Cell-type dependent modulation of Notch signaling by the amyloid precursor protein.
The amyloid precursor protein is a ubiquitously expressed transmembrane protein that has been long implicated in the pathogenesis of Alzheimer's disease but its normal biological function has remained elusive despite extensive effort. We have previously reported the identification of Notch2 as an amyloid precursor protein interacting protein in E18 rat neurons. Here, we sought to reveal the physiologic consequences of this interaction. We report a functional relationship between amyloid precursor protein and Notch1, which does not affect Delta ligand binding. First, we observed interactions between the amyloid precursor protein and Notch in mouse embryonic stem cells lacking both presenilin 1 and presenilin 2, the active proteolytic components of the gamma-secretase complex, suggesting that these two transmembrane proteins can interact in the absence of presenilin. Next, we demonstrated that the amyloid precursor protein affects Notch signaling by using Notch-dependent luciferase assays in two cell lines, the human embryonic kidney 293 and the monkey kidney, COS7. We found that the amyloid precursor protein exerts opposing effects on Notch signaling in human embryonic kidney 293 vs. COS7 cells. Finally, we show that more Notch Intracellular Domain is found in the nucleus in the presence of exogenous amyloid precursor protein or its intracellular domain, suggesting the mechanism by which the amyloid precursor protein affects Notch signaling in certain cells. Our results provide evidence of potentially important communications between the amyloid precursor protein and Notch.
Oh
Sun Young
SY
Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts, USA.
Chen
Ci-Di
CD
Abraham
Carmela R
CR
D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000502:physiology*; D000818:Animals; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003285:Contractile Proteins / Q000235:genetics; D004622:Embryo, Mammalian; D064448:Filamins; D005434:Flow Cytometry / Q000379:methods; D005786:Gene Expression Regulation / Q000235:genetics; D006801:Humans; D008164:Luminescent Proteins / Q000235:genetics; D051379:Mice; D008840:Microfilament Proteins / Q000235:genetics; D053764:Presenilin-1 / Q000172:deficiency; D053766:Presenilin-2 / Q000172:deficiency; D011485:Protein Binding / Q000187:drug effects; D011506:Proteins / Q000235:genetics; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013234:Stem Cells; D014162:Transfection / Q000379:methods
D016564:Amyloid beta-Protein Precursor; C428808:CRCT1 protein, human; D003285:Contractile Proteins; D064448:Filamins; D008164:Luminescent Proteins; D008840:Microfilament Proteins; C508861:PSEN2 protein, human; D053764:Presenilin-1; D053766:Presenilin-2; D011506:Proteins; D051881:Receptor, Notch1; D053829:Amyloid Precursor Protein Secretases