Notch signaling (WP268)

Homo sapiens

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 [https://assays.cancer.gov/available_assays?wp_id=WP268 CPTAC Assay Portal].

Authors

Alex Pico , Thomas Kelder , Kristina Hanspers , Nathan Salomonis , Friederike Ehrhart , Egon Willighagen , and Eric Weitz

Activity

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Organisms

Homo sapiens

Communities

CPTAC PancCanNet

Annotations

Pathway Ontology

Notch signaling pathway

Participants

Label Type Compact URI Comment
DNA GeneProduct wikidata:Q7430
MAML1 GeneProduct ensembl:ENSG00000161021
PSEN2 GeneProduct ensembl:ENSG00000143801
APH1B GeneProduct ensembl:ENSG00000138613
RBPSUHL GeneProduct ensembl:ENSG00000124232
DVL3 GeneProduct ensembl:ENSG00000161202
DTX3 GeneProduct ensembl:ENSG00000178498
DLL3 GeneProduct ensembl:ENSG00000090932
JAG2 GeneProduct ensembl:ENSG00000184916
HDAC1 GeneProduct ensembl:ENSG00000116478
JAG1 GeneProduct ensembl:ENSG00000101384
DTX2 GeneProduct ensembl:ENSG00000091073
NUMB GeneProduct ensembl:ENSG00000133961
LFNG GeneProduct ensembl:ENSG00000106003
NCOR2 GeneProduct ensembl:ENSG00000196498
TNF GeneProduct ensembl:ENSG00000204490
PTCRA GeneProduct ensembl:ENSG00000171611
DVL2 GeneProduct ensembl:ENSG00000004975
CREBBP GeneProduct ensembl:ENSG00000005339
DTX3L GeneProduct ensembl:ENSG00000163840
GCN5L2 GeneProduct ensembl:ENSG00000108773
APH1A GeneProduct ensembl:ENSG00000117362
NOTCH3 GeneProduct ensembl:ENSG00000074181
DTX1 GeneProduct ensembl:ENSG00000135144
ADAM17 GeneProduct ensembl:ENSG00000151694
NOTCH2 GeneProduct ensembl:ENSG00000134250
DLL1 GeneProduct ensembl:ENSG00000198719
RBPJ GeneProduct ncbigene:3516 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. 
 
DVL1 GeneProduct ensembl:ENSG00000107404
DLL4 GeneProduct ensembl:ENSG00000128917
NUMBL GeneProduct ensembl:ENSG00000105245
RFNG GeneProduct ensembl:ENSG00000169733
NCSTN GeneProduct ensembl:ENSG00000162736
NOTCH4 GeneProduct ensembl:ENSG00000204301
NOTCH1 GeneProduct ensembl:ENSG00000148400
CIR GeneProduct ncbigene:3762
CTBP1 GeneProduct ensembl:ENSG00000159692
SKIP GeneProduct ensembl:ENSG00000132376
MFNG GeneProduct ensembl:ENSG00000100060
HES5 GeneProduct ensembl:ENSG00000197921
HES1 GeneProduct ensembl:ENSG00000114315
DTX4 GeneProduct ensembl:ENSG00000110042
PSEN1 GeneProduct ensembl:ENSG00000080815
MAML3 GeneProduct ensembl:ENSG00000196782
CTBP2 GeneProduct ensembl:ENSG00000175029
PCAF GeneProduct ensembl:ENSG00000114166
HDAC2 GeneProduct ensembl:ENSG00000196591
NICD Protein wikidata:Q50257903

References

  1. The ins and outs of notch signaling. Weinmaster G. Mol Cell Neurosci. 1997;9(2):91–102. PubMed Europe PMC Scholia