The Use of Nutraceuticals to Counteract Atherosclerosis: The Role of the Notch Pathway

Figure 2

Canonical and noncanonical Notch signaling pathway. In the canonical Notch pathway, precursor of Notch receptors undergoes Furin-mediated cleavage (S1) in the Golgi apparatus, which is necessary to form the functional heterodimeric receptor. Upon Notch glycosylation by the Fringe family of glycosyltransferases, the Notch receptor translocates to the plasma membrane, where it interacts with a Delta/Jagged ligand, present on the surface of an adjacent cell. Notch signaling is activated when the ligand, bound to the receptor, is ubiquitylated by MIB1, an event that generates the mechanical force necessary for exposing the second cleavage site of Notch receptors. This event leads ADAM to perform the second cleavage (S2). The third cleavage (S3), by the γ-secretase complex, promotes the release of the intracellular domain of the receptor (NICD). NICD translocates into the nucleus where it promotes the transcription of canonical Notch target genes, such as Hey1 and 2 and HES1. The noncanonical Notch signaling pathway may be γ-secretase dependent or independent. This later may also occur either in the presence or in the absence of its ligand. Noncanonical Notch signaling is also independent of CSL, and it is mediated by the interaction with PI3K, mTORC2, AKT, Wnt, NF-κB, YY1, or HIF-1α pathways at either the cytoplasmic and/or nuclear levels.