{"doi":"10.1101/2024.01.10.575035","title":"Enhanced PI3K/Akt Signaling in Response to p85α Loss is Regulated by Endosomal PI3Kα and PI3P","abstract":"SUMMARY PI3Kα is a heterodimer of p110α catalytic subunit and p85 adaptor subunit that is activated by agonist-stimulated receptor tyrosine kinases. Although the interaction of p85α with activated receptors recruits p110α to membranes, studies have demonstrated that p85α loss, which occurs commonly in cancer, paradoxically promotes agonist-stimulated PI3K/Akt signaling. We recently demonstrated that p110α localizes to microtubules via MAP4, facilitating its interaction with activated receptor kinases in endosomes to initiate PI3K/Akt signaling. Here, we demonstrate that in response to agonist stimulation and p85α knock down the residual p110α, coupled predominantly to p85β, exhibits enhanced microtubule localization, MAP4 binding and interaction with endosomal receptor tyrosine kinases, thereby augmenting PI3K/Akt signaling. The interaction of the C2 domain of p110α with PI3P is required for recruiting p110α into endomembranes and enhancing PI3K/Akt signaling. These findings provide a mechanism for the augmented agonist-stimulated PI3K/Akt signaling upon p85α loss and point to novel therapeutic targets for cancer. IN BRIEF This study provides the comprehensive mechanism for p85α loss induced and receptor tyrosine kinase stimulated PI3K/Akt signaling.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2024,"id":493263,"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":0,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9487,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1052983,"name":"Mo Chen","orcid":"0000-0002-3274-5889","position":1,"is_corresponding":false},{"id":285809,"name":"Vincent L. Cryns","orcid":"0000-0003-0355-2268","position":2,"is_corresponding":false},{"id":334121,"name":"Richard A. Anderson","orcid":"0000-0001-6265-8359","position":3,"is_corresponding":false},{"id":335621,"name":"Narendra Thapa","orcid":null,"position":0,"is_corresponding":true}],"reference_count":39,"raw_metadata":null,"created_at":"2026-07-19T02:09:00.148120Z","pmid":null,"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":[]}