Notch signaling pathway (WP29)

Mus musculus

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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.

Authors

Thomas Kelder , Daniela Digles , Martina Summer-Kutmon , Egon Willighagen , Kristina Hanspers , Eric Weitz , and Alex Pico

Activity

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Organisms

Mus musculus

Communities

Annotations

Pathway Ontology

Notch signaling pathway

Participants

Label Type Compact URI Comment
RBP-J GeneProduct ncbigene:19664 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.
Jag1 GeneProduct ncbigene:16449
Maml3 GeneProduct ncbigene:433586
Dtx1 GeneProduct ncbigene:14357
Hdac2 GeneProduct ncbigene:15182
Dvl3 GeneProduct ncbigene:13544
Adam17 GeneProduct ncbigene:11491
Ctbp2 GeneProduct ncbigene:13017
Notch3 GeneProduct ncbigene:18131
Maml1 GeneProduct ncbigene:103806
Dvl2 GeneProduct ncbigene:13543
Dvl1 GeneProduct ncbigene:13542
CIR GeneProduct ncbigene:66935
Ncstn GeneProduct ncbigene:59287
Aph1a GeneProduct ncbigene:226548
RBPSUHL GeneProduct ncbigene:19668
Notch1 GeneProduct ncbigene:18128
Ncor2 GeneProduct ncbigene:20602
Numb GeneProduct ncbigene:18222
Dtx3l GeneProduct ncbigene:209200
Dll1 GeneProduct ncbigene:13388
SKIP GeneProduct ncbigene:66354
Psen2 GeneProduct ncbigene:19165
Dll4 GeneProduct ncbigene:54485
Notch2 GeneProduct ncbigene:18129
Notch4 GeneProduct ncbigene:18132
Crebbp GeneProduct ncbigene:12914
Dtx3 GeneProduct ncbigene:80904
Dtx2 GeneProduct ncbigene:74198
Hes1 GeneProduct ncbigene:15205
PCAF GeneProduct uniprot:Q9JHD1
Dtx4 GeneProduct ncbigene:207521
Lfng GeneProduct ncbigene:16848
Hdac1 GeneProduct ncbigene:433759
Jag2 GeneProduct ncbigene:16450
Psen1 GeneProduct ncbigene:19164
Ctbp1 GeneProduct ncbigene:13016
Dll3 GeneProduct ncbigene:13389
Mfng GeneProduct ncbigene:17305
Numbl GeneProduct ncbigene:18223
Tnf GeneProduct ncbigene:21926
Rfng GeneProduct ncbigene:19719
Ptcra GeneProduct ncbigene:19208
Aph1b GeneProduct ncbigene:208117
GCN5L2 GeneProduct ncbigene:14534
Hes5 GeneProduct ncbigene:15208

References

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