Implication of APP secretases in notch signaling

Signaling via notch receptors and their ligands is an evolutionary ancient and highly conserved mechanism governing cell-fate decisions throughout the animal kingdom. Upon ligand binding, notch receptors are subject to a two- step proteolysis essential for signal transduction. First, the ectodomain i s removed by an enzyme cleaving near the outer-membrane surface ("site2"). Consecutively, the notch intracellular domain is liberated by a second prot ease cutting within the transmembrane sequence ("site3"). The intracellular domain is then transferred to the nucleus to act as a transcriptional coac tivator. The proteases involved in notch receptor activation are shared wit h other proteins undergoing regulated intramembrane proteolysis, with intri guing parallels to APP. Specifically, site3 cleavage of Notch, as well as g amma -secretase processing of APP depend both critically on presenilins 1 a nd 2. Moreover, ADAM 10 and ADAM 17, the proteases proposed to perform site 2 cleavage, are also the most probable candidate alpha -secretases to cleav e APP. While the biological significance of APP processing remains to be further e lucidated, interference with notch signaling has been shown to have severe consequences both in small animal models as well as in humans. Thus a growi ng number of long known genetic syndromes like Alagille syndrome or Fallot' s tetralogy can be caused by mutations of genes relevant for the notch sign aling pathway. Likewise, the anticipated interference of gamma -secretase i nhibitors with site3 cleavage may turn out to be a major obstacle for this therapeutic approach to Alzheimer's disease.