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 is removed by an enzyme cleaving near the outer-membrane surface ("site2"). Consecutively, the notch intracellular domain is liberated by a second protease cutting within the transmembrane sequence ("site3"). The intracellular domain is then transferred to the nucleus to act as a transcriptional coactivator. The proteases involved in notch receptor activation are shared with other proteins undergoing regulated intramembrane proteolysis, with intriguing parallels to APP. Specifically, site3 cleavage of Notch, as well as gamma-secretase processing of APP depend both critically on presenilins 1 and 2. Moreover, ADAM 10 and ADAM 17, the proteases proposed to perform site2 cleavage, are also the most probable candidate alpha-secretases to cleave APP. While the biological significance of APP processing remains to be further elucidated, interference with notch signaling has been shown to have severe consequences both in small animal models as well as in humans. Thus, a growing number of long known genetic syndromes like Alagille syndrome or Fallot's tetralogy can be caused by mutations of genes relevant for the notch signaling pathway. Likewise, the anticipated interference of gamma-secretase inhibitors with site3 cleavage may turn out to be a major obstacle for this therapeutic approach to Alzheimer's disease.
Hartmann
D
D
Center for Human Genetics, Neuronal Cell Biology Laboratory, K.U.Leuven and Flanders Interuniversity Institute for Biotechnology, Leuven, Belgium.
Tournoy
J
J
Saftig
P
P
Annaert
W
W
De Strooper
B
B
D051722:ADAM Proteins; D000072198:ADAM17 Protein; D000544:Alzheimer Disease / Q000378:metabolism* / Q000503:physiopathology; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D010450:Endopeptidases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D053764:Presenilin-1; D053766:Presenilin-2; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors
D016564:Amyloid beta-Protein Precursor; D008565:Membrane Proteins; C497761:NOTCH1 protein, human; C508853:PSEN1 protein, human; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D051881:Receptor, Notch1; D011956:Receptors, Cell Surface; D014157:Transcription Factors; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human