{"doi":"10.1101/2023.01.25.525550","title":"PI(3,5)P <sub>2</sub> Controls the Signaling Activity of Class I PI3K","abstract":"ABSTRACT 3-Phosphoinositides are ubiquitous cellular lipids that play pivotal regulatory roles in health and disease. Among 3-phosphoinositides, phosphatidylinositol-3,5-bisphosphate (PI(3,5)P 2 ) remains the least understood species in terms of its spatiotemporal dynamics and physiological function due to the lack of a specific sensor that allows spatiotemporally resolved quantitative imaging of PI(3,5)P 2 . Using a newly developed ratiometric PI(3,5)P 2 sensor engineered from the C-terminal SH2 domain of Class I phosphoinositide 3-kinases (PI3K)-p85α subunit we demonstrate that a unique pool of PI(3,5)P 2 is generated on lysosomes and late endosomes in response to growth factor stimulation. This PI(3,5)P 2 , the formation of which is mediated sequentially by Class II PI3KC2β and PIKfyve, plays a crucial role in terminating the activity of growth factor-stimulated Class I PI3K, one of the most frequently mutated proteins in cancer, via specific interaction with its regulatory p85 subunit. A small molecule inhibitor of p85α-PI(3,5)P 2 binding specifically blocks the feedback inhibition of Class I PI3K by PI(3,5)P 2 and thus serves as a PI3K activator that promotes neurite growth. Furthermore, cancer-causing mutations of the Class I PI3K-p85 subunit inhibit p85-PI(3,5)P 2 interaction and thereby induce sustained activation of Class I PI3K. Our results unravel a hitherto unknown spatiotemporally specific regulatory function of PI(3,5)P 2 that links Class I and II PI3Ks and modulates the magnitude of PI3K-mediated growth factor signaling. These results also suggest new therapeutic possibilities for treating cancer patients with p85 mutations and promoting wound healing and tissue regeneration.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2023,"id":398278,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9608,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1174560,"name":"Julian Zalejski","orcid":null,"position":1,"is_corresponding":false},{"id":1174561,"name":"Seo-Hyeon Song","orcid":null,"position":2,"is_corresponding":false},{"id":891695,"name":"Ashutosh Sharma","orcid":"0000-0003-0455-9963","position":3,"is_corresponding":false},{"id":400441,"name":"Wei Wang","orcid":"0000-0002-7276-5841","position":4,"is_corresponding":false},{"id":892334,"name":"Yusi Hu","orcid":null,"position":5,"is_corresponding":false},{"id":1174314,"name":"Wen‐Ting Lo","orcid":"0000-0001-7904-6834","position":6,"is_corresponding":false},{"id":1174315,"name":"Philipp Alexander Koch","orcid":"0000-0003-0543-7482","position":7,"is_corresponding":false},{"id":976501,"name":"Jagriti Singh","orcid":"0000-0003-1164-1375","position":8,"is_corresponding":false},{"id":436542,"name":"Indira Singaram","orcid":"0000-0001-7508-7997","position":9,"is_corresponding":false},{"id":1174562,"name":"Baoshu An","orcid":null,"position":10,"is_corresponding":false},{"id":236062,"name":"Jean J. Zhao","orcid":"0000-0002-4561-5688","position":11,"is_corresponding":false},{"id":1174563,"name":"Liang-Wei Gong","orcid":null,"position":12,"is_corresponding":false},{"id":71008,"name":"Volker Haucke","orcid":"0000-0003-3119-6993","position":13,"is_corresponding":false},{"id":261770,"name":"Ruixuan Gao","orcid":"0000-0001-7137-2512","position":14,"is_corresponding":false},{"id":436544,"name":"Wonhwa Cho","orcid":"0000-0003-1410-2481","position":15,"is_corresponding":false},{"id":436541,"name":"Jiachen Sun","orcid":"0000-0002-0278-6831","position":0,"is_corresponding":true}],"reference_count":76,"raw_metadata":null,"created_at":"2026-07-19T01:19:43.776284Z","pmid":"36747849","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}