title: The APP intracellular domain (AICD) inhibits Wnt signalling and promotes neurite outgrowth.
abstract: β- and γ-secretase cleave the amyloid precursor protein (APP) to release the amyloidogenic β-amyloid peptides (Aβ) and the APP intracellular domain (AICD). Aβ has been widely believed to initiate pathogenic cascades culminating in Alzheimer's disease (AD). However, the physiological functions of the AICD remain elusive. In this study, we found the AICD to strongly inhibit Wnt-induced transcriptional reporter activity, and to counteract Wnt-induced c-Myc expression. Loss of the AICD resulted in an increased responsiveness to Wnt/β-catenin-mediated transcription. Mechanically, the AICD was found to interact with glycogen synthase kinase 3 beta (GSK3β) and promote its kinase activity. The subsequent AICD-strengthened Axin-GSK3β complex potentiates β-catenin poly-ubiquitination. Functional studies in N(2)a mouse neuroblastoma cells, rat pheochromocytoma PC12 cells and primary neurons showed that the AICD facilitated neurite outgrowth. And AICD antagonised Wnt3a-suppressed growth arrest and neurite outgrowth in N2a and PC12 cells. Taken together, our results identify the AICD as a novel inhibitory factor of the canonical Wnt signalling pathway and suggest its regulatory role in neuronal cell proliferation and differentiation.
authors.affiliation: School of Life Sciences, Tsinghua University, Beijing, China.
authors.forename: Fangfang
authors.initials: F
authors.lastname: Zhou
authors.forename: Kai
authors.initials: K
authors.lastname: Gong
authors.forename: Bo
authors.initials: B
authors.lastname: Song
authors.forename: Tuo
authors.initials: T
authors.lastname: Ma
authors.forename: Theo
authors.initials: T
authors.lastname: van Laar
authors.forename: Yandao
authors.initials: Y
authors.lastname: Gong
authors.forename: Long
authors.initials: L
authors.lastname: Zhang
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D049109:Cell Proliferation; D015870:Gene Expression; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D057809:HEK293 Cells; D006801:Humans; D049410:Luciferases, Renilla / Q000096:biosynthesis / Q000235:genetics; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D020932:Nerve Growth Factor / Q000502:physiology; D016501:Neurites / Q000502:physiology*; D009474:Neurons / Q000378:metabolism / Q000502:physiology; D061251:Primary Cell Culture; D017434:Protein Structure, Tertiary; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway
chemical_list: D016564:Amyloid beta-Protein Precursor; D008562:Membrane Glycoproteins; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; C413604:nicastrin protein; D020932:Nerve Growth Factor; D049410:Luciferases, Renilla; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; C000605508:Gsk3b protein, rat; D038362:Glycogen Synthase Kinase 3; D053829:Amyloid Precursor Protein Secretases