ABSTRACT
C leavage of APP by α-, β-and γ-secretases strikingly resembles regulated intramembrane proteolysis (RIP), which is normally employed to generate signal-transducing fragments from transmembrane proteins. Protein ‘RlPping’ is initiated by signals like ligand binding causing the removal of the ectodomain by a sheddase-like activity. This exposes the transmembrane stub to an intramembrane-cleaving protease (i-Clip) releasing the intracellular domain that acts as a signal transducer directed towards the nucleus. At present, the presumed signaling function of APP remains largely enigmatic, as both the putative signal triggering RlPping and the elicited cellular response in vertebrates are unknown. Signaling deficits have mostly been defined in C. elegans> inhibiting pharyngeal motility.
