Phosphorylation of Nicastrin by SGK1 Leads to Its Degradation through Lysosomal and Proteasomal Pathways
Figure 7
Proposed model for the role of SGK1 in the regulation of NCT protein level.
Proteolytic processing of amyloid precursor protein (APP) by the two proteases beta and gamma-secretase controls the generation of the amyloid peptide (Abeta) and the APP intracellular domain. The gamma-secretase complex consists of four essential proteins: presenilin (PS1 or PS2), PEN-2, APH-1 and the nicastrin (NCT). The NCT glycosylation has central role in gamma-secretase assembly and substrate binding. In the glucocorticoid stimulation of SGK expression and activation via glucocorticoid receptor (GR), the immature form of NCT is directly bind and phosphorylated by SGK1, which initiated proteasomal and lysosomal mediated degradation of NCT. Therefore, SGK1 plays a unique and pivotal role in reducing gamma-secretase activity through phosphorylation dependent regulation of NCT protein degradation.