{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T18:12:00Z","timestamp":1789755120430,"version":"4.0.1"},"reference-count":37,"publisher":"Public Library of Science (PLoS)","issue":"9","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100005006","name":"Asan Institute for Life Sciences, Asan Medical Center","doi-asserted-by":"publisher","award":["2024IL0025"],"award-info":[{"award-number":["2024IL0025"]}],"id":[{"id":"10.13039\/501100005006","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>Insulin attenuates the effects of advanced glycation end products (AGEs) by inducing a disintegrin and metalloprotease 10 (ADAM10)-mediated cleavage of the receptor for AGEs (RAGE); however, the molecular mechanism underlying this process remains incompletely understood. We investigated the mechanism by which insulin promotes ADAM10-mediated RAGE shedding in cultured human aortic endothelial cells (HAECs). AGE-modified bovine serum albumin (AGE-BSA) increased intercellular adhesion molecule-1 (ICAM-1) expression, whereas insulin pretreatment (0.1\u2013100 nM) attenuated this effect. Mechanistically, insulin activated AKT1, AKT2, and AKT3, promoted ADAM10 translocation to the cell surface, and enhanced RAGE ectodomain shedding. In contrast, treatment with GI254023X (an ADAM10 inhibitor) or ADAM10 knockdown using siRNA abolished insulin-induced RAGE ectodomain shedding. Likewise, knockdown of AKT1, AKT2, or AKT3 using siRNA, as well as treatment with the pan-AKT inhibitor MK-2206, inhibited insulin-induced ADAM10 cell surface translocation and RAGE ectodomain shedding. Co-immunoprecipitation analysis further demonstrated an interaction between Rab14 and ADAM10. Insulin enhanced this interaction and promoted the translocation of both Rab14 and ADAM10 to the cell surface. Conversely, Rab14 knockdown blocked insulin-induced ADAM10 cell surface translocation and RAGE ectodomain shedding, thereby abolishing the protective effect of insulin against AGE-BSA-induced ICAM-1 expression. Collectively, these findings demonstrate that insulin promotes Rab14-mediated trafficking of ADAM10 to the cell surface through AKT activation in HAECs, resulting in enhanced RAGE ectodomain shedding.<\/jats:p>","DOI":"10.1371\/journal.pone.0358445","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T17:49:06Z","timestamp":1789753746000},"page":"e0358445","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Insulin enhances RAGE ectodomain shedding by inducing Rab14-dependent ADAM10 cell surface trafficking in human aortic endothelial cells"],"prefix":"10.1371","volume":"21","author":[{"given":"Chung Hee","family":"Baek","sequence":"first","affiliation":[{"name":"Asan Medical Center, University of Ulsan College of Medicine","place":["Seoul, Republic of Korea"],"department":["Division of Nephrology, Department of Internal 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