Figure 2.

Canonical Notch signaling pathway. After (S1) cleavage by furin or furin-like convertases the heterodimeric Notch receptor translocates to the cell membrane. Right: Following ligand binding, proteolytic cleavage mediated by ADAM/TACE results in the release of NEC (S2) and additional cleavage at the transmembrane region by the γ-secretase complex creates the NICD (S3), which is able to translocate into the nucleus with subsequent activation of gene transcription. Left: Alternatively, after ubiquitination by E3-ligases, internalization of Notch to endosomes is possible. From endosomes, Notch can be recycled to the plasma membrane, pooled by cis-inhibition by DSL or degraded in the lysosome. ADAM/TACE: metalloproteinase containing protein; CSL: C-promoter binding factor-1 (CBF1 in humans, also known as CSL); DSL: Delta/Serrate Ligand; E3: E3-ligases; MAML: mastermind-like; NEC: Notch extracellular; NICD: Notch intracellular domain; SKIP: Ski-interacting protein.