Open AccessPhosphorylation of Nicastrin by SGK1 Leads to Its Degradation through Lysosomal and Proteasomal Pathways
Author(s) -
Jung-Soon Mo,
Ji-Hye Yoon,
Ji Ae Hong,
Mi-Yeon Kim,
Eun-Jung Ann,
JiSeon Ahn,
SuMan Kim,
Hyeong-Jin Baek,
Florian Läng,
Eui-Ju Choi,
Hee-Sae Park
Publication year - 2012
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0037111
Subject(s) - sgk1 , nicastrin , phosphorylation , microbiology and biotechnology , proteolysis , kinase , chemistry , biology , biochemistry , amyloid precursor protein , enzyme , alzheimer's disease , medicine , disease
The gamma-secretase complex is involved in the intramembranous proteolysis of a variety of substrates, including the amyloid precursor protein and the Notch receptor. Nicastrin (NCT) is an essential component of the gamma-secretase complex and functions as a receptor for gamma-secretase substrates. In this study, we determined that serum- and glucocorticoid-induced protein kinase 1 (SGK1) markedly reduced the protein stability of NCT. The SGK1 kinase activity was decisive for NCT degradation and endogenous SGK1 inhibited gamma-secretase activity. SGK1 downregulates NCT protein levels via proteasomal and lysosomal pathways. Furthermore, SGK1 directly bound to and phosphorylated NCT on Ser437, thereby promoting protein degradation. Collectively, our findings indicate that SGK1 is a gamma-secretase regulator presumably effective through phosphorylation and degradation of NCT.
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