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Adv."],"published-print":{"date-parts":[[2026,10,2]]},"abstract":"<jats:p>\n                    3-Phosphoinositides are essential cellular lipids regulating health and disease. Among them, phosphatidylinositol-3,5-bisphosphate [PI(3,5)P\n                    <jats:sub>2<\/jats:sub>\n                    ] remains the least understood. Using a newly developed ratiometric PI(3,5)P\n                    <jats:sub>2<\/jats:sub>\n                    sensor that enables spatiotemporally resolved PI(3,5)P\n                    <jats:sub>2<\/jats:sub>\n                    quantification, we demonstrate that growth factor stimulation generates a distinct PI(3,5)P\n                    <jats:sub>2<\/jats:sub>\n                    pool on lysosomes and late endosomes. Formed sequentially by class II PI3KC2\u03b2 and PIKfyve, this PI(3,5)P\n                    <jats:sub>2<\/jats:sub>\n                    pool terminates growth factor\u2013stimulated class I phosphatidylinositol 3-kinase (PI3K) activity through a specific interaction with its regulatory p85 subunit. Disrupting this p85-PI(3,5)P\n                    <jats:sub>2<\/jats:sub>\n                    interaction via a small-molecule inhibitor or cancer-causing mutations blocks feedback inhibition, driving sustained class I PI3K activation and promoting neurite growth. Our findings uncover a spatiotemporally specific regulatory function of PI(3,5)P\n                    <jats:sub>2<\/jats:sub>\n                    that links class I and II PI3Ks to tune growth factor signaling. This mechanism offers therapeutic strategies for treating p85-mutant cancers and advancing tissue regeneration.\n                  <\/jats:p>","DOI":"10.1126\/sciadv.aeh8582","type":"journal-article","created":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T17:58:26Z","timestamp":1790791106000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":0,"title":["PI(3,5)P\n                    <sub>2<\/sub>\n                    controls the signaling activity of class I PI3K"],"prefix":"10.1126","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0278-6831","authenticated-orcid":true,"given":"Jiachen","family":"Sun","sequence":"first","affiliation":[{"name":"Department of Chemistry, University of Illinois Chicago, Chicago, IL 60607, 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