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Here, we identify Kuzbanian (Kuz) expression as a key spatially controlled determinant in the Drosophila midgut. Kuz is suppressed in the copper cell region by BMP signaling and induced by EGFR activity in adjacent compartments, directly explaining regional differences in Notch activation. Strikingly, elevated Kuz expression alone is sufficient to cleave Notch and trigger ligand-independent signaling. cis-Delta potently inhibits this non-canonical activation, establishing it as a key safeguard. Furthermore, high Kuz levels enable trans-Delta ligands on neighboring cells to overcome cis-inhibition. These findings support a model in which spatially defined Kuz expression sets a proteolytic threshold that determines the outcome of competition between cis-inhibition and trans-activation. Our findings reposition Kuz\/ADAM10 as a crucial spatial regulator of Notch signaling, providing a new framework for understanding signal integration in vivo.<\/jats:p>","DOI":"10.1242\/dev.204789","type":"journal-article","created":{"date-parts":[[2026,1,20]],"date-time":"2026-01-20T08:08:58Z","timestamp":1768896538000},"source":"Crossref","is-referenced-by-count":1,"title":["Kuzbanian expression levels dictate Notch signaling outcomes via interplay between\n                    <i>cis-<\/i>\n                    and\n                    <i>trans-<\/i>\n                    Delta"],"prefix":"10.1242","volume":"153","author":[{"given":"Fenyu","family":"Shi","sequence":"first","affiliation":[{"name":"School of Basic Medicine, Institute for Brain Research, Tongji Medical College, Huazhong University of Science and Technology 1 Department of Medical Genetics , , Wuhan 430030 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Li","family":"Qiao","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Institute for Brain Research, Tongji Medical College, Huazhong University of Science and Technology 1 Department of Medical Genetics , , Wuhan 430030 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"You","family":"Wu","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Institute for Brain Research, Tongji Medical College, Huazhong University of Science and Technology 1 Department of Medical Genetics , , Wuhan 430030 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2874-7141","authenticated-orcid":false,"given":"Zheng","family":"Guo","sequence":"additional","affiliation":[{"name":"School of Basic Medicine, Institute for Brain Research, Tongji Medical College, Huazhong University of Science and Technology 1 Department of Medical Genetics , , Wuhan 430030 ,","place":["China"]},{"name":"Cell Architecture Research Center, Huazhong University of Science and Technology 2 , Wuhan 430030 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2026,1,20]]},"reference":[{"key":"2026012003084999800_DEV204789C1","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1146\/annurev-pathol-052016-100127","article-title":"The varied roles of notch in cancer","volume":"12","author":"Aster","year":"2017","journal-title":"Annu. 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