Phosphorylation of nicastrin by SGK1 leads to its degradation through lysosomal and proteasomal pathways

Jung Soon Mo; Ji Hye Yoon; Ji Ae Hong; Mi Yeon Kim; Eun Jung Ann; Ji Seon Ahn; Su Man Kim; Hyeong Jin Baek; Florian Lang; Eui Ju Choi; Hee Sae Park

doi:10.1371/journal.pone.0037111

Phosphorylation of nicastrin by SGK1 leads to its degradation through lysosomal and proteasomal pathways

Jung Soon Mo, Ji Hye Yoon, Ji Ae Hong, Mi Yeon Kim, Eun Jung Ann, Ji Seon Ahn, Su Man Kim, Hyeong Jin Baek, Florian Lang, Eui Ju Choi, Hee Sae Park

Department of Life Sciences

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

Abstract

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.

Original language	English
Article number	e37111
Journal	PloS one
Volume	7
Issue number	5
DOIs	https://doi.org/10.1371/journal.pone.0037111
Publication status	Published - 2012 May 10

ASJC Scopus subject areas

Biochemistry, Genetics and Molecular Biology(all)
Agricultural and Biological Sciences(all)
General

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title = "Phosphorylation of nicastrin by SGK1 leads to its degradation through lysosomal and proteasomal pathways",

abstract = "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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T1 - Phosphorylation of nicastrin by SGK1 leads to its degradation through lysosomal and proteasomal pathways

AU - Mo, Jung Soon

AU - Yoon, Ji Hye

AU - Hong, Ji Ae

AU - Kim, Mi Yeon

AU - Ann, Eun Jung

AU - Ahn, Ji Seon

AU - Kim, Su Man

AU - Baek, Hyeong Jin

AU - Lang, Florian

AU - Choi, Eui Ju

AU - Park, Hee Sae

PY - 2012/5/10

Y1 - 2012/5/10

N2 - 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.

AB - 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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Phosphorylation of nicastrin by SGK1 leads to its degradation through lysosomal and proteasomal pathways

Abstract

ASJC Scopus subject areas

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