Signaling by NOTCH2 (Homo sapiens)

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8, 10, 15, 20, 21, 23...101014, 43, 648, 57, 11321, 41, 58, 842, 8, 25, 42, 46...887588113557580, 98753, 5, 29, 65, 67...56, 65, 11375202027, 36NOTCH2 [plasmamembrane]Fringe-modifiedNOTCH2 [plasmamembrane]MDK [extracellularregion]NOTCH2 CoactivatorComplex:HES5 gene[nucleoplasm]DLL4:NOTCH2 [plasmamembrane]MDK [extracellularregion]Signal Receiving CellNOTCH2 [plasmamembrane]DLL1:NOTCH2 [plasmamembrane]NOTCH2 CoactivatorComplex:FCER2 gene[nucleoplasm]NOTCH2 [plasmamembrane]NOTCH2 [plasmamembrane]NOTCH2 CoactivatorComplex[nucleoplasm]DLL4:NOTCH2 [plasmamembrane]NOTCH2 [plasmamembrane]CNTN1:NOTCH2 [plasmamembrane]APH-1 [plasmamembrane]JAG2:NOTCH2 [plasmamembrane]cytosolMDK:NOTCH2 [plasmamembrane]NOTCH2 [plasmamembrane]NOTCH2 CoactivatorComplex[nucleoplasm]Fringe-modifiedNOTCH2 [plasmamembrane]NOTCH2fragment:DLL/JAG[plasma membrane]NOTCH2 [plasmamembrane]nucleoplasmNOTCH2 [plasmamembrane]NOTCH2 CoactivatorComplex[nucleoplasm]JAG1:NOTCH2 [plasmamembrane]NOTCH2 CoactivatorComplex[nucleoplasm]JAG2:NOTCH2 [plasmamembrane]NOTCH2/Fringe-modifiedNOTCH2 [plasmamembrane]NOTCH2 CoactivatorComplex:HES1 gene[nucleoplasm]NOTCH2 CoactivatorComplex[nucleoplasm]NOTCH2 [plasmamembrane]PSEN2 dimer [plasmamembrane]Fringe-modifiedNOTCH2 [plasmamembrane]NOTCH2 [plasmamembrane]Ub [cytosol]NOTCH2/Fringe-modifiedNOTCH2 [plasmamembrane]DLL/JAG:NOTCH2[plasma membrane]NOTCH2 coactivatorcomplex:p-S133-CREB1:EP300:GZMBGene [nucleoplasm]DLL1:NOTCH2 [plasmamembrane]NOTCH2/Fringe-modifiedNOTCH2 [plasmamembrane]NOTCH2/Fringe-modifiedNOTCH2 [plasmamembrane]gamma-secretasecomplex [plasmamembrane]cytosolUb [cytosol]ADAM10:Zn++ [plasmamembrane]Ub-DLL/JAG:NOTCH2[plasma membrane]Fringe-modifiedNOTCH2 [plasmamembrane]NOTCH2 [plasmamembrane]DLL/JAG [plasmamembrane]NOTCH2 [plasmamembrane]Signal Sending CellFringe-modifiedNOTCH2 [plasmamembrane]NOTCH2/Fringe-modifiedNOTCH2 [plasmamembrane]JAG1:NOTCH2 [plasmamembrane]18xFucT-16xGlcS-FucS-NOTCH2(26-1581)[extracellularregion]GZMBHES5DLL1RBPJ [nucleoplasm]GZMB GeneHES1UBC(229-304)[cytosol]MDK:NOTCH2MDKNOTCH2(1582-2471)[plasma membrane]DLL1 [plasmamembrane]APH1A [plasmamembrane]JAG2UBC(305-380)[cytosol]NOTCH2/Fringe-modifiedNOTCH218xFucT-16xGlcS-FucS-NOTCH2(26-1581)[extracellularregion]RBPJ [nucleoplasm]HES5 gene[nucleoplasm]RBPJ [nucleoplasm]FRINGE-modifiedNOTCH2 ExtracellularFragment (NECD2)[plasma membrane]JAG1 [plasmamembrane]NICD2 [nucleoplasm]UBC(1-76) [cytosol]RPS27A(1-76)[cytosol]RBPJ [nucleoplasm]UBB(1-76) [cytosol]NICD2 [nucleoplasm]JAG1 [plasmamembrane]NOTCH2(1582-2471)[plasma membrane]FRINGE-modifiedNOTCH2 ExtracellularFragment (NECD2)[plasma membrane]RBPJ [nucleoplasm]FRINGE-modifiedNOTCH2 ExtracellularFragment (NECD2)[plasma membrane]18xFucT-16xGlcS-FucS-NOTCH2(26-1581)[extracellularregion]UBA52(1-76)[cytosol]FCER2 geneJAG1:NOTCH2CNTN1(21-993)[plasma membrane]MDK [extracellularregion]NOTCH2(1582-1665)[extracellularregion]18xFucT-16xGlcS-FucS-NOTCH2(26-1581)[extracellularregion]NOTCH2(1582-2471)[plasma membrane]NICD2 [nucleoplasm]NICD2FCER2 gene[nucleoplasm]UBC(77-152)[cytosol]18xFucT-16xGlcS-FucS-NOTCH2(26-1581)[extracellularregion]JAG2 [plasmamembrane]NICD2p-S133-CREB1FRINGE-modifiedNOTCH2 ExtracellularFragment (NECD2)[plasma membrane]DLL4:NOTCH2NCSTN [plasmamembrane]18xFucT-16xGlcS-FucS-NOTCH2(26-1581)[extracellularregion]UBC(77-152)[cytosol]NICD2 [nucleoplasm]APH1B [plasmamembrane]ADAM10:Zn++CNTN1:NOTCH2DLL1 [plasmamembrane]Pre-NOTCH Expressionand Processing18xFucT-16xGlcS-FucS-NOTCH2(26-1581)[extracellularregion]EP300(1-2414)UBB(77-152)[cytosol]NOTCH2 CoactivatorComplex:FCER2 gene18xFucT-16xGlcS-FucS-NOTCH2(26-1581)[extracellularregion]UBA52(1-76)[cytosol]JAG1NOTCH2NOTCH2/Fringe-modifiedNOTCH2UBB(1-76) [cytosol]NOTCH2(1582-2471)[plasma membrane]NOTCH2 CoactivatorComplex:HES5 geneNEXT2DLL4 [plasmamembrane]FCER2(1-321)UBC(457-532)[cytosol]HES1 gene[nucleoplasm]UbJAG2:NOTCH2MDK [extracellularregion]DLL/JAG:NOTCH2Signaling by NOTCH1UBC(381-456)[cytosol]UBC(533-608)[cytosol]PSEN2(1-297) [plasmamembrane]NOTCH2(1582-2471)[plasma membrane]NOTCH2(1666-1696)HES1 geneNOTCH2(1582-2471)[plasma membrane]18xFucT-16xGlcS-FucS-NOTCH2(26-1581)[extracellularregion]UBC(229-304)[cytosol]DLL1:NOTCH2NOTCH2(1582-2471)[plasma membrane]DLL4 [plasmamembrane]NOTCH2 coactivatorcomplex:p-S133-CREB1:EP300:GZMBGeneDLL1 [plasmamembrane]18xFucT-16xGlcS-FucS-NOTCH2(26-1581)[extracellularregion]UBC(153-228)[cytosol]NOTCH2(1582-2471)[plasma membrane]JAG2 [plasmamembrane]gamma-secretasecomplexRBPJUBC(533-608)[cytosol]NOTCH2RPS27A(1-76)[cytosol]MAMLNOTCH2fragment:DLL/JAG18xFucT-16xGlcS-FucS-NOTCH2(26-1581)[extracellularregion]FRINGE-modifiedNOTCH2 ExtracellularFragment (NECD2)[plasma membrane]DLL4UBC(381-456)[cytosol]UBC(457-532)[cytosol]JAG2 [plasmamembrane]NOTCH2(1582-2471)[plasma membrane]UBB(153-228)[cytosol]ADAM10 [plasmamembrane]UBC(609-684)[cytosol]NOTCH2(1582-2471)[plasma membrane]NOTCH2NICD2 [nucleoplasm]UBB(153-228)[cytosol]NOTCH2(1582-2471)[plasma membrane]NOTCH2 CoactivatorComplex:HES1 genep-S133-CREB1[nucleoplasm]MIB/NEURLPSENEN [plasmamembrane]UBC(609-684)[cytosol]EP300(1-2414)[nucleoplasm]HES5 geneUBC(153-228)[cytosol]GZMB Gene[nucleoplasm]UBC(305-380)[cytosol]JAG1 [plasmamembrane]DLL4 [plasmamembrane]UBC(1-76) [cytosol]Zn2+ [plasmamembrane]CNTN1(21-993)18xFucT-16xGlcS-FucS-NOTCH2(26-1581)[extracellularregion]NOTCH2 CoactivatorComplexUb-DLL/JAG:NOTCH2NOTCH2(1582-2471)[plasma membrane]UBB(77-152)[cytosol]143-7, 9-13, 16...1, 17, 22, 35, 37...43, 64


Description

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). Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1980145

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  80. Kovall RA, Blacklow SC.; ''Mechanistic insights into Notch receptor signaling from structural and biochemical studies.''; PubMed Europe PMC
  81. 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
  82. 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
  83. D'Souza B, Meloty-Kapella L, Weinmaster G.; ''Canonical and non-canonical Notch ligands.''; PubMed Europe PMC
  84. McCright B, Gao X, Shen L, Lozier J, Lan Y, Maguire M, Herzlinger D, Weinmaster G, Jiang R, Gridley T.; ''Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation.''; PubMed Europe PMC
  85. 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
  86. Meloty-Kapella L, Shergill B, Kuon J, Botvinick E, Weinmaster G.; ''Notch ligand endocytosis generates mechanical pulling force dependent on dynamin, epsins, and actin.''; PubMed Europe PMC
  87. 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
  88. 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
  89. 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
  90. 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
  91. 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
  92. Struhl G, Adachi A.; ''Nuclear access and action of notch in vivo.''; PubMed Europe PMC
  93. 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
  94. 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
  95. Habib R, Dommergues JP, Gubler MC, Hadchouel M, Gautier M, Odievre M, Alagille D.; ''Glomerular mesangiolipidosis in Alagille syndrome (arteriohepatic dysplasia).''; PubMed Europe PMC
  96. 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
  97. 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
  98. 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
  99. 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
  100. 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
  101. Hashimoto Y, Akiyama Y, Otsubo T, Shimada S, Yuasa Y.; ''Involvement of epigenetically silenced microRNA-181c in gastric carcinogenesis.''; PubMed Europe PMC
  102. 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
  103. 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
  104. 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
  105. Groot AJ, Habets R, Yahyanejad S, Hodin CM, Reiss K, Saftig P, Theys J, Vooijs M.; ''Regulated proteolysis of NOTCH2 and NOTCH3 receptors by ADAM10 and presenilins.''; PubMed Europe PMC
  106. 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
  107. Lecourtois M, Schweisguth F.; ''Indirect evidence for Delta-dependent intracellular processing of notch in Drosophila embryos.''; PubMed Europe PMC
  108. Chan YM, Jan YN.; ''Roles for proteolysis and trafficking in notch maturation and signal transduction.''; PubMed Europe PMC
  109. 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
  110. 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
  111. Brückner K, Perez L, Clausen H, Cohen S.; ''Glycosyltransferase activity of Fringe modulates Notch-Delta interactions.''; PubMed Europe PMC
  112. 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
  113. 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
  114. 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
  115. McCright B, Lozier J, Gridley T.; ''A mouse model of Alagille syndrome: Notch2 as a genetic modifier of Jag1 haploinsufficiency.''; PubMed Europe PMC
  116. 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
  117. 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
  118. McGill MA, Dho SE, Weinmaster G, McGlade CJ.; ''Numb regulates post-endocytic trafficking and degradation of Notch1.''; PubMed Europe PMC

History

View all...
CompareRevisionActionTimeUserComment
101639view11:50, 1 November 2018ReactomeTeamreactome version 66
101175view21:37, 31 October 2018ReactomeTeamreactome version 65
100701view20:09, 31 October 2018ReactomeTeamreactome version 64
100251view16:55, 31 October 2018ReactomeTeamreactome version 63
99803view15:19, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99351view12:48, 31 October 2018ReactomeTeamreactome version 62
93912view13:44, 16 August 2017ReactomeTeamreactome version 61
93488view11:24, 9 August 2017ReactomeTeamreactome version 61
87179view19:55, 18 July 2016EgonwOntology Term : 'signaling pathway' added !
86584view09:21, 11 July 2016ReactomeTeamreactome version 56
83123view10:02, 18 November 2015ReactomeTeamVersion54
81462view12:59, 21 August 2015ReactomeTeamVersion53
76935view08:20, 17 July 2014ReactomeTeamFixed remaining interactions
76640view12:01, 16 July 2014ReactomeTeamFixed remaining interactions
75970view10:02, 11 June 2014ReactomeTeamRe-fixing comment source
75673view10:58, 10 June 2014ReactomeTeamReactome 48 Update
75028view13:54, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74672view08:44, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

View all...
NameTypeDatabase referenceComment
18xFucT-16xGlcS-FucS-NOTCH2(26-1581)

[extracellular

region]
ProteinQ04721 (Uniprot-TrEMBL)
ADAM10 [plasma membrane]ProteinO14672 (Uniprot-TrEMBL)
ADAM10:Zn++ComplexREACT_3937 (Reactome)
APH1A [plasma membrane]ProteinQ96BI3 (Uniprot-TrEMBL)
APH1B [plasma membrane]ProteinQ8WW43 (Uniprot-TrEMBL)
CNTN1(21-993) [plasma membrane]ProteinQ12860 (Uniprot-TrEMBL)
CNTN1(21-993)ProteinQ12860 (Uniprot-TrEMBL)
CNTN1:NOTCH2ComplexREACT_164498 (Reactome)
DLL/JAG:NOTCH2REACT_3398 (Reactome)
DLL1 [plasma membrane]ProteinO00548 (Uniprot-TrEMBL)
DLL1:NOTCH2ComplexREACT_161496 (Reactome)
DLL1ProteinO00548 (Uniprot-TrEMBL)
DLL4 [plasma membrane]ProteinQ9NR61 (Uniprot-TrEMBL)
DLL4:NOTCH2ComplexREACT_160825 (Reactome)
DLL4ProteinQ9NR61 (Uniprot-TrEMBL)
EP300(1-2414) [nucleoplasm]ProteinQ09472 (Uniprot-TrEMBL)
EP300(1-2414)ProteinQ09472 (Uniprot-TrEMBL)
FCER2 gene [nucleoplasm]ProteinENSG00000104921 (ENSEMBL)
FCER2 geneENSG00000104921 (ENSEMBL)
FCER2(1-321)ProteinP06734 (Uniprot-TrEMBL)
FRINGE-modified

NOTCH2 Extracellular Fragment (NECD2)

[plasma membrane]
ProteinQ04721 (Uniprot-TrEMBL)
GZMB Gene [nucleoplasm]ProteinENSG00000100453 (ENSEMBL)
GZMB GeneENSG00000100453 (ENSEMBL)
GZMBProteinP10144 (Uniprot-TrEMBL)
HES1 gene [nucleoplasm]ProteinENSG00000114315 (ENSEMBL)
HES1 geneENSG00000114315 (ENSEMBL)
HES1ProteinQ14469 (Uniprot-TrEMBL)
HES5 gene [nucleoplasm]ProteinENSG00000197921 (ENSEMBL)
HES5 geneENSG00000197921 (ENSEMBL)
HES5ProteinQ5TA89 (Uniprot-TrEMBL)
JAG1 [plasma membrane]ProteinP78504 (Uniprot-TrEMBL)
JAG1:NOTCH2ComplexREACT_161372 (Reactome)
JAG1ProteinP78504 (Uniprot-TrEMBL)
JAG2 [plasma membrane]ProteinQ9Y219 (Uniprot-TrEMBL)
JAG2:NOTCH2ComplexREACT_161407 (Reactome)
JAG2ProteinQ9Y219 (Uniprot-TrEMBL)
MAMLProteinREACT_15027 (Reactome)
MDK [extracellular region]ProteinP21741 (Uniprot-TrEMBL)
MDK:NOTCH2ComplexREACT_165236 (Reactome)
MDKComplexREACT_164100 (Reactome)
MIB/NEURLProteinREACT_119394 (Reactome)
NCSTN [plasma membrane]ProteinQ92542 (Uniprot-TrEMBL)
NEXT2ProteinQ04721 (Uniprot-TrEMBL)
NICD2 [nucleoplasm]ProteinQ04721 (Uniprot-TrEMBL)
NICD2ProteinQ04721 (Uniprot-TrEMBL)
NOTCH2 fragment:DLL/JAGComplexREACT_4751 (Reactome)
NOTCH2 Coactivator Complex:FCER2 geneComplexREACT_164980 (Reactome)
NOTCH2 Coactivator Complex:HES1 geneComplexREACT_164322 (Reactome)
NOTCH2 Coactivator Complex:HES5 geneComplexREACT_164969 (Reactome)
NOTCH2 Coactivator ComplexComplexREACT_164738 (Reactome)
NOTCH2 coactivator

complex:p-S133-CREB1:EP300:GZMB

Gene
ComplexREACT_164308 (Reactome)
NOTCH2(1582-1665)

[extracellular

region]
ProteinQ04721 (Uniprot-TrEMBL)
NOTCH2(1582-2471) [plasma membrane]ProteinQ04721 (Uniprot-TrEMBL)
NOTCH2(1666-1696)ProteinQ04721 (Uniprot-TrEMBL)
NOTCH2/Fringe-modified NOTCH2ComplexREACT_161170 (Reactome)
NOTCH2ComplexREACT_5316 (Reactome)
PSEN2(1-297) [plasma membrane]ProteinP49810 (Uniprot-TrEMBL)
PSENEN [plasma membrane]ProteinQ9NZ42 (Uniprot-TrEMBL)
Pre-NOTCH Expression and ProcessingPathwayWP2786 (WikiPathways) 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.
RBPJ [nucleoplasm]ProteinQ06330 (Uniprot-TrEMBL)
RBPJProteinQ06330 (Uniprot-TrEMBL)
RPS27A(1-76) [cytosol]ProteinP62979 (Uniprot-TrEMBL)
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.

UBA52(1-76) [cytosol]ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) [cytosol]ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) [cytosol]ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) [cytosol]ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) [cytosol]ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) [cytosol]ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) [cytosol]ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) [cytosol]ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) [cytosol]ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) [cytosol]ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) [cytosol]ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) [cytosol]ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) [cytosol]ProteinP0CG48 (Uniprot-TrEMBL)
Ub-DLL/JAG:NOTCH2ComplexREACT_161553 (Reactome)
UbProteinREACT_3316 (Reactome)
Zn2+ [plasma membrane]MetaboliteCHEBI:29105 (ChEBI)
gamma-secretase complexComplexREACT_5292 (Reactome)
p-S133-CREB1 [nucleoplasm]ProteinP16220 (Uniprot-TrEMBL)
p-S133-CREB1ProteinP16220 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADAM10:Zn++mim-catalysisREACT_267 (Reactome)
CNTN1(21-993)REACT_163984 (Reactome)
CNTN1:NOTCH2ArrowREACT_163984 (Reactome)
CNTN1:NOTCH2REACT_163946 (Reactome)
DLL/JAG:NOTCH2REACT_160100 (Reactome)
DLL1:NOTCH2ArrowREACT_160318 (Reactome)
DLL1REACT_160318 (Reactome)
DLL4:NOTCH2ArrowREACT_160320 (Reactome)
DLL4REACT_160320 (Reactome)
EP300(1-2414)REACT_163689 (Reactome)
FCER2 geneREACT_163746 (Reactome)
FCER2 geneREACT_163815 (Reactome)
FCER2(1-321)ArrowREACT_163746 (Reactome)
GZMB GeneREACT_163689 (Reactome)
GZMB GeneREACT_163817 (Reactome)
GZMBArrowREACT_163817 (Reactome)
HES1 geneREACT_163739 (Reactome)
HES1 geneREACT_163918 (Reactome)
HES1ArrowREACT_163918 (Reactome)
HES5 geneREACT_163748 (Reactome)
HES5 geneREACT_163858 (Reactome)
HES5ArrowREACT_163858 (Reactome)
JAG1:NOTCH2ArrowREACT_160180 (Reactome)
JAG1REACT_160180 (Reactome)
JAG2:NOTCH2ArrowREACT_160207 (Reactome)
JAG2REACT_160207 (Reactome)
MAMLREACT_163655 (Reactome)
MDK:NOTCH2ArrowREACT_163967 (Reactome)
MDKREACT_163967 (Reactome)
MIB/NEURLmim-catalysisREACT_160100 (Reactome)
NEXT2ArrowREACT_267 (Reactome)
NEXT2REACT_1306 (Reactome)
NICD2ArrowREACT_1091 (Reactome)
NICD2ArrowREACT_1306 (Reactome)
NICD2ArrowREACT_163946 (Reactome)
NICD2REACT_1091 (Reactome)
NICD2REACT_163655 (Reactome)
NOTCH2 fragment:DLL/JAGArrowREACT_267 (Reactome)
NOTCH2 Coactivator Complex:FCER2 geneArrowREACT_163746 (Reactome)
NOTCH2 Coactivator Complex:FCER2 geneArrowREACT_163815 (Reactome)
NOTCH2 Coactivator Complex:HES1 geneArrowREACT_163739 (Reactome)
NOTCH2 Coactivator Complex:HES1 geneArrowREACT_163918 (Reactome)
NOTCH2 Coactivator Complex:HES5 geneArrowREACT_163748 (Reactome)
NOTCH2 Coactivator Complex:HES5 geneArrowREACT_163858 (Reactome)
NOTCH2 Coactivator ComplexArrowREACT_163655 (Reactome)
NOTCH2 Coactivator ComplexREACT_163689 (Reactome)
NOTCH2 Coactivator ComplexREACT_163739 (Reactome)
NOTCH2 Coactivator ComplexREACT_163748 (Reactome)
NOTCH2 Coactivator ComplexREACT_163815 (Reactome)
NOTCH2 coactivator

complex:p-S133-CREB1:EP300:GZMB

Gene
ArrowREACT_163689 (Reactome)
NOTCH2 coactivator

complex:p-S133-CREB1:EP300:GZMB

Gene
ArrowREACT_163817 (Reactome)
NOTCH2(1666-1696)ArrowREACT_1306 (Reactome)
NOTCH2/Fringe-modified NOTCH2REACT_160180 (Reactome)
NOTCH2/Fringe-modified NOTCH2REACT_160318 (Reactome)
NOTCH2REACT_160207 (Reactome)
NOTCH2REACT_160320 (Reactome)
NOTCH2REACT_163967 (Reactome)
NOTCH2REACT_163984 (Reactome)
RBPJREACT_163655 (Reactome)
REACT_1091 (Reactome) The cytosolic NICD2 translocates to the nucleus.
REACT_1306 (Reactome) NEXT2 fragment of NOTCH2 is further cleaved at the S3 site by the gamma-secretase complex, which releases the intracellular domain NICD2 into the cytosol (Saxena et al. 2001, De Strooper et al. 1999, Schroeter et al. 1998, Fortini 2002).
REACT_160100 (Reactome) NOTCH ligands DLL1, DLL4, JAG1 and JAG2 undergo ubiquitination and endocytosis after binding NOTCH2 in trans. Integrity of the intracellular domain of DLL1 was shown to be essential for the successful release of NOTCH2 intracellular domain, NICD2, in response to DLL1 binding (Shimizu et al. 2002). In Drosophila, ubiquitination of Delta and Serrate ligands is performed by either Mindbomb or Neuralized ubiquitin ligase. In mammals, there are two Mindbomb homologues, MIB1 and MIB2 and two Neuralized homologues, NEURL (also known as NEUR1) and NEURL1B (also known as NEUR2). Although both Mib1 and Mib2 ubiquitinate Delta (Koo et al. 2005), only Mib1 was shown to be essential for normal development in mice, with Mib1 deficient mice exhibiting typical Notch deficiency phenotypes (Koo et al. 2007). This could be due to different expression patterns of Mib1 and Mib2. While Mib1 is abundantly expressed in embryos and adult tissues, Mib2 expression is limited to adult tissues only (Koo et al. 2005). Mouse Neurl was directly shown to ubiquitinate Jag1 but not other Notch ligands in vitro. N-terminal myristoylation targets Neurl to the plasma membrane and this is a prerequisite for Jag1 internalization (Koutelou et al. 2008). Mouse Neurl1b was shown to directly bind and ubiquitinate recombinant Xenopus Delta and to cooperate with Mib1 in Delta endocytosis (Song et al. 2006). Ubiquitination of NOTCH ligands by MIB and NEURL ubiquitin ligases triggers ligand endocytosis. Drosophila Neuralized needs to interact with membrane phosphoinositides through its phosphoinositide-binding motif to trigger endocytosis of ubiquitinated Delta (Skwarek et al. 2007). The pulling force model states that the endocytosis of ubiquitinated Notch ligands mechanically pulls the ligand-bound Notch receptor, exposing the S2 cleavage site and resulting in Notch receptor cleavage by ADAM10 and/or ADAM17 metalloproteases (Itoh et al. 2003). Using a cell-bead optical tweezers system to measure rupture force specific for cells expressing Dll1 bound to laser trapped Notch1 beads, it was shown that the mechanical force required for the activation of Notch signaling depends on ligand ubiquitination and subsequent clathrin-mediated endocytosis that involves dynamin, epsins and actin (Meloty-Kapella et al. 2012). Ligand endocytosis and recycling does not directly influence Dll1 and Notch1 interaction, except that it regulates the amount of ligand on the cell surface that is available to activate Notch (Shergill et al. 2012).
REACT_160180 (Reactome) JAG1, expressed on a neighboring cell, binds NOTCH2 and activates intracellular NOTCH2 signaling (Shimizu et al. 1999, Shimizu et al. 2000). In contrast to NOTCH1, where fringe-mediated modification reduces the affinity of JAG1 for NOTCH1, it seems that fringe-mediated modification of NOTCH2 extracellular domain enhances activation of NOTCH2 signaling by JAG1 (Hicks et al. 2000).

JAG1-NOTCH2 signaling axis is affected in Alagille syndrome (AGS), a dominant congenital disorder characterized by hepatic bile duct abnormalities, as well as craniofacial, heart and kidney defects (Alagille et al. 1975, Habib et al. 1987). AGS is predominantly caused by mutations in JAG1 (Oda et al. 1997, Li et al. 1997) and less frequently by mutations in NOTCH2 (McDaniell et al. 2006).

JAG1 and NOTCH2 are expressed in kidney glomeruli and JAG1-NOTH2 signaling plays an important role in kidney development, as shown in mice mutant for JAG1 or NOTCH2 or both (McCright et al. 2001, McCright et al. 2002).
REACT_160207 (Reactome) JAG2, expressed on a neighboring cell, binds NOTCH2 and activates intracellular NOTCH2 signaling (Shimizu et al. 2000).
REACT_160318 (Reactome) DLL1, expressed on the surface of a neighboring cell, binds NOTCH2 and activates NOTCH2-mediated intracellular signaling (Shimizu et al. 2000). Modification of NOTCH2 extracellular domain by fringe enzymes enhances NOTCH2 activation by DLL1 (Hicks et al. 2000). Activation of NOTCH2 signaling by DLL1 may regulate regeneration and proliferation of renal tubules during acute kidney injury (Kobayashi et al. 2008).
REACT_160320 (Reactome) DLL4, expressed on a neighboring cell, binds NOTCH2 receptor and activates NOTCH2 intracellular signaling. The study used recombinant NOTCH2 and DLL4, exogenously expressed in Chinese hamster ovary cells. The species origin of NOTCH2 and DLL4 is not specified in the manuscript by Ji et al. 2004. The impact of fringe-mediated modification of NOTCH2 on activation by DLL4 has not been examined.
REACT_163655 (Reactome) In the nucleus, NICD2 forms a complex with RBPJ (CBF1, CSL) and MAML (mastermind). NICD2:RBPJ:MAML complex activates transcription from RBPJ-binding promoter elements (Wu et al. 2000).

Besides NICD2, RBPJ and MAML, NOTCH2 coactivator complex likely includes other proteins, shown as components of the NOTCH1 coactivator complex. Since disruption of the RBPJ:NCOR corepressor and MAML-mediated recruitment of transcriptional activators has not been studied in the context of NICD2, it is not shown here. More details are available in the pathway Signaling by NOTCH1.

Many NOTCH-regulated genes have paired RBPJ-binding sites in their promoters, in head-to-head arrangement, and require cooperative formation of dimeric NOTCH transcription complexes for transcriptional activation (Nam et al. 2007).
REACT_163689 (Reactome) GZMB (granzyme B) promoter contains several RBPJ binding elements (RBEs). NOTCH2 coactivator complex occupies the proximal RBE and at the same time interacts with phosphorylated CREB1, bound to an adjacent CRE site. EP300 transcriptional coactivator is also recruited to this complex through association with CREB1 (Maekawa et al. 2008).
REACT_163739 (Reactome) NOTCH2 intracellular domain, NICD2, as a part of the NOTCH2 coactivator complex, binds RBPJ elements in the promoter of HES1 gene (Shimizu et al. 2002).
REACT_163746 (Reactome) Transient transfection of a human pre-B-cell line REH with a vector encoding recombinant rat NICD2 induces endogenous 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. The Epstein-Barr virus protein EBNA2 can also activate FCER2 transcription through RBPJ promoter elements, possibly by mimicking NOTCH2 signaling (Hubmann et al. 2002).
REACT_163748 (Reactome) NOTCH2 intracellular domain, NICD2, as a part of the NOTCH2 coactivator complex, binds RBPJ elements in the promoter of HES5 gene (Shimizu et al. 2002).
REACT_163815 (Reactome) The promoter of FCER2 (CD23A) contains several RBPJ (CSL i.e. CBF) binding sites that are occupied by RBPJ transcription complexes that contain NICD2, but not NICD1. The association of NICD2 with RBPJ promoter elements of FCER2 gene was demonstrated by electromobility shift assays on nuclear extracts of human B-cell chronic lymphocytic leukemia (B-CLL) cells (Hubmann et al. 2002).
REACT_163817 (Reactome) NOTCH2 coactivator complex together with CREB1 and EP300 stimulates transcription of GZMB (granzyme B), which is important for the cytotoxic function of CD8+ T-cells (Maekawa et al. 2008).
REACT_163858 (Reactome) NOTCH2 coactivator complex bound to HES5 promoter stimulates HES5 transcription (Shimizu et al. 2002).
REACT_163918 (Reactome) NOTCH2 coactivator complex bound to RBPJ elements in the promoter of HES1 gene stimulates HES1 transcription (Shimizu et al. 2002).
REACT_163946 (Reactome) Binding of CNTN1 to NOTCH2 results in release of the intracellular domain of NOTCH2, NICD2 in a gamma-secretase-dependent way. The role of ADAM10 metalloprotease in this process has not been directly examined (Hu et al. 2003).
REACT_163967 (Reactome) MDK (Midkine, MK) is a secreted, heparin-binding growth factor that acts as a homodimer (Iwasaki et al. 1997). Both the full-length and the C-terminal region of MDK can bind the N-terminus of NOTCH2. In the presence of MDK, NICD2 accumulates in the nucleus in a dose-dependent fashion and epithelial-to-mesenchymal-transition (EMT) morphological changes are induced through a mechanism that has not been fully elucidated (Huang et al. 2008, Gungor et al. 2011).
REACT_163984 (Reactome) CNTN1 (F3, contactin-1) is a neuronal cell adhesion protein that can bind and activate NOTCH2, as well as NOTCH1, and these interactions are thought to play a role in oligodendrocyte maturation. While NOTCH1 activation by CNTN1 was shown to be deltex-dependent, the involvement of deltex in CNTN1-mediated activation of NOTCH2, although likely, has not been examined (Hu et al. 2003).
REACT_267 (Reactome) Ligand binding induces a conformational change in NOTCH2, through mechanical pulling of NOTCH triggered by endocytosis of the receptor-attached ligand (Meloty-Kapella et al. 2012). This conformational change exposes the S2 site in the extracellular region of NOTCH2 and results in cleavage of NOTCH2 by ADAM10 metalloprotease (Gibb et al. 2010), generating the membrane-anchored NOTCH2 fragment NEXT2 (Shimizu et al. 2000). The extracellular NOTCH2 portion remains attached to the ligand presented on the plasma membrane of a neighboring cell.
Ub-DLL/JAG:NOTCH2ArrowREACT_160100 (Reactome)
Ub-DLL/JAG:NOTCH2REACT_267 (Reactome)
UbREACT_160100 (Reactome)
gamma-secretase complexArrowREACT_163946 (Reactome)
gamma-secretase complexmim-catalysisREACT_1306 (Reactome)
p-S133-CREB1REACT_163689 (Reactome)
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