title: Presenilin regulates insulin signaling via a gamma-secretase-independent mechanism.
abstract: Presenilin (PS), a causative molecule of familial Alzheimer disease, acts as a crucial component of the γ-secretase complex, which is required to cleave type I transmembrane proteins such as amyloid precursor protein and Notch. However, it also functions through γ-secretase-independent pathways. Recent reports suggested that PS could regulate the expression level of cell surface receptors, including the PDGF and EGF receptors, followed by modulating their downstream pathways via γ-secretase-independent mechanisms. The main purpose of this study was to clarify the effect of PS on expression of the insulin receptor (IR) as well as on insulin signaling. Here, we demonstrate that PS inhibited IR transcription and reduced IR expression, and this was followed by down-regulation of insulin signaling. Moreover, we suggest that neither γ-secretase activity nor Wnt/β-catenin signaling can reduce the expression of IR, but a PS-mediated increase in the intracellular Ca(2+) level can be associated with it. These results clearly indicate that PS can functionally regulate insulin signaling by controlling IR expression.
authors.affiliation: School of Human Health Sciences, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Maesako
authors.forename: Kengo
authors.initials: K
authors.lastname: Uemura
authors.forename: Akira
authors.initials: A
authors.lastname: Kuzuya
authors.forename: Kazuki
authors.initials: K
authors.lastname: Sasaki
authors.forename: Megumi
authors.initials: M
authors.lastname: Asada
authors.forename: Kiwamu
authors.initials: K
authors.lastname: Watanabe
authors.forename: Koichi
authors.initials: K
authors.lastname: Ando
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kubota
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kihara
authors.forename: Ayae
authors.initials: A
authors.lastname: Kinoshita
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000502:physiology*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000502:physiology*; D007328:Insulin / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D053763:Presenilins / Q000235:genetics / Q000378:metabolism*; D011972:Receptor, Insulin / Q000096:biosynthesis* / Q000235:genetics; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000502:physiology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D007328:Insulin; D053763:Presenilins; D051153:Wnt Proteins; D051176:beta Catenin; D011972:Receptor, Insulin; D053829:Amyloid Precursor Protein Secretases; D002118:Calcium