PI(3,5)P 2 controls the signaling activity of class I PI3K
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.
Authors
- Indira Singaram (ORCID: https://orcid.org/0000-0001-7508-7997)
- Wonhwa Cho (ORCID: https://orcid.org/0000-0003-1410-2481)
- Volker Haucke (ORCID: https://orcid.org/0000-0003-3119-6993)
- Wen‐Ting Lo (ORCID: https://orcid.org/0000-0001-7904-6834)
- Ruixuan Gao (ORCID: https://orcid.org/0000-0001-7137-2512)
- Philipp Alexander Koch (ORCID: https://orcid.org/0000-0003-0543-7482)
- Jean J. Zhao (ORCID: https://orcid.org/0000-0002-4561-5688)
- Duy‐Viet Vo (ORCID: https://orcid.org/0000-0002-9268-6358)
- Baoshu An
- Hirushi Gunasekara (ORCID: https://orcid.org/0000-0002-3750-2309)
- Julian Zalejski (ORCID: https://orcid.org/0009-0006-5024-8647)
- Ying Hu (ORCID: https://orcid.org/0000-0002-3912-7063)
- Jiachen Sun (ORCID: https://orcid.org/0000-0002-0278-6831)
- Ashutosh K. Sharma (ORCID: https://orcid.org/0000-0003-0455-9963)
- Liang‐Wei Gong (ORCID: https://orcid.org/0000-0002-5868-6039)
- Yusi Hu (ORCID: https://orcid.org/0000-0003-2053-6032)
- Wei Wang (ORCID: https://orcid.org/0009-0007-3019-2479)
- Jagriti Singh
- Seohyeon Song
Institutions
- Pohang University of Science and Technology (KR)
- Harvard University (US)
- Illinois College (US)
- University of Illinois Chicago (US)
- University of Chicago (US)
- Leibniz-Forschungsinstitut für Molekulare Pharmakologie (DE)
- Dana-Farber Cancer Institute (US)
Publication Details
- Journal
- Science Advances
- Published
- 2026-09-30
- DOI
- https://doi.org/10.1126/sciadv.aeh8582
- Primary Topic
- PI3K/AKT/mTOR signaling in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00