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Calsenilin regulates presenilin 1/γ‐secretase‐mediated N‐cadherin ∊‐cleavage and β‐catenin signaling
Author(s) -
Jang Changhwan,
Choi JinKyu,
Na YeoJung,
Jang Byungki,
Wasco Wilma,
Buxbaum Joseph D.,
Kim YongSun,
Choi EunKyoung
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.11-185926
Subject(s) - presenilin , cadherin , catenin , microbiology and biotechnology , signal transduction , beta catenin , chemistry , biology , medicine , biochemistry , alzheimer's disease , wnt signaling pathway , disease , cell
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 ∊‐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 ∊‐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.—Jang, C., Choi, J.‐K., Na, Y.‐J., Jang, B., Wasco, W., Buxbaum, J. D., Kim, Y.‐S., Choi, E.‐K. Calsenilin regulates presenilin 1/γ‐secretase‐mediated N‐cadherin ∊‐cleavage and β‐catenin signaling. FASEB J. 25, 4174–4183 (2011). www.fasebj.org