Fig. (1). Overview of Notch proteolysis.

A schematic overview of the Notch signaling pathway showing the proteolytic events. During maturation and transport of the receptor to the membrane Notch gets cleaved in the Golgi system at Site-1 (S1) by a furin-like convertase, resulting in a heterodimeric transmembrane receptor. At the cell surface in the absence of ligand the receptor is proteolysis-resistant. Only upon binding of ligand, inducing a substantial conformational change, the metalloprotease ADAM10 is able to cleave Notch at the newly exposed Site-2 (S2). This sheds off the NECD which can be transendocytosed into the ligand-expressing cell. On the receptor-expressing cell S2 cleavage results in a NEXT fragment that either is directly cleaved at the membrane at Val1744 (NICD-V) by the γ-secretase complex, or NEXT is internalized and processed in endocytic compartments by γ-secretase at Ser1747 (NICD-S). NICD translocates to the nucleus where it participates in a co-activator complex binding to CSL and starts target gene transcription. An additional cleavage at Site-4 (S4) is mediated by the γ-secretase in the centre of the transmembrane domain resulting in the N fragment, probably meant to clear residual Notch fragments from the membrane.