Notch signaling (Homo sapiens)

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The Notch signaling pathway is an evolutionarily conserved, intercellular signaling mechanism essential for proper embryonic development in all metazoan organisms in the Animal kingdom. The Notch proteins (Notch1-Notch4 in vertebrates) are single-pass receptors that are activated by the Delta (or Delta-like) and Jagged/Serrate families of membrane-bound ligands. They are transported to the plasma membrane as cleaved, but otherwise intact polypeptides. Interaction with ligand leads to two additional proteolytic cleavages that liberate the Notch intracellular domain (NICD) from the plasma membrane. The NICD translocates to the nucleus, where it forms a complex with the DNA binding protein CSL, displacing a histone deacetylase (HDAc)-co-repressor (CoR) complex from CSL. Components of an activation complex, such as MAML1 and histone acetyltransferases (HATs), are recruited to the NICD-CSL complex, leading to the transcriptional activation of Notch target genes. Proteins on this pathway have targeted assays available via the CPTAC Assay Portal.

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  1. Weinmaster G; ''The ins and outs of notch signaling.''; Mol Cell Neurosci, 1997 PubMed Europe PMC Scholia


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126344view09:19, 23 April 2023EgonwAdded two missing identifiers
126343view09:14, 23 April 2023EgonwMade a complex and DNA data nodes
126342view09:05, 23 April 2023EgonwLicense is CCZero
117167view09:52, 18 May 2021EweitzModified title
115418view15:43, 18 February 2021EgonwAnother pathway clickable
107281view19:00, 17 September 2019KhanspersModified description
105466view05:14, 8 August 2019KhanspersModified description
104981view19:14, 27 June 2019KhanspersModified description
102319view08:12, 20 December 2018FehrhartChanged title due to overlap with other pathway
94808view00:23, 6 October 2017AlexanderPicoAdded compartments, converted lines
70096view18:40, 12 July 2013MaintBotupdating to 2013 schema
59203view19:14, 22 February 2013MaintBotUpdated Ensembl and UniProt data source
45531view01:14, 17 October 2011NsalomonisAdded gene ID
45529view01:07, 17 October 2011NsalomonisPeriodical save, work in progress
45342view20:23, 7 October 2011KhanspersOntology Term : 'Notch signaling pathway' added !
41194view23:43, 1 March 2011MaintBotRemoved redundant pathway information and comments
38866view18:20, 24 September 2010KhanspersChanged line types
38865view18:19, 24 September 2010Khanspers
38799view07:11, 24 September 2010Thomaslinked to mapk signaling pathway
35608view15:55, 12 February 2010Thomasadded literature
35607view15:54, 12 February 2010ThomasModified description
35606view15:53, 12 February 2010ThomasModified description
32378view16:54, 15 August 2009MaintBotFixed text labels
32019view13:23, 14 August 2009MaintBotFixed group labels
29891view11:17, 9 June 2009Thomasupdated ensembl references
29217view01:01, 15 April 2009AlexanderPicofixed ID systems
29216view00:55, 15 April 2009AlexanderPicoPeriodical save, work in progress
21243view11:31, 14 November 2008MaintBot[[Pathway:Homo sapiens:Notch signaling KEGG]] moved to [[Pathway:WP268]]: Moved to stable identifier
14983view20:09, 24 May 2008AlexanderPicoGrouped and connected
12961view10:56, 17 May 2008MaintBotSticky edges patch by Sjoerd
8278view13:46, 7 January 2008MaintBot[[Pathway:Human:Notch signaling KEGG]] moved to [[Pathway:Homo sapiens:Notch signaling KEGG]]: Renaming species
7759view16:16, 18 December 2007MaintBotfixed category names
7280view12:41, 4 November 2007MaintBotAdded categories to GPML
6354view22:18, 22 May 2007169.230.77.174gpml file for [[Human:Notch_signaling_KEGG]]

External references


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NameTypeDatabase referenceComment
ADAM17GeneProductENSG00000151694 (Ensembl)
APH1AGeneProductENSG00000117362 (Ensembl)
APH1BGeneProductENSG00000138613 (Ensembl)
CIRGeneProduct3762 (Entrez Gene)
CREBBPGeneProductENSG00000005339 (Ensembl)
CTBP1GeneProductENSG00000159692 (Ensembl)
CTBP2GeneProductENSG00000175029 (Ensembl)
DLL1GeneProductENSG00000198719 (Ensembl)
DLL3GeneProductENSG00000090932 (Ensembl)
DLL4GeneProductENSG00000128917 (Ensembl)
DNAGeneProductQ7430 (Wikidata)
DTX1GeneProductENSG00000135144 (Ensembl)
DTX2GeneProductENSG00000091073 (Ensembl)
DTX3GeneProductENSG00000178498 (Ensembl)
DTX3LGeneProductENSG00000163840 (Ensembl)
DTX4GeneProductENSG00000110042 (Ensembl)
DVL1GeneProductENSG00000107404 (Ensembl)
DVL2GeneProductENSG00000004975 (Ensembl)
DVL3GeneProductENSG00000161202 (Ensembl)
GCN5L2GeneProductENSG00000108773 (Ensembl)
HDAC1GeneProductENSG00000116478 (Ensembl)
HDAC2GeneProductENSG00000196591 (Ensembl)
HES1GeneProductENSG00000114315 (Ensembl)
HES5GeneProductENSG00000197921 (Ensembl)
JAG1GeneProductENSG00000101384 (Ensembl)
JAG2GeneProductENSG00000184916 (Ensembl)
LFNGGeneProductENSG00000106003 (Ensembl)
MAML1GeneProductENSG00000161021 (Ensembl)
MAML3GeneProductENSG00000196782 (Ensembl)
MAPK signaling pathwayPathwayWP382 (WikiPathways)
MFNGGeneProductENSG00000100060 (Ensembl)
NCOR2GeneProductENSG00000196498 (Ensembl)
NCSTNGeneProductENSG00000162736 (Ensembl)
NICDProteinQ50257903 (Wikidata)
NOTCH1GeneProductENSG00000148400 (Ensembl)
NOTCH2GeneProductENSG00000134250 (Ensembl)
NOTCH3GeneProductENSG00000074181 (Ensembl)
NOTCH4GeneProductENSG00000204301 (Ensembl)
NUMBGeneProductENSG00000133961 (Ensembl)
NUMBLGeneProductENSG00000105245 (Ensembl)
PCAFGeneProductENSG00000114166 (Ensembl)
PSEN1GeneProductENSG00000080815 (Ensembl)
PSEN2GeneProductENSG00000143801 (Ensembl)
PTCRAGeneProductENSG00000171611 (Ensembl)
RBPJGeneProduct3516 (Entrez Gene) aka RBP-Jkappa aka CBF1. Serves as a co-factor for the processed notch receptor after translocation to the nucleus to activate down-stream notch transcription. PMID: 15187023. In the nucleus, NIC (processed notch) regulates transcription through association with the DNA-binding protein RBP-J (also known as CBF1, KBF2, or CSL). The primary gene targets of RBP-J include members of the hairy and enhancer of split (HES) and hairy related transcription factor (HRT) families of basic-helix-loop-helix transcriptional repressors. In the absence of NIC, RBP-J actively represses transcription by way of recruitment of a corepressor complex.8 Nuclear translocation of NIC leads to dissociation of repressor proteins from RBP-J and formation of a coactivator complex.9-13. PMID: 15194757. RBP-J is a downstream target of the Notch pathway, a conserved signal transduction pathway that is important in development and cell fate determination (43). The intracellular domain (ICD) of activated Notch is released from the membrane through proteolytic cleavage and is translocated to the nucleus, where it is directed to target promoters through interaction with RBP-J (47, 68). RBP-J is a repressor in the ground state; its interaction with Notch ICD relieves this repression and turns on target genes. Interestingly, KSHV is not the only virus that has parasitized this pathway. Several viral transcription factors, e.g., EBNA2 and EBNA3 of Epstein-Barr virus and the 13S isoform of adenovirus E1A, are known to bind and activate target genes via RBP-J interactions (1, 22, 25, 26, 29). In all cases, the viral proteins target the same (central repressive) domain of RBP-J that is targeted by Notch, although KSHV RTA is capable of interactions with an additional region of RBP-J in vitro (33). RBP-J can bind RTA and recruit it to its cognate recognition site; when this happens, the activation function of RTA can relieve RBP-J-mediated repression and upregulate expression of the targeted gene. EMSA studies reveal that both sites A and C can bind to RBP-J; sequence inspection reveals that site A is a novel functional variant of known RBP-J recognition sites. 

RBPSUHLGeneProductENSG00000124232 (Ensembl)
RFNGGeneProductENSG00000169733 (Ensembl)
SKIPGeneProductENSG00000132376 (Ensembl)
TNFGeneProductENSG00000204490 (Ensembl)

Annotated Interactions

No annotated interactions

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