Signaling by NOTCH3 (Homo sapiens)

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1, 6, 316, 12, 312, 7, 11DLL/JAG DLL/JAG cytosolgamma-secretase complex PSEN2 dimer cytosolNOTCH3 DLL/JAGNOTCH3 ADAM10Zn++ Signal sending cellnucleoplasmSignal receiving cellAPH-1 NOTCH3 fragmentDLL/JAG NOTCH3 APH1B NEXT3JAG2 DLL1 NOTCH3JAG1 NICD3NOTCH3 fragmentDLL/JAGNICD3DLL4 DLL/JAGNOTCH3JAG1 ADAM10 NOTCH3JAG2 DLL4 ADAM10Zn++APH1A NOTCH3PSEN2gamma-secretase complexNOTCH314xGlcS-10xFucT-4xFucS-NOTCH3NCSTN NOTCH3Pre-NOTCH Expression and ProcessingDLL/JAGPSENEN 14xGlcS-10xFucT-4xFucS-NOTCH3DLL1 Zn2+ 3-5, 8-10, 13...


Description

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. Original Pathway at Reactome: http://www.reactome.org/PathwayBrowser/#DB=gk_current&FOCUS_SPECIES_ID=48887&FOCUS_PATHWAY_ID=1980148

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114804view16:30, 25 January 2021ReactomeTeamReactome version 75
113248view11:31, 2 November 2020ReactomeTeamReactome version 74
112466view15:41, 9 October 2020ReactomeTeamReactome version 73
101375view11:26, 1 November 2018ReactomeTeamreactome version 66
100913view21:01, 31 October 2018ReactomeTeamreactome version 65
100454view19:36, 31 October 2018ReactomeTeamreactome version 64
100001view16:19, 31 October 2018ReactomeTeamreactome version 63
99001view15:17, 22 October 2018DeSlchanged reactome ID number, since old number no longer exists.
93913view13:44, 16 August 2017ReactomeTeamreactome version 61
93489view11:25, 9 August 2017ReactomeTeamreactome version 61
87182view19:57, 18 July 2016EgonwOntology Term : 'signaling pathway' added !
86585view09:21, 11 July 2016ReactomeTeamreactome version 56
83126view10:02, 18 November 2015ReactomeTeamVersion54
81466view13:00, 21 August 2015ReactomeTeamVersion53
76939view08:21, 17 July 2014ReactomeTeamFixed remaining interactions
76644view12:01, 16 July 2014ReactomeTeamFixed remaining interactions
75974view10:03, 11 June 2014ReactomeTeamRe-fixing comment source
75677view11:00, 10 June 2014ReactomeTeamReactome 48 Update
75032view13:54, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74676view08:44, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
14xGlcS-10xFucT-4xFucS-NOTCH3ProteinQ9UM47 (Uniprot-TrEMBL)
ADAM10 Zn++ComplexREACT_3937 (Reactome)
ADAM10 ProteinO14672 (Uniprot-TrEMBL)
APH1A ProteinQ96BI3 (Uniprot-TrEMBL)
APH1B ProteinQ8WW43 (Uniprot-TrEMBL)
DLL/JAG NOTCH3ComplexREACT_2798 (Reactome)
DLL/JAGProteinREACT_5356 (Reactome)
DLL1 ProteinO00548 (Uniprot-TrEMBL)
DLL4 ProteinQ9NR61 (Uniprot-TrEMBL)
JAG1 ProteinP78504 (Uniprot-TrEMBL)
JAG2 ProteinQ9Y219 (Uniprot-TrEMBL)
NCSTN ProteinQ92542 (Uniprot-TrEMBL)
NEXT3ProteinQ9UM47 (Uniprot-TrEMBL)
NICD3ProteinQ9UM47 (Uniprot-TrEMBL)
NOTCH3 fragment DLL/JAGComplexREACT_2424 (Reactome)
NOTCH3ProteinQ9UM47 (Uniprot-TrEMBL)
NOTCH3ComplexREACT_4341 (Reactome)
PSEN2ProteinP49810 (Uniprot-TrEMBL)
PSENEN 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.
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
gamma-secretase complexComplexREACT_5292 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADAM10 Zn++REACT_1552 (Reactome)
DLL/JAGREACT_452 (Reactome)
NEXT3ArrowREACT_1552 (Reactome)
NICD3ArrowREACT_1803 (Reactome)
NOTCH3 fragment DLL/JAGArrowREACT_1552 (Reactome)
NOTCH3ArrowREACT_1803 (Reactome)
NOTCH3REACT_452 (Reactome)
REACT_1135 (Reactome) The cytosolic NICD3 translocates to the nucleus.
REACT_1552 (Reactome) Ligand binding induces a conformational change in the NOTCH3, probably through mechanical pulling of NOTCH3 triggered by endocytosis of receptor-attached ligand. This conformational change exposes the S2 site in the extracellular region of NOTCH3 and results in cleavage of NOTCH3 by ADAM10 metalloprotease, generating the membrane-anchored NOTCH3 fragment NEXT3. The extracellular NOTCH3 portion remains attached to the ligand presented on the plasma membrane of a neighboring cell.
REACT_1803 (Reactome) NEXT3 fragment of NOTCH3 is further cleaved at the S3 site by the gamma-secretase complex, which relases the intracellular domain NICD3 into the cytosol.
REACT_452 (Reactome) The NOTCH3 receptor is activated by binding a Delta-like (DLL) or Jagged (JAG) ligand presented on the plasma membrane of a neighbouring cell.
gamma-secretase complexREACT_1803 (Reactome)
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