Signaling by NOTCH4 (Homo sapiens)

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1, 16, 303, 8, 101, 5, 30nucleoplasmcytosolcytosolSignal sending cellSignal Receiving Cell12xFucT-11xGlcS-6xFucS-NOTCH4(24-1336) JAG1 DLL1 NOTCH4(1432-1466)NOTCH4(24-1431) gamma-secretasecomplexJAG2 NOTCH4(1337-2003) ADAM10 Zn2+ DLL1 NICD4JAG1 ADAM10:Zn++JAG1 NOTCH4NEXT4DLL4 PSEN2(1-297) DLL1 Pre-NOTCH Expressionand ProcessingNOTCH4fragment:DLL/JAGDLL/JAG:NOTCH4NCSTN 12xFucT-11xGlcS-6xFucS-NOTCH4(24-1336) DLL4 DLL4 PSENEN DLL/JAGJAG2 APH1A NOTCH4(1337-2003) NICD4JAG2 APH1B 2, 4, 6, 7, 9...


Description

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. View original pathway at:Reactome.

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Bibliography

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History

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CompareRevisionActionTimeUserComment
114660view16:12, 25 January 2021ReactomeTeamReactome version 75
113108view11:17, 2 November 2020ReactomeTeamReactome version 74
112342view15:26, 9 October 2020ReactomeTeamReactome version 73
101242view11:13, 1 November 2018ReactomeTeamreactome version 66
100781view20:40, 31 October 2018ReactomeTeamreactome version 65
99024view15:31, 24 October 2018DeSlchanged reactome ID number, since old number no longer exists.
93915view13:44, 16 August 2017ReactomeTeamreactome version 61
93491view11:25, 9 August 2017ReactomeTeamreactome version 61
87181view19:56, 18 July 2016EgonwOntology Term : 'signaling pathway' added !
86587view09:21, 11 July 2016ReactomeTeamreactome version 56
83125view10:02, 18 November 2015ReactomeTeamVersion54
81465view13:00, 21 August 2015ReactomeTeamVersion53
76938view08:21, 17 July 2014ReactomeTeamFixed remaining interactions
76643view12:01, 16 July 2014ReactomeTeamFixed remaining interactions
75973view10:03, 11 June 2014ReactomeTeamRe-fixing comment source
75676view11:00, 10 June 2014ReactomeTeamReactome 48 Update
75031view13:54, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74675view08:44, 30 April 2014ReactomeTeamNew pathway

External references

DataNodes

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NameTypeDatabase referenceComment
12xFucT-11xGlcS-6xFucS-NOTCH4(24-1336) ProteinQ99466 (Uniprot-TrEMBL)
ADAM10 ProteinO14672 (Uniprot-TrEMBL)
ADAM10:Zn++ComplexR-HSA-157186 (Reactome)
APH1A ProteinQ96BI3 (Uniprot-TrEMBL)
APH1B ProteinQ8WW43 (Uniprot-TrEMBL)
DLL/JAG:NOTCH4ComplexR-HSA-157653 (Reactome)
DLL/JAGComplexR-HSA-157643 (Reactome)
DLL1 ProteinO00548 (Uniprot-TrEMBL)
DLL4 ProteinQ9NR61 (Uniprot-TrEMBL)
JAG1 ProteinP78504 (Uniprot-TrEMBL)
JAG2 ProteinQ9Y219 (Uniprot-TrEMBL)
NCSTN ProteinQ92542 (Uniprot-TrEMBL)
NEXT4ProteinQ99466 (Uniprot-TrEMBL)
NICD4ProteinQ99466 (Uniprot-TrEMBL)
NOTCH4 fragment:DLL/JAGComplexR-HSA-157627 (Reactome)
NOTCH4(1337-2003) ProteinQ99466 (Uniprot-TrEMBL)
NOTCH4(1432-1466)ProteinQ99466 (Uniprot-TrEMBL)
NOTCH4(24-1431) ProteinQ99466 (Uniprot-TrEMBL)
NOTCH4ComplexR-HSA-157053 (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.
Zn2+ MetaboliteCHEBI:29105 (ChEBI)
gamma-secretase complexComplexR-HSA-157343 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ADAM10:Zn++mim-catalysisR-HSA-157649 (Reactome)
DLL/JAG:NOTCH4ArrowR-HSA-157633 (Reactome)
DLL/JAG:NOTCH4R-HSA-157649 (Reactome)
DLL/JAGR-HSA-157633 (Reactome)
NEXT4ArrowR-HSA-157649 (Reactome)
NEXT4R-HSA-157648 (Reactome)
NICD4ArrowR-HSA-157648 (Reactome)
NICD4ArrowR-HSA-157941 (Reactome)
NICD4R-HSA-157941 (Reactome)
NOTCH4 fragment:DLL/JAGArrowR-HSA-157649 (Reactome)
NOTCH4(1432-1466)ArrowR-HSA-157648 (Reactome)
NOTCH4R-HSA-157633 (Reactome)
R-HSA-157633 (Reactome) The NOTCH4 receptor is activated by binding a Delta-like (DLL) or Jagged (JAG) ligand presented on the plasma membrane of a neighbouring cell.
R-HSA-157648 (Reactome) NEXT4 fragment of NOTCH4 is further cleaved at the S3 site by the gamma-secretase complex, which relases the intracellular domain NICD4 into the cytosol.
R-HSA-157649 (Reactome) Ligand binding induces a conformational change in the NOTCH4, probably through mechanical pulling of NOTCH4 triggered by endocytosis of receptor-attached ligand. This conformational change exposes the S2 site in the extracellular region of NOTCH4 and results in cleavage of NOTCH4 by ADAM10 metalloprotease, generating the membrane-anchored NOTCH4 fragment NEXT4. The extracellular NOTCH4 portion remains attached to the ligand presented on the plasma membrane of a neighboring cell.
R-HSA-157941 (Reactome) The cytosolic NICD4 translocates to the nucleus.
gamma-secretase complexmim-catalysisR-HSA-157648 (Reactome)
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