Fig. 2

SERCA and the Notch trafficking. a Schematic representation of the effects of SERCA inhibition on the maturation and trafficking of NOTCH1. In physiologic conditions, SERCA pumps Ca²⁺ into the ER required for the proper folding of NOTCH1 proteins. A furin-like protease (S1) releases from the ER/Golgi the non-covalent heterodimer NFL1 that migrates through the cytosol toward the cell membrane. Following the interaction of the extracellular NECD1 with the Notch ligands, NOTCH1 is cleaved sequentially by metalloproteases (S2) and γ-secretases [GS (S3)]. The final cleaved protein NICD1 migrates to the nucleus to complex with co-activators and activates transcription. b SERCA blockade by SERCA inhibitors (e.g., thapsigargin) induces a leak of ER and the accumulation of the full-length isoform of NOTCH1 at the ER/Golgi level. As a consequence, no substrate for metalloprotease or γ-secretase is available with the result of a reduced level of nuclear NICD1 proteins