PI(3,5)P ₂ controls the signaling activity of class I PI3K
9 affiliations
- 1Department of Chemistry, University of Illinois Chicago, Chicago, IL 60607, USA.
- 2Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 790-784, Korea.
- 3Leibniz-Forschungsinstitut für Molekulare Pharmakologie (FMP), 13125 Berlin, Germany.
- 4Department of Biological Sciences, University of Illinois Chicago, Chicago, IL 60607, USA.
- 5Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
- 6Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
- 7Department of Biomedical Engineering, Colleges of Engineering and Medicine, University of Illinois Chicago, Chicago, IL 60607, USA.
- 8Department of Biochemistry and Molecular Genetics, College of Medicine, University of Illinois Chicago, Chicago, IL 60607, USA.
- 9University of Illinois Cancer Center, Chicago, IL 60612, USA.
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.
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BibTeX
@article{sun2026pi35p,
title = {{PI(3,5)P ₂ controls the signaling activity of class I PI3K}},
author = {Jiachen Sun and Julian Zalejski and Seohyeon Song and Ashutosh Sharma and Wei Wang and Yusi Hu and Wen-Ting Lo and Philipp Alexander Koch and Duy-Viet Vo and Jagriti Singh and Indira Singaram and Baoshu An and Hirushi Gunasekara and Jean J. Zhao and Liang-Wei Gong and Ying S. Hu and Volker Haucke and Ruixuan Gao and Wonhwa Cho},
journal = {Science Advances},
year = {2026},
month = oct,
doi = {10.1126/sciadv.aeh8582},
url = {https://www.science.org/doi/10.1126/sciadv.aeh8582},
note = {CC BY-NC},
}
RIS
TY - JOUR
TI - PI(3,5)P ₂ controls the signaling activity of class I PI3K
AU - Jiachen Sun
AU - Julian Zalejski
AU - Seohyeon Song
AU - Ashutosh Sharma
AU - Wei Wang
AU - Yusi Hu
AU - Wen-Ting Lo
AU - Philipp Alexander Koch
AU - Duy-Viet Vo
AU - Jagriti Singh
AU - Indira Singaram
AU - Baoshu An
AU - Hirushi Gunasekara
AU - Jean J. Zhao
AU - Liang-Wei Gong
AU - Ying S. Hu
AU - Volker Haucke
AU - Ruixuan Gao
AU - Wonhwa Cho
PY - 2026
DA - 2026/10/02
JO - Science Advances
DO - 10.1126/sciadv.aeh8582
UR - https://www.science.org/doi/10.1126/sciadv.aeh8582
AB - 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.
SN - 2375-2548
ER -