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.
authors.affiliation: School of Biological Sciences and Technology, Hormone Research Center, Chonnam National University, Gwangju, Republic of Korea.
authors.forename: Jung-Soon
authors.initials: JS
authors.lastname: Mo
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Yoon
authors.forename: Ji-Ae
authors.initials: JA
authors.lastname: Hong
authors.forename: Mi-Yeon
authors.initials: MY
authors.lastname: Kim
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Ann
authors.forename: Ji-Seon
authors.initials: JS
authors.lastname: Ahn
authors.forename: Su-Man
authors.initials: SM
authors.lastname: Kim
authors.forename: Hyeong-Jin
authors.initials: HJ
authors.lastname: Baek
authors.forename: Florian
authors.initials: F
authors.lastname: Lang
authors.forename: Eui-Ju
authors.initials: EJ
authors.lastname: Choi
authors.forename: Hee-Sae
authors.initials: HS
authors.lastname: Park
mesh_terms: D053829:Amyloid Precursor Protein Secretases / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D057809:HEK293 Cells; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008247:Lysosomes / Q000235:genetics / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation / Q000502:physiology; D046988:Proteasome Endopeptidase Complex / Q000235:genetics / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D055550:Protein Stability; D059748:Proteolysis; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D053829:Amyloid Precursor Protein Secretases; D017874:Immediate-Early Proteins; D008562:Membrane Glycoproteins; D046988:Proteasome Endopeptidase Complex; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases; C413604:nicastrin protein