Phosphorylation of Nicastrin by SGK1 Leads to Its Degradation through Lysosomal and Proteasomal Pathways

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

Stable (H, O, C) and noble-gas (He and Ar) isotopic compositions from calcite and fluorite in the Speewah Dome, Kimberley Region, Western Australia: implications for the conditions of crystallization and evidence for the influence of crustal-mantle fluid mixing

In this study, the C-O-isotopic data from calcite at Yungul and Wilmott (Speewah. Western-Australia) are integrated with microthermometry, H2O-, CO2-content and H-He-Ar-isotopic data from fluid inclusions in genetically related calcite and fluorite to map the origin and crystallization paths of the fluids. In addition to the hydrogen isotopic compositions of fluid inclusions in fluorite, oxygen isotopic compositions were also determined by cavity ring-down spectroscopy. The geochemical data suggest mixing of a CO2-dominated mantle fluid and a H2O-domintated crustal brine. The fluid produced by this mixing is characterized by radiogenic (crustal-like) He-3/He-4 ratios, crustal-like dD values, relatively high salinity (19-24wt.% NaCl eq.), moderate homogenization temperatures (150-450 degrees C) and mantle-like CO2/He-3 ratios. Moreover, the large isotopic and elemental variations found in calcite indicate that its formation was accompanied by an extensive degassing (open system) leading to a decrease in dD and an increase in the CO2/He-3 values relative to the starting fluid composition. This degassing is consistent with the fluidal- and breccia-like texture of calcite observed in the field. In contrast, the fluorite which has coarse-grained banded to vughy textures formed in a passive aqueous system. Apparently the fluid that formed the fluorite has the same origin as the calcite, but the higher water content and the more radiogenic He-3/He-4 ratios reflect a greater involvement of crustal fluids. The historical description of the calcite-fluorite system in the Speewah area as "carbonatite" is now considered inappropriate because there is no evidence that crystallization is dominated by magmatic processes