{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:55:06Z","timestamp":1790794506059,"version":"4.1.0"},"reference-count":70,"publisher":"American Society for Clinical Investigation","issue":"19","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,10,1]]},"abstract":"<jats:p>\u03b3-Secretase is a transmembrane protease complex that cleaves multiple type I transmembrane proteins, including amyloid precursor protein and neurogenic locus notch homolog protein (NOTCH). Although numerous \u03b3-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 \u03b3-secretase subunit nicastrin (NCSTN). We further demonstrate that DOCK2 regulates mannosylation of NCSTN N-glycans, which in turn modulates \u03b3-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 \u03b3-secretase and suggest a promising therapeutic strategy for Notch-related diseases.<\/jats:p>","DOI":"10.1172\/jci203202","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T18:01:22Z","timestamp":1790791282000},"source":"Crossref","is-referenced-by-count":0,"title":["Targeting mannosylation of nicastrin N-glycans attenuates \u03b3-secretase activity and notch-dependent leukemia progression"],"prefix":"10.1172","volume":"136","author":[{"given":"Hua","family":"Jiang","sequence":"first","affiliation":[{"name":"School of Life Sciences, Westlake University, Hangzhou, Zhejiang, China."},{"name":"Department of Urology, Institute of Urologic Science and Technology, The First Affiliated Hospital, School of Medicine, 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