Pre-NOTCH Expression and Processing (Homo sapiens)

From WikiPathways

Revision as of 11:29, 9 August 2017 by ReactomeTeam (Talk | contribs)
Jump to: navigation, search
1, 4, 15, 23, 32...29, 32, 39, 50, 7015, 23, 59, 12318, 62, 801231145, 112, 12161, 8523102, 13751, 533, 16, 33, 42, 55...15, 23, 48, 67, 13994, 11811811, 31, 34, 38, 45...14, 112, 1262343, 63, 96, 126, 1331, 12648, 98, 129, 13988, 1314, 7, 41, 69, 112...12648, 98, 129, 1395910213722, 1269411cytosolnucleoplasmendoplasmic reticulum lumenGolgi lumenEIF2C3 EIF2C4 KAT2A EIF2C3 NOTCH1 mRNA:miR-449RISCEIF2C2 miR-34C GDPTFDP1 FURINTNRC6B EIF2C2 TNRC6B EIF2C4 E2F1 RBPJ EIF2C2 EP300 miR-34 RISCmiR-449A miR-150 miR-200C NOTCH3 mRNA:miR-150RISCEIF2C2 TNRC6C MOV10 TNRC6B miR-34B ST3GAL4 12xFucT-8xGlcS-6xFucS-NOTCH4(24-2003) TNRC6C MOV10 MAML3 TFDP1 NOTCH2 mRNA EIF2C3 Signaling by NOTCH3Glc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCH3 MAML1 Pre-NOTCHPOGLUT1TNRC6B EIF2C4 EIF2C1 MIR34A gene EIF2C4 EIF2C4 miR-34C NOTCH4(1337-2003) EIF2C2 TNRC6A Glc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCH2 12xFucT-8xGlcS-6xFucS-NOTCH4(24-2003) EIF2C1 ATP2A1-3NOTCH4 mRNANOTCH3(1572-2321) UDPNOTCH4 mRNA:miR-181CRISCTNRC6A miR-449B miR-449A EIF2C4 NOTCH3 mRNA:miR-206RISCTNRC6C EIF2C3 miR-449B TNRC6B MFNG CCND1:CREBBP:NOTCH1GeneE2F1/3:DP1/2:NOTCH1GeneGlc,Fuc-Pre-NOTCHMIR34C gene NOTCH1 genemiR-34C 12xFucT-6xFucS-NOTCH4(24-2003) Pre-NOTCH1 MOV10 MOV10 NOTCH1 mRNA Glc,GlcNAc-Fuc-Pre-NOTCH1 NOTCH4 mRNA MOV10 Glc,GlcNAc-Fuc-Pre-NOTCH3 TNRC6C TNRC6A RFNG TFDP2 miR-206 CREBBP miR-150 TNRC6A ATP2A3 UDPTNRC6A TP53 Pre-NOTCH1TNRC6A Fringe-modifiedNOTCHTP53 Tetramer:MIR34genesTNRC6A miR-200B EIF2C4 19xFucT-14xGlcS-2xFucS-NOTCH1(19-2555) NOTCH2 mRNA:miR-34RISCNOTCH1 gene TNRC6B EIF2C1 TNRC6C ST3GAL3 TNRC6B NOTCH1 mRNA EIF2C1 EIF2C3 Signaling by NOTCH4EIF2C1 EIF2C2 EIF2C1 18xFucT-16xGlcS-FucS-NOTCH2(26-1581) 18xFucT-16xGlcS-FucS-NOTCH2(26-2471) miR-302A Glc,Gal-GlcNAc-Fuc-Pre-NOTCH4 EIF2C3 NOTCH1(1665-2555) NOTCH3 mRNA TNRC6C miR-34A UDP-GalTNRC6B NOTCH1 mRNAEIF2C3 TFDP2 EIF2C1 TNRC6C NOTCH1 CoactivatorComplexNOTCH1(1665-2555) TNRC6B RAB6ATNRC6C EIF2C3 NOTCH1(1665-2555) EIF2C4 EIF2C2 miR-181C Pre-NOTCH3 TNRC6C EIF2C3 Fuc-Pre-NOTCHFRINGE-modified NOTCH1 Extracellular Fragment (NECD1) NOTCH3(1572-2321) Glc,Gal-GlcNAc-Fuc-Pre-NOTCH2 Pre-NOTCH2 CREBBP CMP-Neu5AcEIF2C1 miR-449C NOTCH3 geneUDPEIF2C1 TNRC6C NOTCHCMPmiR-206 RISCNOTCH3 mRNA EIF2C2 TNRC6C TNRC6B miR-34A 14xGlcS-10xFucT-4xFucS-NOTCH3(40-1571) EIF2C1 FRINGE-modified NOTCH2 extracellular fragment (NECD2) TNRC6C FRINGE-modified NOTCH3 Extracellular fragment (NECD3) Pre-NOTCH3MIR34B gene miR-181C NICD1 18xFucT-16xGlcS-FucS-NOTCH2(26-1581) EIF2C2 FRINGE-modified NOTCH1 Extracellular Fragment (NECD1) MOV10 NOTCH4(1337-2003) NOTCH2(1582-2471) TNRC6B NOTCHTNRC6A Glc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCH1 NOTCH3 CoactivatorComplexCCND1 TNRC6A EIF2C3 Glc,GlcNAc-Fuc-Pre-NOTCH2 17xFucT-14xGlcS-2xFucS-NOTCH1(19-1664) E2F1/3:DP1/2ST3GAL6 Glc,Fuc-Pre-NOTCHNOTCH4 geneFRINGE-modifiedNOTCHmiR-200B TNRC6C FRINGE-modified NOTCH4 Extracellular Fragment (NECD4) NOTCH2 mRNAmiR-181C RISC12xFucT-11xGlcS-6xFucS-NOTCH4(24-1336) 18xFucT-16xGlcS-FucS-NOTCH2(26-2471) TNRC6C KAT2B NOTCH4(1337-2003) MOV10 Glc,Gal-GlcNAc-Fuc-Pre-NOTCH1 MAMLD1 miR-302A NOTCH1mRNA:miR-200B/CRISCmiR-302A RISCEIF2C1 Pre-NOTCH2Glc,GlcNAc-Fuc-Pre-NOTCHEIF2C3 18xFucT-FucS-NOTCH2(26-2471) B4GALT1 homodimerTNRC6A EIF2C2 EIF2C4 miR-449C CREBBP NOTCH3(1572-2321) EIF2C4 19xFucT-16xGlcS-2xFucS-NOTCH1(19-1664) miR-200B/C RISCATP2A2 NOTCH1 gene Glc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCH4 E2F3 14xGlcS-10xFucT-4xFucS-NOTCH3(40-1571) Pre-NOTCH4 MOV10 EIF2C2 CCND1 TP53 NOTCH3 mRNACCND1:CREBBPEIF2C2 B4GALT1 MOV10 Signaling by NOTCH2FRINGE-modified NOTCH3 Extracellular Fragment (NECD3) miR-34B TP53 Tetramer10xFucT-4xFucS-NOTCH3(40-2321) JUNNOTCH2(1582-2471) NOTCH4 mRNA 17xFucT-14xGlcS-2xFucS-NOTCH1(19-2555) NOTCH2 geneMOV10 TNRC6B MAML3 EIF2C4 NOTCH1 mRNA E2F3 TNRC6B NOTCH4(1337-2003) MOV10 TNRC6A MOV10 Glc,GlcNAc-Fuc-Pre-NOTCH4 MAML2 TNRC6B TNRC6B ST3GAL3/4/6MIR34C gene Signaling by NOTCH1miR-200C 12xFucT-8xGlcS-6xFucS-NOTCH4(24-1336) MIR34B gene NICD3 NOTCH1(1665-2555) MOV10 MAML1 E2F1 UDP-GlcNAcTNRC6A Glc,Sia-Gal-GlcNAc-Fuc-Pre-NOTCHEIF2C4 NOTCH1 mRNA:miR-34RISCPOFUT1SNW1 UDP-GlcEIF2C1 TNRC6A TNRC6C EIF2C3 EIF2C2 EIF2C1 NOTCH3(1572-2321) MOV10 TNRC6A EIF2C4 TNRC6A miR-206 Pre-NOTCH4ATP2A1 miR-449 RISCEIF2C3 EIF2C1 NOTCH2(1582-2471) MAML2 FRINGE-modified NOTCH2 Extracellular Fragment (NECD2) FRINGE-modified NOTCH4 Extracellular fragment (NECD4) MIR34 genes14xGlcS-10xFucT-4xFucS-NOTCH3(40-2321) MAMLD1 Fringe familyEIF2C2 miR-34B EIF2C3 NOTCH2(1582-2471) MIR34A gene RBPJ 17xFucT-2xFucS-NOTCH1(19-2555) 14xGlcS-10xFucT-4xFucS-NOTCH3(40-2321) EIF2C4 EIF2C1 EIF2C4 GDP-FucEIF2C2 SEL1LmiR-150 RISCMOV10 Glc,Gal-GlcNAc-Fuc-Pre-NOTCH3 EIF2C3 Glc,Gal-GlcNAc-Fuc-Pre-NOTCHLFNG NOTCH4 mRNA:miR-302ARISCmiR-34A TMED22, 6, 8-10, 12...1141141148, 98, 129, 1396012, 13, 18, 21, 35...


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

Reactome-Converter 
Pathway is converted from Reactome ID: 1912422
Reactome-version 
Reactome version: 61
Reactome Author 
Reactome Author: Egan, SE, Orlic-Milacic, Marija

Try the New WikiPathways

View approved pathways at the new wikipathways.org.

Quality Tags

Ontology Terms

 

Bibliography

View all...
  1. Kong D, Banerjee S, Ahmad A, Li Y, Wang Z, Sethi S, Sarkar FH.; ''Epithelial to mesenchymal transition is mechanistically linked with stem cell signatures in prostate cancer cells.''; PubMed Europe PMC Scholia
  2. Majewski J, Schwartzentruber JA, Caqueret A, Patry L, Marcadier J, Fryns JP, Boycott KM, Ste-Marie LG, McKiernan FE, Marik I, Van Esch H, FORGE Canada Consortium, Michaud JL, Samuels ME.; ''Mutations in NOTCH2 in families with Hajdu-Cheney syndrome.''; PubMed Europe PMC Scholia
  3. Palomero T, Lim WK, Odom DT, Sulis ML, Real PJ, Margolin A, Barnes KC, O'Neil J, Neuberg D, Weng AP, Aster JC, Sigaux F, Soulier J, Look AT, Young RA, Califano A, Ferrando AA.; ''NOTCH1 directly regulates c-MYC and activates a feed-forward-loop transcriptional network promoting leukemic cell growth.''; PubMed Europe PMC Scholia
  4. Fryer CJ, Lamar E, Turbachova I, Kintner C, Jones KA.; ''Mastermind mediates chromatin-specific transcription and turnover of the Notch enhancer complex.''; PubMed Europe PMC Scholia
  5. He L, He X, Lim LP, de Stanchina E, Xuan Z, Liang Y, Xue W, Zender L, Magnus J, Ridzon D, Jackson AL, Linsley PS, Chen C, Lowe SW, Cleary MA, Hannon GJ.; ''A microRNA component of the p53 tumour suppressor network.''; PubMed Europe PMC Scholia
  6. Periz G, Fortini ME.; ''Ca(2+)-ATPase function is required for intracellular trafficking of the Notch receptor in Drosophila.''; PubMed Europe PMC Scholia
  7. Maekawa Y, Minato Y, Ishifune C, Kurihara T, Kitamura A, Kojima H, Yagita H, Sakata-Yanagimoto M, Saito T, Taniuchi I, Chiba S, Sone S, Yasutomo K.; ''Notch2 integrates signaling by the transcription factors RBP-J and CREB1 to promote T cell cytotoxicity.''; PubMed Europe PMC Scholia
  8. Wallberg AE, Pedersen K, Lendahl U, Roeder RG.; ''p300 and PCAF act cooperatively to mediate transcriptional activation from chromatin templates by notch intracellular domains in vitro.''; PubMed Europe PMC Scholia
  9. McDaniell R, Warthen DM, Sanchez-Lara PA, Pai A, Krantz ID, Piccoli DA, Spinner NB.; ''NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway.''; PubMed Europe PMC Scholia
  10. Pang RT, Leung CO, Ye TM, Liu W, Chiu PC, Lam KK, Lee KF, Yeung WS.; ''MicroRNA-34a suppresses invasion through downregulation of Notch1 and Jagged1 in cervical carcinoma and choriocarcinoma cells.''; PubMed Europe PMC Scholia
  11. Cohen B, Bashirullah A, Dagnino L, Campbell C, Fisher WW, Leow CC, Whiting E, Ryan D, Zinyk D, Boulianne G, Hui CC, Gallie B, Phillips RA, Lipshitz HD, Egan SE.; ''Fringe boundaries coincide with Notch-dependent patterning centres in mammals and alter Notch-dependent development in Drosophila.''; PubMed Europe PMC Scholia
  12. Perissi V, Aggarwal A, Glass CK, Rose DW, Rosenfeld MG.; ''A corepressor/coactivator exchange complex required for transcriptional activation by nuclear receptors and other regulated transcription factors.''; PubMed Europe PMC Scholia
  13. Costa FF, Seftor EA, Bischof JM, Kirschmann DA, Strizzi L, Arndt K, Bonaldo Mde F, Soares MB, Hendrix MJ.; ''Epigenetically reprogramming metastatic tumor cells with an embryonic microenvironment.''; PubMed Europe PMC Scholia
  14. Chang TC, Wentzel EA, Kent OA, Ramachandran K, Mullendore M, Lee KH, Feldmann G, Yamakuchi M, Ferlito M, Lowenstein CJ, Arking DE, Beer MA, Maitra A, Mendell JT.; ''Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis.''; PubMed Europe PMC Scholia
  15. Bray SJ, Takada S, Harrison E, Shen SC, Ferguson-Smith AC.; ''The atypical mammalian ligand Delta-like homologue 1 (Dlk1) can regulate Notch signalling in Drosophila.''; PubMed Europe PMC Scholia
  16. Ji CY, Cui CS, Ma DX, Zhao JQ, Guo NJ, Zhang MH.; ''Function of Delta4 gene and its effects on 32D cell differentiation.''; PubMed Europe PMC Scholia
  17. Shao L, Moloney DJ, Haltiwanger R.; ''Fringe modifies O-fucose on mouse Notch1 at epidermal growth factor-like repeats within the ligand-binding site and the Abruptex region.''; PubMed Europe PMC Scholia
  18. Li Y, Guessous F, Zhang Y, Dipierro C, Kefas B, Johnson E, Marcinkiewicz L, Jiang J, Yang Y, Schmittgen TD, Lopes B, Schiff D, Purow B, Abounader R.; ''MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes.''; PubMed Europe PMC Scholia
  19. Raver-Shapira N, Marciano E, Meiri E, Spector Y, Rosenfeld N, Moskovits N, Bentwich Z, Oren M.; ''Transcriptional activation of miR-34a contributes to p53-mediated apoptosis.''; PubMed Europe PMC Scholia
  20. Blaumueller CM, Qi H, Zagouras P, Artavanis-Tsakonas S.; ''Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane.''; PubMed Europe PMC Scholia
  21. Huang Y, Hoque MO, Wu F, Trink B, Sidransky D, Ratovitski EA.; ''Midkine induces epithelial-mesenchymal transition through Notch2/Jak2-Stat3 signaling in human keratinocytes.''; PubMed Europe PMC Scholia
  22. Simpson MA, Irving MD, Asilmaz E, Gray MJ, Dafou D, Elmslie FV, Mansour S, Holder SE, Brain CE, Burton BK, Kim KH, Pauli RM, Aftimos S, Stewart H, Kim CA, Holder-Espinasse M, Robertson SP, Drake WM, Trembath RC.; ''Mutations in NOTCH2 cause Hajdu-Cheney syndrome, a disorder of severe and progressive bone loss.''; PubMed Europe PMC Scholia
  23. Hu QD, Ang BT, Karsak M, Hu WP, Cui XY, Duka T, Takeda Y, Chia W, Sankar N, Ng YK, Ling EA, Maciag T, Small D, Trifonova R, Kopan R, Okano H, Nakafuku M, Chiba S, Hirai H, Aster JC, Schachner M, Pallen CJ, Watanabe K, Xiao ZC.; ''F3/contactin acts as a functional ligand for Notch during oligodendrocyte maturation.''; PubMed Europe PMC Scholia
  24. Viatour P, Ehmer U, Saddic LA, Dorrell C, Andersen JB, Lin C, Zmoos AF, Mazur PK, Schaffer BE, Ostermeier A, Vogel H, Sylvester KG, Thorgeirsson SS, Grompe M, Sage J.; ''Notch signaling inhibits hepatocellular carcinoma following inactivation of the RB pathway.''; PubMed Europe PMC Scholia
  25. Chan YM, Jan YN.; ''Roles for proteolysis and trafficking in notch maturation and signal transduction.''; PubMed Europe PMC Scholia
  26. Lardelli M, Dahlstrand J, Lendahl U.; ''The novel Notch homologue mouse Notch 3 lacks specific epidermal growth factor-repeats and is expressed in proliferating neuroepithelium.''; PubMed Europe PMC Scholia
  27. Jarriault S, Le Bail O, Hirsinger E, Pourquié O, Logeat F, Strong CF, Brou C, Seidah NG, Isra l A.; ''Delta-1 activation of notch-1 signaling results in HES-1 transactivation.''; PubMed Europe PMC Scholia
  28. Weinmaster G, Roberts VJ, Lemke G.; ''A homolog of Drosophila Notch expressed during mammalian development.''; PubMed Europe PMC Scholia
  29. Koo BK, Yoon KJ, Yoo KW, Lim HS, Song R, So JH, Kim CH, Kong YY.; ''Mind bomb-2 is an E3 ligase for Notch ligand.''; PubMed Europe PMC Scholia
  30. Song G, Zhang Y, Wang L.; ''MicroRNA-206 targets notch3, activates apoptosis, and inhibits tumor cell migration and focus formation.''; PubMed Europe PMC Scholia
  31. Koutelou E, Sato S, Tomomori-Sato C, Florens L, Swanson SK, Washburn MP, Kokkinaki M, Conaway RC, Conaway JW, Moschonas NK.; ''Neuralized-like 1 (Neurl1) targeted to the plasma membrane by N-myristoylation regulates the Notch ligand Jagged1.''; PubMed Europe PMC Scholia
  32. Sundaram M, Greenwald I.; ''Suppressors of a lin-12 hypomorph define genes that interact with both lin-12 and glp-1 in Caenorhabditis elegans.''; PubMed Europe PMC Scholia
  33. van Tetering G, van Diest P, Verlaan I, van der Wall E, Kopan R, Vooijs M.; ''Metalloprotease ADAM10 is required for Notch1 site 2 cleavage.''; PubMed Europe PMC Scholia
  34. Maier MM, Gessler M.; ''Comparative analysis of the human and mouse Hey1 promoter: Hey genes are new Notch target genes.''; PubMed Europe PMC Scholia
  35. Güngör C, Zander H, Effenberger KE, Vashist YK, Kalinina T, Izbicki JR, Yekebas E, Bockhorn M.; ''Notch signaling activated by replication stress-induced expression of midkine drives epithelial-mesenchymal transition and chemoresistance in pancreatic cancer.''; PubMed Europe PMC Scholia
  36. De Strooper B, Annaert W, Cupers P, Saftig P, Craessaerts K, Mumm JS, Schroeter EH, Schrijvers V, Wolfe MS, Ray WJ, Goate A, Kopan R.; ''A presenilin-1-dependent gamma-secretase-like protease mediates release of Notch intracellular domain.''; PubMed Europe PMC Scholia
  37. Itoh M, Kim CH, Palardy G, Oda T, Jiang YJ, Maust D, Yeo SY, Lorick K, Wright GJ, Ariza-McNaughton L, Weissman AM, Lewis J, Chandrasekharappa SC, Chitnis AB.; ''Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta.''; PubMed Europe PMC Scholia
  38. Kovall RA, Blacklow SC.; ''Mechanistic insights into Notch receptor signaling from structural and biochemical studies.''; PubMed Europe PMC Scholia
  39. Irvin DK, Zurcher SD, Nguyen T, Weinmaster G, Kornblum HI.; ''Expression patterns of Notch1, Notch2, and Notch3 suggest multiple functional roles for the Notch-DSL signaling system during brain development.''; PubMed Europe PMC Scholia
  40. Acar M, Jafar-Nejad H, Takeuchi H, Rajan A, Ibrani D, Rana NA, Pan H, Haltiwanger RS, Bellen HJ.; ''Rumi is a CAP10 domain glycosyltransferase that modifies Notch and is required for Notch signaling.''; PubMed Europe PMC Scholia
  41. Faux CH, Turnley AM, Epa R, Cappai R, Bartlett PF.; ''Interactions between fibroblast growth factors and Notch regulate neuronal differentiation.''; PubMed Europe PMC Scholia
  42. Francisco AB, Singh R, Li S, Vani AK, Yang L, Munroe RJ, Diaferia G, Cardano M, Biunno I, Qi L, Schimenti JC, Long Q.; ''Deficiency of suppressor enhancer Lin12 1 like (SEL1L) in mice leads to systemic endoplasmic reticulum stress and embryonic lethality.''; PubMed Europe PMC Scholia
  43. Ghisi M, Corradin A, Basso K, Frasson C, Serafin V, Mukherjee S, Mussolin L, Ruggero K, Bonanno L, Guffanti A, De Bellis G, Gerosa G, Stellin G, D'Agostino DM, Basso G, Bronte V, Indraccolo S, Amadori A, Zanovello P.; ''Modulation of microRNA expression in human T-cell development: targeting of NOTCH3 by miR-150.''; PubMed Europe PMC Scholia
  44. Wang Y, Shao L, Shi S, Harris RJ, Spellman MW, Stanley P, Haltiwanger RS.; ''Modification of epidermal growth factor-like repeats with O-fucose. Molecular cloning and expression of a novel GDP-fucose protein O-fucosyltransferase.''; PubMed Europe PMC Scholia
  45. Cordle J, Redfieldz C, Stacey M, van der Merwe PA, Willis AC, Champion BR, Hambleton S, Handford PA.; ''Localization of the delta-like-1-binding site in human Notch-1 and its modulation by calcium affinity.''; PubMed Europe PMC Scholia
  46. Johnston SH, Rauskolb C, Wilson R, Prabhakaran B, Irvine KD, Vogt TF.; ''A family of mammalian Fringe genes implicated in boundary determination and the Notch pathway.''; PubMed Europe PMC Scholia
  47. Hashimoto Y, Akiyama Y, Otsubo T, Shimada S, Yuasa Y.; ''Involvement of epigenetically silenced microRNA-181c in gastric carcinogenesis.''; PubMed Europe PMC Scholia
  48. Li L, Milner LA, Deng Y, Iwata M, Banta A, Graf L, Marcovina S, Friedman C, Trask BJ, Hood L, Torok-Storb B.; ''The human homolog of rat Jagged1 expressed by marrow stroma inhibits differentiation of 32D cells through interaction with Notch1.''; PubMed Europe PMC Scholia
  49. Jackson MD, Denu JM.; ''Structural identification of 2'- and 3'-O-acetyl-ADP-ribose as novel metabolites derived from the Sir2 family of beta -NAD+-dependent histone/protein deacetylases.''; PubMed Europe PMC Scholia
  50. Ji Q, Hao X, Zhang M, Tang W, Yang M, Li L, Xiang D, Desano JT, Bommer GT, Fan D, Fearon ER, Lawrence TS, Xu L.; ''MicroRNA miR-34 inhibits human pancreatic cancer tumor-initiating cells.''; PubMed Europe PMC Scholia
  51. Moloney DJ, Panin VM, Johnston SH, Chen J, Shao L, Wilson R, Wang Y, Stanley P, Irvine KD, Haltiwanger RS, Vogt TF.; ''Fringe is a glycosyltransferase that modifies Notch.''; PubMed Europe PMC Scholia
  52. Shimizu K, Chiba S, Saito T, Kumano K, Hirai H.; ''Physical interaction of Delta1, Jagged1, and Jagged2 with Notch1 and Notch3 receptors.''; PubMed Europe PMC Scholia
  53. Dang L, Yoon K, Wang M, Gaiano N.; ''Notch3 signaling promotes radial glial/progenitor character in the mammalian telencephalon.''; PubMed Europe PMC Scholia
  54. Gustafsson MV, Zheng X, Pereira T, Gradin K, Jin S, Lundkvist J, Ruas JL, Poellinger L, Lendahl U, Bondesson M.; ''Hypoxia requires notch signaling to maintain the undifferentiated cell state.''; PubMed Europe PMC Scholia
  55. Li S, Francisco AB, Munroe RJ, Schimenti JC, Long Q.; ''SEL1L deficiency impairs growth and differentiation of pancreatic epithelial cells.''; PubMed Europe PMC Scholia
  56. Hicks C, Johnston SH, diSibio G, Collazo A, Vogt TF, Weinmaster G.; ''Fringe differentially modulates Jagged1 and Delta1 signalling through Notch1 and Notch2.''; PubMed Europe PMC Scholia
  57. Saxena MT, Schroeter EH, Mumm JS, Kopan R.; ''Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis.''; PubMed Europe PMC Scholia
  58. Hartmann D, de Strooper B, Serneels L, Craessaerts K, Herreman A, Annaert W, Umans L, Lübke T, Lena Illert A, von Figura K, Saftig P.; ''The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts.''; PubMed Europe PMC Scholia
  59. Alagille D, Odièvre M, Gautier M, Dommergues JP.; ''Hepatic ductular hypoplasia associated with characteristic facies, vertebral malformations, retarded physical, mental, and sexual development, and cardiac murmur.''; PubMed Europe PMC Scholia
  60. Krebs LT, Xue Y, Norton CR, Sundberg JP, Beatus P, Lendahl U, Joutel A, Gridley T.; ''Characterization of Notch3-deficient mice: normal embryonic development and absence of genetic interactions with a Notch1 mutation.''; PubMed Europe PMC Scholia
  61. Fischer A, Schumacher N, Maier M, Sendtner M, Gessler M.; ''The Notch target genes Hey1 and Hey2 are required for embryonic vascular development.''; PubMed Europe PMC Scholia
  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)
ATP2A1 ProteinO14983 (Uniprot-TrEMBL)
ATP2A1-3ComplexR-HSA-418312 (Reactome)
ATP2A2 ProteinP16615 (Uniprot-TrEMBL)
ATP2A3 ProteinQ93084 (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)
EIF2C2 ProteinQ9UKV8 (Uniprot-TrEMBL)
EIF2C3 ProteinQ9H9G7 (Uniprot-TrEMBL)
EIF2C4 ProteinQ9HCK5 (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)
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 ProteinENSG00000207865 (Ensembl)
MIR34B gene ProteinENSG00000207811 (Ensembl)
MIR34C gene ProteinENSG00000207562 (Ensembl)
MOV10 ProteinQ9HCE1 (Uniprot-TrEMBL)
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 gene ProteinENSG00000148400 (Ensembl)
NOTCH1 geneGeneProductENSG00000148400 (Ensembl)
NOTCH1 mRNA ProteinENST00000277541 (Ensembl)
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 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 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)
POFUT1ProteinQ9H488 (Uniprot-TrEMBL)
POGLUT1ProteinQ8NBL1 (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)
SEL1LProteinQ9UBV2 (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, 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 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-1980148 (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.
Signaling by NOTCH4PathwayR-HSA-1980150 (Reactome) 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.
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)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ATP2A1-3ArrowR-HSA-1912374 (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)
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)
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 geneR-HSA-1912416 (Reactome)
NOTCH1 geneR-HSA-4395227 (Reactome)
NOTCH1 geneR-HSA-4395231 (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 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 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 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)
POFUT1mim-catalysisR-HSA-1912349 (Reactome)
POGLUT1mim-catalysisR-HSA-1912353 (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).
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).
RAB6AArrowR-HSA-1912374 (Reactome)
SEL1LTBarR-HSA-1912374 (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)
Personal tools