Extracellular domain shedding of NOTCH3 during endocytosis associated with heterogeneity between different CADASIL mutant activation mechanisms.

ABSTRACT:

Background

Mutations in NOTCH3 cause CADASIL, a dominantly inherited condition, linked to recurrent stroke and vascular dementia and associated with accumulation of the ECD of NOTCH3. The latter has a toxic effect on VSMCs. Misregulated signalling may also play a role in disease progression. ECD detachment is an obligatory step in NOTCH3 activation, but some CADASIL mutants prevent ligand-induced activation and so ligand interactions are not a common underlying requirement. Here we investigated whether basal NOTCH3 endocytosis that is associated with ligand-independent activation mechanisms can be source of ECD shedding in CADASIL mutants.

Methods

We used transient transfection of hTERT-RPE1 cells to express WT, R90C, C212Y and C455R mutant NOTCH3 constructs. Internalisation

SUBMITTER: Hosseini-Alghaderi S 

PROVIDER: S-EPMC12326875 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature