Canonical and non-canonical Notch signaling (WP3845)

Homo sapiens

This pathway is based on figure 1 of "Alteration of Notch signaling in skeletal development and disease" (see bibliography). In the NOTCH signaling pathway, mammals have 11 ligands (JAG, DLL, DLK, etc.) and 4 NOTCH receptors (NOTCH1,2,3,4). The pathway is activated by the interaction between a ligand in a ligand expressing cell and a NOTCH receptor in an adjacent, receptor expressing cell. At this point, proteases (ADAM10 and PSEN1/2) cleave the intracellular domain (NICD) of the NOTCH protein from the extracellular domain (NECD). In the canonical pathway, NICD travels into the nucleus where it forms a transcription complex with other proteins (RBPJ and MAML1,2,3). This transcriptional complex regulates the transcription of downstream canonical target genes, such as HES1 and HEY1. In the non-canonical pathway, otherwise known as RBPJ-independent NOTCH signaling, NOTCH can activate through R-Ras to promote cell adhesion. Alternatively, NOTCH may interact with IKKa in the NF-kB pathway, or LEF1 in the Wnt pathway.While the role that the canonical NOTCH pathway plays in skeletal biology is well understood, our understanding of the role of the non-canonical pathway remains primitive.


AAR&Co , Kristina Hanspers , Alex Pico , Chris Evelo , Egon Willighagen , and Eric Weitz


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Homo sapiens



Pathway Ontology

signaling pathway Notch signaling pathway


Label Type Compact URI Comment
MAML2 GeneProduct ensembl:ENSG00000184384
DLL4 GeneProduct ensembl:ENSG00000128917
JAG2 GeneProduct ensembl:ENSG00000184916
JAG1 GeneProduct ensembl:ENSG00000101384
DLL3 GeneProduct ensembl:ENSG00000090932
DLK1 GeneProduct ensembl:ENSG00000185559
RBPJ GeneProduct ensembl:ENSG00000168214
HES1 GeneProduct ensembl:ENSG00000114315
LEF1 GeneProduct ensembl:ENSG00000138795
DLK2 GeneProduct ensembl:ENSG00000171462
RRAS GeneProduct ensembl:ENSG00000126458
MAGP1 GeneProduct ensembl:ENSG00000140259
DLL1 GeneProduct ensembl:ENSG00000198719
PSEN2 GeneProduct ensembl:ENSG00000143801
MAGP2 GeneProduct ensembl:ENSG00000117122
IKKa GeneProduct ensembl:ENSG00000213341
NB3 GeneProduct ensembl:ENSG00000134115
MAML1 GeneProduct ensembl:ENSG00000161021
HEY1 GeneProduct ensembl:ENSG00000164683
DNER GeneProduct ensembl:ENSG00000187957
MAML3 GeneProduct ensembl:ENSG00000196782
PSEN1 GeneProduct ensembl:ENSG00000080815
ADAM10 GeneProduct ensembl:ENSG00000137845
NOTCH3 GeneProduct ensembl:ENSG00000074181
NOTCH1 GeneProduct ensembl:ENSG00000148400
NOTCH2 GeneProduct ensembl:ENSG00000134250
NOTCH4 GeneProduct ensembl:ENSG00000204301


  1. Alteration of Notch signaling in skeletal development and disease. Tao J, Chen S, Lee B. Ann N Y Acad Sci. 2010 Mar;1192:257–68. PubMed Europe PMC Scholia