Canonical and non-canonical Notch signaling (Homo sapiens)

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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.