694 (Reactome)
Glc,Fuc-Pre-NOTCHArrowREACT_118657 (Reactome)
Glc,Fuc-Pre-NOTCHREACT_118594 (Reactome)
Glc,Gal-GlcNAc-Fuc-Pre-NOTCHArrowREACT_118855 (Reactome)
Glc,Gal-GlcNAc-Fuc-Pre-NOTCHREACT_118739 (Reactome)
Glc,GlcNAc-Fuc-Pre-NOTCHArrowREACT_118594 (Reactome)
Glc,GlcNAc-Fuc-Pre-NOTCHREACT_118855 (Reactome)
Glc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCHArrowREACT_118739 (Reactome)
JUNArrowREACT_118639 (Reactome)
NOTCH1 Coactivator ComplexArrowREACT_118626 (Reactome)
NOTCH1 mRNA miR-200B/C RISCTBarREACT_118745 (Reactome)
NOTCH1 mRNA miR-34 RISCTBarREACT_118745 (Reactome)
NOTCH1 mRNA miR-449 RISCTBarREACT_118745 (Reactome)
NOTCH1 mRNAREACT_118599 (Reactome)
NOTCH1 mRNAREACT_118670 (Reactome)
NOTCH1 mRNAREACT_118755 (Reactome)
NOTCH2 mRNA miR-34 RISCTBarREACT_118612 (Reactome)
NOTCH2 mRNAREACT_118850 (Reactome)
NOTCH3 Coactivator ComplexArrowREACT_118757 (Reactome)
NOTCH3 mRNA miR-150 RISCTBarREACT_118714 (Reactome)
NOTCH3 mRNA miR-206 RISCTBarREACT_118714 (Reactome)
NOTCH3 mRNAREACT_118686 (Reactome)
NOTCH3 mRNAREACT_118736 (Reactome)
NOTCH4 mRNA miR-181C RISCTBarREACT_118578 (Reactome)
NOTCH4 mRNA miR-302A RISCTBarREACT_118578 (Reactome)
NOTCH4 mRNAREACT_118737 (Reactome)
NOTCH4 mRNAREACT_118819 (Reactome)
POFUT1REACT_118694 (Reactome)
POGLUT1REACT_118657 (Reactome)
Pre-NOTCHREACT_118694 (Reactome)
RAB6AArrowREACT_118577 (Reactome)
REACT_118576 (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.
REACT_118577 (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.
REACT_118578 (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.
REACT_118594 (Reactome) The Fringe family of glycosyl transferases in mammals includes LFNG (lunatic fringe), MFNG (manic fringe) and RFNG (radical fringe). 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 (Moloney et al. 2000). Fringe enzymes (LFNG, MNFG and RFNG) elongate conserved O fucosyl residues conjugated to EGF repeats of NOTCH, resulting in formation of disaccharide chains on NOTCH (GlcNAc beta1,3 fucitol). Fringe enzymes modulate NOTCH activity (Cohen et al. 1997, Johnston et al. 1997) by decreasing the affinity of NOTCH extracellular domain for JAG ligands (Brückner 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 position is shown.
REACT_118599 (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.
REACT_118612 (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.
REACT_118626 (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).

CCCND1 (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).
REACT_118639 (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).
REACT_118657 (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.
REACT_118670 (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.
REACT_118686 (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.
REACT_118694 (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).
REACT_118708 (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.
REACT_118714 (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.
REACT_118736 (Reactome) Translation of NOTCH3 mRNA is inhibited by microRNA miR-206 which binds to the 3'UTR of NOTCH3 mRNA.
REACT_118737 (Reactome) miR-181C microRNA inhibits translation of NOTCH4 mRNA by binding to its 3'UTR. miR181c is a candidate tumor suppressor in gastric cancer.
REACT_118739 (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).
REACT_118745 (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.
REACT_118747 (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.
REACT_118755 (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.
REACT_118757 (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).
REACT_118767 (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.
REACT_118819 (Reactome) MicroRNA miR-302A, upregulated in melanoma, binds the 3'UTR of NOTCH4, resulting in inhibition of NOTCH4 mRNA translation.
REACT_118827 (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.
REACT_118833 (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).
REACT_118850 (Reactome) Translation of NOTCH2 mRNA is inhibited by MIR34 microRNAs (MIR34A, MIR34B and MIR34C), which bind to the 3'UTR of NOTCH2 mRNA.
REACT_118855 (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.
SEL1LTBarREACT_118577 (Reactome)
ST3GAL3/4/6REACT_118739 (Reactome)
TMED2TBarREACT_118708 (Reactome)
TMED2TBarREACT_118747 (Reactome)
TP53ArrowREACT_118576 (Reactome)
UDP-GalREACT_118855 (Reactome)
UDP-GlcNAcREACT_118594 (Reactome)
UDP-GlcREACT_118657 (Reactome)
UDPArrowREACT_118594 (Reactome)
UDPArrowREACT_118657 (Reactome)
UDPArrowREACT_118855 (Reactome)
miR-150 RISCREACT_118686 (Reactome)
miR-181C RISCREACT_118737 (Reactome)
miR-200B/C RISCREACT_118670 (Reactome)
miR-206 RISCREACT_118736 (Reactome)
miR-302A RISCREACT_118819 (Reactome)
miR-34 RISCREACT_118599 (Reactome)
miR-34 RISCREACT_118850 (Reactome)
miR-449 RISCREACT_118755 (Reactome)
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