Signaling by NOTCH2 (Homo sapiens)

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5, 12, 13, 17, 18, 28...175, 74, 10612, 10330, 7317138413, 56, 11613, 28, 32, 36, 41...1790671831, 79, 89, 1123, 10, 16, 25, 42...8413, 27, 94179018Signal Receiving CellnucleoplasmcytosolSignal Sending CellcytosolDLL1 18xFucT-16xGlcS-FucS-NOTCH2(26-1581) PSEN2(1-297) UBC(153-228) JAG2 JAG1 Signaling by NOTCH1APH1B FRINGE-modifiedNOTCH2ExtracellularFragment (NECD2) NICD2 Zn2+ UBA52(1-76) EP300 GZMB18xFucT-16xGlcS-FucS-NOTCH2(26-1581) NOTCH2(1582-2471) NOTCH2 CoactivatorComplex:HES1 geneDLL4 EP300UBB(153-228) JAG2 NOTCH2(1582-2471) UbHES5UBC(533-608) gamma-secretasecomplexUBB(77-152) MDK HES5 Gene UBC(305-380) FRINGE-modifiedNOTCH2ExtracellularFragment (NECD2) ADAM10 MDKUBC(153-228) NOTCH2coactivatorcomplex:p-S133-CREB1:EP300:GZMB GeneNOTCH2fragment:DLL/JAGRPS27A(1-76) RBPJ 18xFucT-16xGlcS-FucS-NOTCH2(26-1581) ADAM10:Zn++UBC(229-304) JAG1:NOTCH2UBC(1-76) UBC(381-456) NOTCH2(1582-2471) DLL1DLL1 UBC(457-532) CNTN1 NICD2 Pre-NOTCH Expressionand ProcessingHES5 GeneHES1RPS27A(1-76) NICD2 NEXT2APH1A NOTCH2/Fringe-modified NOTCH2DLL4 GZMB Gene NOTCH2(1666-1696)18xFucT-16xGlcS-FucS-NOTCH2(26-1581) UBC(77-152) NOTCH2(1582-2471) FRINGE-modifiedNOTCH2ExtracellularFragment (NECD2) JAG2 UBA52(1-76) UBC(609-684) NOTCH2(1582-1665) JAG2FRINGE-modifiedNOTCH2ExtracellularFragment (NECD2) MDK:NOTCH2DLL4:NOTCH2RBPJ UBC(305-380) RBPJ UBC(609-684) NOTCH2 CoactivatorComplex:FCER2 geneUBB(77-152) FCER2 geneUBB(1-76) NOTCH2 CoactivatorComplex:HES5 geneNOTCH2(1582-2471) UBC(1-76) NICD2UBB(1-76) MDK NICD2 UBC(533-608) CNTN118xFucT-16xGlcS-FucS-NOTCH2(26-1581) NOTCH2HES1 Gene 18xFucT-16xGlcS-FucS-NOTCH2(26-1581) RBPJMAMLRBPJ DLL1:NOTCH2NOTCH218xFucT-16xGlcS-FucS-NOTCH2(26-1581) FRINGE-modifiedNOTCH2ExtracellularFragment (NECD2) DLL/JAG:NOTCH2CNTN1:NOTCH218xFucT-16xGlcS-FucS-NOTCH2(26-1581) NCSTN UBC(457-532) UBB(153-228) 18xFucT-16xGlcS-FucS-NOTCH2(26-1581) 18xFucT-16xGlcS-FucS-NOTCH2(26-1581) NOTCH2DLL1 18xFucT-16xGlcS-FucS-NOTCH2(26-1581) 18xFucT-16xGlcS-FucS-NOTCH2(26-1581) NOTCH2(1582-2471) NOTCH2(1582-2471) DLL4 p-S133-CREB1JAG1NOTCH2(1582-2471) UBC(77-152) NOTCH2(1582-2471) NOTCH2(1582-2471) JAG1 RBPJ NOTCH2/Fringe-modified NOTCH2NICD2FCER2(1-321)NICD2 DLL4HES1 GeneFCER2 gene UBC(229-304) NOTCH2(1582-2471) JAG2:NOTCH2JAG1 p-S133-CREB1 Ub-DLL/JAG:NOTCH2GZMB GeneUBC(381-456) PSENEN MIB/NEURLNOTCH2(1582-2471) NOTCH2 CoactivatorComplex5, 106743, 4, 6, 10, 14...1, 2, 7-9, 11...


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). Source:Reactome.

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  93. Kopan R, Ilagan MX.; ''The canonical Notch signaling pathway: unfolding the activation mechanism.''; PubMed Europe PMC Scholia
  94. 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
  95. Maier MM, Gessler M.; ''Comparative analysis of the human and mouse Hey1 promoter: Hey genes are new Notch target genes.''; PubMed Europe PMC Scholia
  96. 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
  97. Saxena MT, Schroeter EH, Mumm JS, Kopan R.; ''Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis.''; PubMed Europe PMC Scholia
  98. Pitsouli C, Delidakis C.; ''The interplay between DSL proteins and ubiquitin ligases in Notch signaling.''; PubMed Europe PMC Scholia
  99. Habib R, Dommergues JP, Gubler MC, Hadchouel M, Gautier M, Odievre M, Alagille D.; ''Glomerular mesangiolipidosis in Alagille syndrome (arteriohepatic dysplasia).''; PubMed Europe PMC Scholia
  100. 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
  101. McGill MA, Dho SE, Weinmaster G, McGlade CJ.; ''Numb regulates post-endocytic trafficking and degradation of Notch1.''; PubMed Europe PMC Scholia
  102. 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
  103. Shimizu K, Chiba S, Saito T, Takahashi T, Kumano K, Hamada Y, Hirai H.; ''Integrity of intracellular domain of Notch ligand is indispensable for cleavage required for release of the Notch2 intracellular domain.''; PubMed Europe PMC Scholia
  104. 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
  105. 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
  106. 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
  107. Fryer CJ, White JB, Jones KA.; ''Mastermind recruits CycC:CDK8 to phosphorylate the Notch ICD and coordinate activation with turnover.''; PubMed Europe PMC Scholia
  108. 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
  109. 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
  110. 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
  111. 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
  112. Fortini ME.; ''Gamma-secretase-mediated proteolysis in cell-surface-receptor signalling.''; PubMed Europe PMC Scholia
  113. 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
  114. 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
  115. 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
  116. 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
  117. 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
  118. Hashimoto Y, Akiyama Y, Otsubo T, Shimada S, Yuasa Y.; ''Involvement of epigenetically silenced microRNA-181c in gastric carcinogenesis.''; PubMed Europe PMC Scholia

History

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CompareRevisionActionTimeUserComment
115082view17:03, 25 January 2021ReactomeTeamReactome version 75
113524view12:00, 2 November 2020ReactomeTeamReactome version 74
112723view16:12, 9 October 2020ReactomeTeamReactome version 73
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) ProteinQ04721 (Uniprot-TrEMBL)
ADAM10 ProteinO14672 (Uniprot-TrEMBL)
ADAM10:Zn++ComplexR-HSA-157186 (Reactome)
APH1A ProteinQ96BI3 (Uniprot-TrEMBL)
APH1B ProteinQ8WW43 (Uniprot-TrEMBL)
CNTN1 ProteinQ12860 (Uniprot-TrEMBL)
CNTN1:NOTCH2ComplexR-HSA-2220817 (Reactome)
CNTN1ProteinQ12860 (Uniprot-TrEMBL)
DLL/JAG:NOTCH2R-HSA-157637 (Reactome)
DLL1 ProteinO00548 (Uniprot-TrEMBL)
DLL1:NOTCH2ComplexR-HSA-1980050 (Reactome)
DLL1ProteinO00548 (Uniprot-TrEMBL)
DLL4 ProteinQ9NR61 (Uniprot-TrEMBL)
DLL4:NOTCH2ComplexR-HSA-1980053 (Reactome)
DLL4ProteinQ9NR61 (Uniprot-TrEMBL)
EP300 ProteinQ09472 (Uniprot-TrEMBL)
EP300ProteinQ09472 (Uniprot-TrEMBL)
FCER2 gene ProteinENSG00000104921 (ENSEMBL)
FCER2 geneENSG00000104921 (ENSEMBL)
FCER2(1-321)ProteinP06734 (Uniprot-TrEMBL)
FRINGE-modified

NOTCH2 Extracellular

Fragment (NECD2) 		ProteinQ04721 (Uniprot-TrEMBL)
GZMB Gene ProteinENSG00000100453 (ENSEMBL)
GZMB GeneENSG00000100453 (ENSEMBL)
GZMBProteinP10144 (Uniprot-TrEMBL)
HES1 Gene ProteinENSG00000114315 (ENSEMBL)
HES1 GeneENSG00000114315 (ENSEMBL)
HES1ProteinQ14469 (Uniprot-TrEMBL)
HES5 Gene ProteinENSG00000197921 (ENSEMBL)
HES5 GeneENSG00000197921 (ENSEMBL)
HES5ProteinQ5TA89 (Uniprot-TrEMBL)
JAG1 ProteinP78504 (Uniprot-TrEMBL)
JAG1:NOTCH2ComplexR-HSA-1980058 (Reactome)
JAG1ProteinP78504 (Uniprot-TrEMBL)
JAG2 ProteinQ9Y219 (Uniprot-TrEMBL)
JAG2:NOTCH2ComplexR-HSA-1980059 (Reactome)
JAG2ProteinQ9Y219 (Uniprot-TrEMBL)
MAMLProteinR-HSA-212357 (Reactome)
MDK ProteinP21741 (Uniprot-TrEMBL)
MDK:NOTCH2ComplexR-HSA-2974762 (Reactome)
MDKComplexR-HSA-2974753 (Reactome)
MIB/NEURLProteinR-HSA-1911464 (Reactome)
NCSTN ProteinQ92542 (Uniprot-TrEMBL)
NEXT2ProteinQ04721 (Uniprot-TrEMBL)
NICD2 ProteinQ04721 (Uniprot-TrEMBL)
NICD2ProteinQ04721 (Uniprot-TrEMBL)
NOTCH2

coactivator

complex:p-S133-CREB1:EP300:GZMB Gene		ComplexR-HSA-2976561 (Reactome)
NOTCH2 fragment:DLL/JAGComplexR-HSA-157630 (Reactome)
NOTCH2 Coactivator Complex:FCER2 geneComplexR-HSA-2976740 (Reactome)
NOTCH2 Coactivator Complex:HES1 geneComplexR-HSA-2976712 (Reactome)
NOTCH2 Coactivator Complex:HES5 geneComplexR-HSA-2976724 (Reactome)
NOTCH2 Coactivator ComplexComplexR-HSA-2127289 (Reactome)
NOTCH2(1582-1665) ProteinQ04721 (Uniprot-TrEMBL)
NOTCH2(1582-2471) ProteinQ04721 (Uniprot-TrEMBL)
NOTCH2(1666-1696)ProteinQ04721 (Uniprot-TrEMBL)
NOTCH2/Fringe-modified NOTCH2ComplexR-HSA-2168114 (Reactome)
NOTCH2ComplexR-HSA-157005 (Reactome)
PSEN2(1-297) ProteinP49810 (Uniprot-TrEMBL)
PSENEN ProteinQ9NZ42 (Uniprot-TrEMBL)
Pre-NOTCH Expression and ProcessingPathwayR-HSA-1912422 (Reactome) 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 ProteinQ06330 (Uniprot-TrEMBL)
RBPJProteinQ06330 (Uniprot-TrEMBL)
RPS27A(1-76) ProteinP62979 (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.

UBA52(1-76) ProteinP62987 (Uniprot-TrEMBL)
UBB(1-76) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(153-228) ProteinP0CG47 (Uniprot-TrEMBL)
UBB(77-152) ProteinP0CG47 (Uniprot-TrEMBL)
UBC(1-76) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(153-228) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(229-304) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(305-380) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(381-456) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(457-532) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(533-608) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(609-684) ProteinP0CG48 (Uniprot-TrEMBL)
UBC(77-152) ProteinP0CG48 (Uniprot-TrEMBL)
Ub-DLL/JAG:NOTCH2ComplexR-HSA-2172171 (Reactome)
UbProteinR-HSA-113595 (Reactome)
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
gamma-secretase complexComplexR-HSA-157343 (Reactome)
p-S133-CREB1 ProteinP16220 (Uniprot-TrEMBL)
p-S133-CREB1ProteinP16220 (Uniprot-TrEMBL)

Annotated Interactions

View all...
SourceTargetTypeDatabase referenceComment
ADAM10:Zn++mim-catalysisR-HSA-157629 (Reactome)
CNTN1:NOTCH2ArrowR-HSA-2220816 (Reactome)
CNTN1:NOTCH2R-HSA-2974731 (Reactome)
CNTN1R-HSA-2220816 (Reactome)
DLL/JAG:NOTCH2R-HSA-2172172 (Reactome)
DLL1:NOTCH2ArrowR-HSA-1980048 (Reactome)
DLL1R-HSA-1980048 (Reactome)
DLL4:NOTCH2ArrowR-HSA-1980051 (Reactome)
DLL4R-HSA-1980051 (Reactome)
EP300R-HSA-2976563 (Reactome)
FCER2 geneR-HSA-2127285 (Reactome)
FCER2 geneR-HSA-2976742 (Reactome)
FCER2(1-321)ArrowR-HSA-2127285 (Reactome)
GZMB GeneR-HSA-2976551 (Reactome)
GZMB GeneR-HSA-2976563 (Reactome)
GZMBArrowR-HSA-2976551 (Reactome)
HES1 GeneR-HSA-2197562 (Reactome)
HES1 GeneR-HSA-2976716 (Reactome)
HES1ArrowR-HSA-2197562 (Reactome)
HES5 GeneR-HSA-2197564 (Reactome)
HES5 GeneR-HSA-2976726 (Reactome)
HES5ArrowR-HSA-2197564 (Reactome)
JAG1:NOTCH2ArrowR-HSA-1980056 (Reactome)
JAG1R-HSA-1980056 (Reactome)
JAG2:NOTCH2ArrowR-HSA-1980061 (Reactome)
JAG2R-HSA-1980061 (Reactome)
MAMLR-HSA-2197588 (Reactome)
MDK:NOTCH2ArrowR-HSA-2974737 (Reactome)
MDKR-HSA-2974737 (Reactome)
MIB/NEURLmim-catalysisR-HSA-2172172 (Reactome)
NEXT2ArrowR-HSA-157629 (Reactome)
NEXT2R-HSA-157640 (Reactome)
NICD2ArrowR-HSA-157640 (Reactome)
NICD2ArrowR-HSA-157933 (Reactome)
NICD2ArrowR-HSA-2974731 (Reactome)
NICD2R-HSA-157933 (Reactome)
NICD2R-HSA-2197588 (Reactome)
NOTCH2

coactivator

complex:p-S133-CREB1:EP300:GZMB Gene		ArrowR-HSA-2976551 (Reactome)
NOTCH2

coactivator

complex:p-S133-CREB1:EP300:GZMB Gene		ArrowR-HSA-2976563 (Reactome)
NOTCH2 fragment:DLL/JAGArrowR-HSA-157629 (Reactome)
NOTCH2 Coactivator Complex:FCER2 geneArrowR-HSA-2127285 (Reactome)
NOTCH2 Coactivator Complex:FCER2 geneArrowR-HSA-2976742 (Reactome)
NOTCH2 Coactivator Complex:HES1 geneArrowR-HSA-2197562 (Reactome)
NOTCH2 Coactivator Complex:HES1 geneArrowR-HSA-2976716 (Reactome)
NOTCH2 Coactivator Complex:HES5 geneArrowR-HSA-2197564 (Reactome)
NOTCH2 Coactivator Complex:HES5 geneArrowR-HSA-2976726 (Reactome)
NOTCH2 Coactivator ComplexArrowR-HSA-2197588 (Reactome)
NOTCH2 Coactivator ComplexR-HSA-2976563 (Reactome)
NOTCH2 Coactivator ComplexR-HSA-2976716 (Reactome)
NOTCH2 Coactivator ComplexR-HSA-2976726 (Reactome)
NOTCH2 Coactivator ComplexR-HSA-2976742 (Reactome)
NOTCH2(1666-1696)ArrowR-HSA-157640 (Reactome)
NOTCH2/Fringe-modified NOTCH2R-HSA-1980048 (Reactome)
NOTCH2/Fringe-modified NOTCH2R-HSA-1980056 (Reactome)
NOTCH2R-HSA-1980051 (Reactome)
NOTCH2R-HSA-1980061 (Reactome)
NOTCH2R-HSA-2220816 (Reactome)
NOTCH2R-HSA-2974737 (Reactome)
R-HSA-157629 (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.
R-HSA-157640 (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).
R-HSA-157933 (Reactome) The cytosolic NICD2 translocates to the nucleus.
R-HSA-1980048 (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).
R-HSA-1980051 (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.
R-HSA-1980056 (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).
R-HSA-1980061 (Reactome) JAG2, expressed on a neighboring cell, binds NOTCH2 and activates intracellular NOTCH2 signaling (Shimizu et al. 2000).
R-HSA-2127285 (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).
R-HSA-2172172 (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).
R-HSA-2197562 (Reactome) NOTCH2 coactivator complex bound to RBPJ elements in the promoter of HES1 gene stimulates HES1 transcription (Shimizu et al. 2002).
R-HSA-2197564 (Reactome) NOTCH2 coactivator complex bound to HES5 promoter stimulates HES5 transcription (Shimizu et al. 2002).
R-HSA-2197588 (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).
R-HSA-2220816 (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).
R-HSA-2974731 (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).
R-HSA-2974737 (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).
R-HSA-2976551 (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).
R-HSA-2976563 (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).
R-HSA-2976716 (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).
R-HSA-2976726 (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).
R-HSA-2976742 (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).
RBPJR-HSA-2197588 (Reactome)
Ub-DLL/JAG:NOTCH2ArrowR-HSA-2172172 (Reactome)
Ub-DLL/JAG:NOTCH2R-HSA-157629 (Reactome)
UbR-HSA-2172172 (Reactome)
gamma-secretase complexArrowR-HSA-2974731 (Reactome)
gamma-secretase complexmim-catalysisR-HSA-157640 (Reactome)
p-S133-CREB1R-HSA-2976563 (Reactome)
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