title: Calsenilin regulates presenilin 1/γ-secretase-mediated N-cadherin ε-cleavage and β-catenin signaling.
abstract: Presenilin 1 (PS1) is a component of the γ-secretase complex that cleaves a variety of type I membrane proteins, including the β-amyloid precursor protein (β-APP), Notch, and neuronal (N)- and epithelial (E)-cadherins. N-cadherin is an essential adhesion molecule that forms a complex with, and is cleaved by, PS1/γ-secretase and β-catenin in the plasma membrane. The purpose of this study was to determine whether calsenilin, a presenilin-interacting protein, has a functional role in PS1/γ-secretase-mediated N-cadherin ε-cleavage using Western blot analysis, RT-PCR, immunoprecipitation, subcellular fractionation, biotinylation, and a luciferase reporter assay in SH-SY5Y neuroblastoma cells. Here, we demonstrate that the expression of calsenilin leads to a disruption of PS1/γ-secretase-mediated ε-cleavage of N-cadherin, which results in the significant accumulation of N-cadherin C-terminal fragment 1 (Ncad/CTF1), the reduction of cytoplasmic Ncad/CTF2 release, and a deceleration of PS1-CTF delivery to the cell surface. Interestingly, we also found that the expression of calsenilin is associated with the redistribution of β-catenin from the cell surface to a cytoplasmic pool, as well as with the negative regulation of genes that are targets of T-cell factor/β-catenin nuclear signaling. Taken together, our findings suggest that calsenilin is a novel negative regulator of N-cadherin processing that plays an important role in β-catenin signaling.
authors.affiliation: Ilsong Institute of Life Science, Hallym University, 1605-4 Gwanyang-dong, Dongan-gu, Anyang, Gyeonggi-do 431-060, Republic of Korea.
authors.forename: Changhwan
authors.initials: C
authors.lastname: Jang
authors.forename: Jin-Kyu
authors.initials: JK
authors.lastname: Choi
authors.forename: Yeo-Jung
authors.initials: YJ
authors.lastname: Na
authors.forename: Byungki
authors.initials: B
authors.lastname: Jang
authors.forename: Wilma
authors.initials: W
authors.lastname: Wasco
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Buxbaum
authors.forename: Yong-Sun
authors.initials: YS
authors.lastname: Kim
authors.forename: Eun-Kyoung
authors.initials: EK
authors.lastname: Choi
mesh_terms: D021581:Active Transport, Cell Nucleus; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism*; D015703:Antigens, CD / Q000737:chemistry / Q000378:metabolism*; D015820:Cadherins / Q000737:chemistry / Q000378:metabolism*; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051605:Kv Channel-Interacting Proteins / Q000235:genetics / Q000378:metabolism*; D008959:Models, Neurological; D009447:Neuroblastoma / Q000235:genetics / Q000378:metabolism; D053764:Presenilin-1 / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; C050361:CDH2 protein, human; C495270:CTNNB1 protein, human; D015820:Cadherins; C496749:KCNIP3 protein, human; D051605:Kv Channel-Interacting Proteins; C508853:PSEN1 protein, human; D053764:Presenilin-1; D012097:Repressor Proteins; D051176:beta Catenin; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3; D053829:Amyloid Precursor Protein Secretases