Targeting Mannosylation of Nicastrin N-glycans Attenuates γ-Secretase Activity and Notch-dependent Leukemia Progression

ABSTRACT: γ-Secretase is a transmembrane protease complex that cleaves multiple type I transmembrane proteins, including amyloid precursor protein and NOTCH. Although numerous γ-secretase inhibitors and modulators targeting Notch-dependent cancers have been developed in recent decades, their clinical translation has been hampered by low substrate specificity and on-target gut toxicity. Using a proteomics-based screening approach, we identified dedicator of cytokinesis protein 2 (DOCK2) as an interactor of the γ-secretase subunit Nicastrin (NCSTN). We further demonstrate that DOCK2 regulates mannosylation of NCSTN N-glycans, which in turn modulates γ-secretase activity toward NOTCH receptors. Both genetic depletion of DOCK2 and pharmacological inhibition of NCSTN mannosylation with Kifunensine attenuated Notch-dependent leukemia progression in vivo. Collectively, these findings uncover a regulatory mechanism underlying substrate-specific activation of γ-secretase and suggest a promising therapeutic strategy for Notch-related diseases.

ORGANISM(S): Homo sapiens

PROVIDER: GSE320527 | GEO | 2026/07/06

REPOSITORIES: GEO