{
  "abstract": "3-Phosphoinositides are essential cellular lipids regulating health and disease. Among them, phosphatidylinositol-3,5-bisphosphate [PI(3,5)P 2 ] remains the least understood. Using a newly developed ratiometric PI(3,5)P 2 sensor that enables spatiotemporally resolved PI(3,5)P 2 quantification, we demonstrate that growth factor stimulation generates a distinct PI(3,5)P 2 pool on lysosomes and late endosomes. Formed sequentially by class II PI3KC2β and PIKfyve, this PI(3,5)P 2 pool terminates growth factor–stimulated class I phosphatidylinositol 3-kinase (PI3K) activity through a specific interaction with its regulatory p85 subunit. Disrupting this p85-PI(3,5)P 2 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 2 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.",
  "abstract_shown": true,
  "affiliations": [
    "Department of Chemistry, University of Illinois Chicago, Chicago, IL 60607, USA.",
    "Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Korea.",
    "Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), 13125 Berlin, Germany.",
    "Department of Biological Sciences, University of Illinois Chicago, Chicago, IL 60607, USA.",
    "Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.",
    "Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.",
    "Department of Biomedical Engineering, Colleges of Engineering and Medicine, University of Illinois Chicago, Chicago, IL 60607, USA.",
    "Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois Chicago, Chicago, IL 60607, USA.",
    "University of Illinois Cancer Center, Chicago, IL 60612, USA."
  ],
  "article_type": null,
  "arxiv": null,
  "author_total": 19,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Jiachen Sun",
      "orcid": "0000-0002-0278-6831"
    },
    {
      "affs": [
        0
      ],
      "name": "Julian Zalejski",
      "orcid": "0009-0006-5024-8647"
    },
    {
      "affs": [
        1
      ],
      "name": "Seohyeon Song"
    },
    {
      "affs": [
        0
      ],
      "name": "Ashutosh Sharma",
      "orcid": "0000-0003-0455-9963"
    },
    {
      "affs": [
        0
      ],
      "name": "Wei Wang",
      "orcid": "0009-0007-3019-2479"
    },
    {
      "affs": [
        0
      ],
      "name": "Yusi Hu"
    },
    {
      "affs": [
        2
      ],
      "name": "Wen-Ting Lo",
      "orcid": "0000-0001-7904-6834"
    },
    {
      "affs": [
        2
      ],
      "name": "Philipp Alexander Koch",
      "orcid": "0000-0003-0543-7482"
    },
    {
      "affs": [
        0
      ],
      "name": "Duy-Viet Vo",
      "orcid": "0000-0002-9268-6358"
    },
    {
      "affs": [
        0
      ],
      "name": "Jagriti Singh"
    },
    {
      "affs": [
        0
      ],
      "name": "Indira Singaram"
    },
    {
      "affs": [
        3
      ],
      "name": "Baoshu An"
    },
    {
      "affs": [
        0
      ],
      "name": "Hirushi Gunasekara"
    },
    {
      "affs": [
        4,
        5
      ],
      "name": "Jean J. Zhao",
      "orcid": "0000-0002-4561-5688"
    },
    {
      "affs": [
        3
      ],
      "name": "Liang-Wei Gong"
    },
    {
      "affs": [
        0,
        6,
        7,
        8
      ],
      "name": "Ying S. Hu",
      "orcid": "0000-0002-3912-7063"
    },
    {
      "affs": [
        2
      ],
      "name": "Volker Haucke"
    },
    {
      "affs": [
        0
      ],
      "name": "Ruixuan Gao",
      "orcid": "0000-0001-7137-2512"
    },
    {
      "affs": [
        0
      ],
      "name": "Wonhwa Cho",
      "orcid": "0000-0003-1410-2481"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/29h5hvev590sv.bib",
  "cited_by": 0,
  "doi": "10.1126/sciadv.aeh8582",
  "fulltext_url": null,
  "id": "29h5hvev590sv",
  "issns": [
    "2375-2548"
  ],
  "landing_url": "https://www.science.org/doi/10.1126/sciadv.aeh8582",
  "language": null,
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "journal",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|PI3K/AKT/mTOR signaling in cancer"
    ]
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  "openalex": "W7214989104",
  "pdf_url": null,
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-02",
  "publisher": "American Association for the Advancement of Science (AAAS)",
  "ris": "https://research.draconitic.com/paper/29h5hvev590sv.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:17:41Z",
      "native_id": "10.1126/sciadv.aeh8582",
      "source": "crossref",
      "url": "https://www.science.org/doi/10.1126/sciadv.aeh8582"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|PI3K/AKT/mTOR signaling in cancer",
      "subfield": "molecular-biology"
    }
  ],
  "title": "PI(3,5)P ₂ controls the signaling activity of class I PI3K",
  "title_text": "PI(3,5)P ₂ controls the signaling activity of class I PI3K",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:17:41Z",
  "url": "https://research.draconitic.com/paper/29h5hvev590sv",
  "venue": "Science Advances",
  "versions": []
}