title: Regulation of Notch1 signaling by the APP intracellular domain facilitates degradation of the Notch1 intracellular domain and RBP-Jk.
abstract: The Notch1 receptor is a crucial controller of cell fate decisions, and is also a key regulator of cell growth and differentiation in a variety of contexts. In this study, we have demonstrated that the APP intracellular domain (AICD) attenuates Notch1 signaling by accelerated degradation of the Notch1 intracellular domain (Notch1-IC) and RBP-Jk, through different degradation pathways. AICD suppresses Notch1 transcriptional activity by the dissociation of the Notch1-IC-RBP-Jk complex after processing by γ-secretase. Notch1-IC is capable of forming a trimeric complex with Fbw7 and AICD, and AICD enhances the protein degradation of Notch1-IC through an Fbw7-dependent proteasomal pathway. AICD downregulates the levels of RBP-Jk protein through the lysosomal pathway. AICD-mediated degradation is involved in the preferential degradation of non-phosphorylated RBP-Jk. Collectively, our results demonstrate that AICD functions as a negative regulator in Notch1 signaling through the promotion of Notch1-IC and RBP-Jk protein degradation.
authors.affiliation: Hormone Research Center, School of Biological Sciences and Technology, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Mi-Yeon
authors.initials: MY
authors.lastname: Kim
authors.forename: Jung-Soon
authors.initials: JS
authors.lastname: Mo
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Ann
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Yoon
authors.forename: Jane
authors.initials: J
authors.lastname: Jung
authors.forename: Yun-Hee
authors.initials: YH
authors.lastname: Choi
authors.forename: Su-Man
authors.initials: SM
authors.lastname: Kim
authors.forename: Hwa-Young
authors.initials: HY
authors.lastname: Kim
authors.forename: Ji-Seon
authors.initials: JS
authors.lastname: Ahn
authors.forename: Hangun
authors.initials: H
authors.lastname: Kim
authors.forename: Kwonseop
authors.initials: K
authors.lastname: Kim
authors.forename: Hyang-Sook
authors.initials: HS
authors.lastname: Hoe
authors.forename: Hee-Sae
authors.initials: HS
authors.lastname: Park
mesh_terms: D000643:Ammonium Chloride / Q000494:pharmacology; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D015536:Down-Regulation / Q000235:genetics; D044783:F-Box Proteins / Q000378:metabolism; D000073979:F-Box-WD Repeat-Containing Protein 7; D017930:Genes, Reporter; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein / Q000378:metabolism*; D007976:Leupeptins / Q000494:pharmacology; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D048057:Mitogen-Activated Protein Kinase 10 / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D055503:Protein Multimerization; D055550:Protein Stability; D017434:Protein Structure, Tertiary; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D015533:Transcriptional Activation; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism
chemical_list: C545487:APP protein, human; D016564:Amyloid beta-Protein Precursor; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D051819:Immunoglobulin J Recombination Signal Sequence-Binding Protein; D007976:Leupeptins; C497761:NOTCH1 protein, human; D061988:Proteasome Inhibitors; C497570:RBPJ protein, human; D051881:Receptor, Notch1; D000643:Ammonium Chloride; D008156:Luciferases; D044767:Ubiquitin-Protein Ligases; D048057:Mitogen-Activated Protein Kinase 10; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde