Figure 1.

Notch canonical and non-canonical signaling. Notch signaling via the canonical pathway is on the left portion of the figure. Membrane-bound Notch receptor is activated by binding with ligand on a neighboring cell, which results in cleavage by ADAM metalloproteases, followed by cleavage with γ-secretase. These cleavage events release the NICD, which then enters the nucleus to affect the gene transcription. The non-canonical signaling pathway is on the right portion of the figure and illustrates that non-canonical signaling may occur either in the presence or absence of ligand. Further, the signaling may occur via the membrane-bound, uncleaved Notch receptor or via the NICD. Non-canonical Notch signaling is independent of CSL and allows for interaction with PI3K/AKT/mTORC2, Wnt/β-catenin, IKKα/β, NFκB, YY1, and HIF1α pathways at the cytoplasmic and/or nuclear level. Abbreviations: ADAM, a disintegrin and metalloprotease; NEXT, Notch extracellular truncation; NICD, Notch intracellular domain; Co-R, corepressor; Co-A, coactivator.