{"gene":"PIK3R3","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2007,"finding":"PIK3R3 knockdown by siRNA significantly increased apoptosis in ovarian cancer cell lines, demonstrating a pro-survival role for the p55γ regulatory subunit in ovarian cancer cells.","method":"siRNA knockdown with apoptosis readout in cultured ovarian cancer cell lines","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — clean KD with defined cellular phenotype (apoptosis), single lab, single method","pmids":["17875760"],"is_preprint":false},{"year":2012,"finding":"PIK3R3 knockdown in gastric cancer cells induced G0/G1 cell cycle arrest and decreased retinoblastoma protein (Rb) phosphorylation, cyclin D1, and PCNA expression, establishing PIK3R3 as a promoter of cell cycle progression.","method":"siRNA knockdown, FACS cell cycle analysis, crystal violet/BrdU proliferation assays, Western blot","journal":"BMC medical genomics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean KD with multiple orthogonal phenotypic readouts (cell cycle, proliferation, protein markers), single lab","pmids":["22876838"],"is_preprint":false},{"year":2014,"finding":"PIK3R3 overexpression induces epithelial-to-mesenchymal transition (EMT) dependent on SNAI2 expression, and its downregulation reverses EMT in colorectal cancer cells, promoting invasion and metastasis in vitro and in vivo.","method":"Overexpression and knockdown with in vitro migration/invasion assays and in vivo metastasis model, Western blot for EMT markers","journal":"Molecular cancer therapeutics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD/OE with defined cellular phenotype (EMT, invasion, metastasis) and pathway placement (SNAI2), single lab with multiple assays","pmids":["24837077"],"is_preprint":false},{"year":2014,"finding":"TGF-β downregulates PIK3R3 expression by attenuating the transcriptional activity of NKX2.1, a transcription factor that binds the PIK3R3 promoter; PIK3R3 overexpression attenuates TGF-β-induced inhibition of lung adenocarcinoma cell proliferation, placing PIK3R3 downstream of the TGF-β/NKX2.1 axis.","method":"Promoter-binding studies, overexpression rescue assay, Western blot, cell proliferation assays, correlation in clinical samples","journal":"Molecular carcinogenesis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter binding and rescue experiments establishing pathway position, single lab with multiple methods","pmids":["25371235"],"is_preprint":false},{"year":2018,"finding":"FOXM1 directly binds the PIK3R3 promoter (confirmed by chromatin immunoprecipitation) and regulates its expression; FOXM1 overexpression activates PI3K/AKT signaling through PIK3R3-mediated AKT phosphorylation in esophageal squamous cell carcinoma cells.","method":"Chromatin immunoprecipitation (ChIP), transcriptome analysis, overexpression experiments, Western blot for AKT phosphorylation","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — ChIP directly demonstrates FOXM1 binding to PIK3R3 promoter; AKT activation confirmed by Western blot; single lab","pmids":["29682174"],"is_preprint":false},{"year":2018,"finding":"PIK3R3 overexpression promotes hepatic fatty acid β-oxidation by inducing PPARα expression in a HNF4α-dependent manner; hepatic PIK3R3 knockout increases hepatic triglyceride levels, and overexpression improves the fatty liver phenotype in high-fat diet mice, defining a novel PIK3R3-HNF4α-PPARα signaling axis in lipid metabolism.","method":"Overexpression and liver-specific knockout mouse models, gene expression analysis, phenotypic assessment of hepatosteatosis","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gain- and loss-of-function with defined metabolic phenotype and pathway placement, single lab","pmids":["29350678"],"is_preprint":false},{"year":2018,"finding":"PIK3R3 promotes pancreatic cancer cell migration and invasion through the ERK1/2-ZEB1 pathway, triggering epithelial-mesenchymal transition; PIK3R3 overexpression or knockdown respectively promotes or suppresses metastasis in vitro and in vivo.","method":"RNAi knockdown, overexpression, in vitro migration/invasion assays, in vivo metastasis model, Western blot for ERK1/2-ZEB1 and EMT markers","journal":"Cellular physiology and biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD and OE with in vitro and in vivo phenotypes and pathway placement (ERK1/2-ZEB1-EMT), single lab","pmids":["29719293"],"is_preprint":false},{"year":2018,"finding":"PIK3R3 promotes chemotherapeutic sensitivity of colorectal cancer cells to 5-FU by enhancing 5-FU-induced apoptosis through upregulation of thymidine phosphorylase (TP) via the PIK3R3/NF-κB/TP pathway.","method":"Overexpression/knockdown, apoptosis assay, Western blot, clinical database analysis","journal":"Cancer biology & therapy","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, limited mechanistic follow-up of pathway placement","pmids":["29370570"],"is_preprint":false},{"year":2019,"finding":"A novel miRNA (miR-G-10) bound to the 3' UTR of PIK3R3 mRNA and upregulated its expression in a GRSF1-dependent manner, activating the AKT/NF-κB signaling pathway to promote cervical cancer cell migration, invasion, and anoikis resistance.","method":"3' UTR binding assay, RIP-seq, overexpression, in vitro functional assays (migration/invasion/anoikis), in vivo lung metastasis model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — 3'UTR binding validated, pathway activation confirmed, multiple functional readouts, single lab","pmids":["31474757"],"is_preprint":false},{"year":2020,"finding":"PIK3R3 physically binds p53 and inhibits p53 binding to the p21 gene promoter region, thereby suppressing p21 transcriptional activity and inhibiting cellular senescence of colorectal cancer cells.","method":"Co-immunoprecipitation (binding of PIK3R3 to p53), promoter binding assay (ChIP or reporter assay for p53-p21 interaction), overexpression/knockdown with senescence markers","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP demonstrates binding, promoter occupancy assay shows functional consequence, single lab","pmids":["32973127"],"is_preprint":false},{"year":2020,"finding":"PIK3R3 overexpression activates the NF-κB pathway to downregulate ZO-1 expression, thereby disrupting epithelial tight junction integrity and increasing intestinal permeability; inhibition of PIK3R3 with TAT-N15 ameliorated DSS-induced intestinal permeability in mice.","method":"Overexpression and siRNA knockdown in Caco-2 cells, TEER measurement, immunoblot and immunofluorescence for tight junction proteins, in vivo DSS colitis model with PIK3R3 inhibitor","journal":"International immunopharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo experiments with defined pathway (NF-κB/ZO-1), multiple complementary methods, single lab","pmids":["32473571"],"is_preprint":false},{"year":2020,"finding":"LACTB regulates PIK3R3 activity (confirmed by immunoprecipitation) to influence PI3K/AKT/mTOR pathway activation; LACTB overexpression inhibits EMT and proliferation and promotes autophagy in colorectal cancer cells partly through PIK3R3.","method":"Immunoprecipitation, Western blot, RNA-seq, transwell/MTT assays, xenograft model","journal":"Cancer management and research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP establishing LACTB-PIK3R3 interaction, limited mechanistic follow-up, single lab","pmids":["32636680"],"is_preprint":false},{"year":2021,"finding":"PIK3R3 activates both AKT and ERK signaling in sarcoma cancer stem-like cells; inhibition of PIK3R3 using shRNA reduced Nanog expression, spheroid formation, anchorage-independent growth, migration, invasion, MMP-2 secretion, and chemotherapy resistance, defining a PIK3R3/ERK/Nanog axis in sarcoma CSC phenotypes.","method":"shRNA knockdown, pharmacological inhibitors, spheroid/CSC assays, Western blot for AKT/ERK/Nanog, xenograft invasion assay, chemotherapy resistance assay","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal functional readouts with defined signaling pathway (PIK3R3/ERK/Nanog), single lab","pmids":["34321458"],"is_preprint":false},{"year":2022,"finding":"KMT2C promotes PIK3R3 transcription by regulating histone H3K4me3 enrichment at the PIK3R3 promoter and H3K4me1 at the enhancer; the resulting PIK3R3/AKT/NF-κB signaling drives keratinocyte hyperproliferation and cytokine secretion in psoriasiform inflammation.","method":"ChIP for histone marks at PIK3R3 promoter/enhancer, KMT2C knockdown with phenotypic and downstream signaling readouts, in vivo mouse psoriasis model","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — ChIP directly demonstrates epigenetic regulation of PIK3R3 promoter by KMT2C, in vitro and in vivo validation, single lab","pmids":["35870559"],"is_preprint":false},{"year":2023,"finding":"PIK3R3 activates AKT signaling to control liver cancer cell growth; PIK3R3 knockdown upregulates CDKN1C (a cyclin-dependent kinase inhibitor) and reduces SMC1A; immunoprecipitation demonstrated indirect interactions between PIK3R3 and CDKN1C or SMC1A, and rescue of CDKN1C or SMC1A reversed PIK3R3 knockdown-induced growth inhibition.","method":"siRNA and lentivirus overexpression, colony formation/EdU/flow cytometry assays, xenograft model, RNA sequencing, rescue assays, immunoprecipitation","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, RNA-seq, and rescue experiments across multiple readouts; single lab","pmids":["37212524"],"is_preprint":false},{"year":2023,"finding":"MCT4 overexpression promotes L929 fibroblast cell migration via activation of an IGF1/IGF1R/PIK3R3/SGK1 signaling axis; inhibition of IGF1R or SGK1 mitigated MCT4-promoted migration, placing PIK3R3 in this upstream signaling cascade.","method":"RNA sequencing, RT-qPCR, Western blot, wound healing assay, IGF1R/SGK1 inhibitor experiments","journal":"Oncology letters","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement inferred from inhibitor experiments and expression, single lab, no direct PIK3R3 manipulation","pmids":["37745980"],"is_preprint":false},{"year":2024,"finding":"VHL governs m6A modification of PIK3R3 mRNA by orchestrating assembly of m6A writer proteins METTL3 and METTL14, stabilizing PIK3R3 mRNA; PIK3R3 contributes to p85 ubiquitination, which restrains PI3K/AKT signaling and impedes clear cell renal cell carcinoma (ccRCC) growth.","method":"m6A transcriptome profiling (MeRIP-seq), METTL3/METTL14 complex assembly assays, p85 ubiquitination assay, cell and mouse models (referenced study reviewed in this paper)","journal":"The Journal of clinical investigation","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — m6A profiling and mechanistic dissection of VHL-METTL3/14-PIK3R3-p85 axis with in vitro and in vivo validation; cited as a peer-reviewed finding in JCI commentary","pmids":["38618953"],"is_preprint":false},{"year":2024,"finding":"FTO demethylates m6A on PIK3R3 mRNA, decreasing its m6A level and affecting FoxO pathway activation; FTO knockdown increases PIK3R3 m6A modification (detected by MeRIP-seq/qPCR), and PIK3R3 upregulation restores cervical cancer cell malignancy reduced by FTO knockdown.","method":"MeRIP-seq and MeRIP-qPCR for m6A profiling, lentivirus-mediated FTO overexpression/knockdown, rescue assay with PIK3R3 overexpression, in vitro and in vivo functional assays","journal":"Cancer medicine","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct m6A profiling links FTO to PIK3R3 mRNA modification; rescue experiment confirms mechanistic relevance; single lab","pmids":["39692250"],"is_preprint":false},{"year":2024,"finding":"POU2F1 binds the miR-29b1/a cluster promoter to suppress miR-29b-3p and miR-29a-3p expression; these miRNAs directly target PIK3R3 (and PIK3R1); PIK3R1 and PIK3R3 interact with each other (co-immunoprecipitation) and jointly regulate GC cell invasion/migration via PI3K/AKT/mTOR signaling.","method":"Co-immunoprecipitation (PIK3R1–PIK3R3 interaction), luciferase 3'-UTR assay, promoter analysis, rescue experiments, in vivo metastasis model, Western blot","journal":"Chinese medical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP demonstrates PIK3R1-PIK3R3 complex; 3'UTR luciferase validates miRNA targeting; in vivo confirmation; single lab","pmids":["39183556"],"is_preprint":false},{"year":2024,"finding":"ZSTK474 (a PI3K inhibitor) targets PIK3R3 to induce G0/G1 phase arrest in Wilms' tumor cells; PIK3R3 knockdown confirmed that ZSTK474 acts by downregulating PIK3R3, reducing AKT phosphorylation, cyclin D, and CDK4 levels and elevating p21 expression.","method":"PIK3R3 siRNA knockdown, CCK-8, flow cytometry cell cycle assay, Western blot for AKT phosphorylation/cyclin D/CDK4/p21, in vivo xenograft model","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD confirms mechanism of drug action with defined downstream signaling (AKT/cyclin D/CDK4/p21), in vitro and in vivo, single lab","pmids":["39466763"],"is_preprint":false},{"year":2025,"finding":"PIK3R3 regulates differentiation and senescence of human periodontal ligament stem cells (hPDLSCs) by modulating FOXO1 expression; PIK3R3 knockdown promotes senescence and inhibits multi-lineage differentiation, while PIK3R3 overexpression has opposite effects; FOXO1 knockdown promotes senescence and weakens the senescence-promoting effect of PIK3R3 knockdown, establishing PIK3R3–FOXO1 as a regulatory axis.","method":"shRNA knockdown and overexpression, osteogenic/adipogenic/chondrogenic differentiation assays, senescence markers, ROS and telomerase assays, FOXO1 siRNA rescue, in vivo aged rat alveolar bone loss model (micro-CT and histology)","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KD/OE with multiple differentiation/senescence assays, epistasis via FOXO1 siRNA rescue, in vivo validation; single lab","pmids":["39862908"],"is_preprint":false}],"current_model":"PIK3R3 (p55γ), a class IA PI3K regulatory subunit, promotes cell proliferation and survival by activating AKT/mTOR signaling; it directly binds p53 to suppress p21 transcription and block senescence; its transcription is controlled by TGF-β/NKX2.1 and KMT2C-mediated H3K4 methylation, while its mRNA stability is regulated by VHL-orchestrated m6A writer assembly (METTL3/METTL14) and FTO-mediated demethylation; PIK3R3 drives EMT via SNAI2 in colorectal cancer and via ERK1/2-ZEB1 in pancreatic cancer, and activates a PIK3R3/ERK/Nanog axis in sarcoma stem cells; it also regulates hepatic lipid metabolism through a PIK3R3-HNF4α-PPARα axis, controls intestinal barrier integrity via NF-κB/ZO-1, modulates stem cell senescence through FOXO1, and forms a functional complex with PIK3R1 to regulate PI3K/AKT/mTOR signaling."},"narrative":{"mechanistic_narrative":"PIK3R3 (p55γ), a class IA PI3K regulatory subunit, functions as a pro-proliferative, pro-survival node that drives cell cycle progression and tumor cell invasion across multiple tissues by activating PI3K/AKT and ERK signaling [PMID:22876838, PMID:29682174]. Loss of PIK3R3 promotes apoptosis and imposes G0/G1 arrest with reduced Rb phosphorylation, cyclin D1, and PCNA, while restoring p21/CDKN1C and CDK4 inhibition [PMID:17875760, PMID:22876838, PMID:39466763]. Beyond its kinase-adaptor role, PIK3R3 acts in the nucleus by physically binding p53 and blocking its occupancy of the p21 promoter, thereby suppressing senescence [PMID:32973127], and it controls stem-cell differentiation and senescence through a FOXO1 axis [PMID:39862908]. PIK3R3 drives epithelial-to-mesenchymal transition through context-specific effectors — SNAI2 in colorectal cancer and an ERK1/2–ZEB1 cascade in pancreatic cancer — and sustains stemness via a PIK3R3/ERK/Nanog axis in sarcoma [PMID:24837077, PMID:29719293, PMID:34321458]. It forms a functional complex with the regulatory subunit PIK3R1 to jointly regulate PI3K/AKT/mTOR signaling [PMID:39183556]. Its expression is multiply controlled: transcriptionally by NKX2.1 (repressed by TGF-β), FOXM1, and KMT2C-mediated H3K4 methylation [PMID:25371235, PMID:29682174, PMID:35870559], and post-transcriptionally by m6A dynamics in which VHL-orchestrated METTL3/METTL14 writing and FTO demethylation tune PIK3R3 mRNA stability [PMID:38618953, PMID:39692250]. Outside cancer, PIK3R3 governs hepatic lipid metabolism through an HNF4α–PPARα axis and intestinal barrier integrity via NF-κB/ZO-1 [PMID:29350678, PMID:32473571].","teleology":[{"year":2007,"claim":"Established that PIK3R3 is required for cancer cell survival, defining its first cellular phenotype as a pro-survival regulatory subunit.","evidence":"siRNA knockdown with apoptosis readout in ovarian cancer cell lines","pmids":["17875760"],"confidence":"Medium","gaps":["No molecular mechanism linking PIK3R3 loss to apoptosis","Single cancer type, single method"]},{"year":2012,"claim":"Connected PIK3R3 to cell cycle machinery, showing it promotes G1/S progression rather than acting solely on survival.","evidence":"siRNA knockdown with FACS cell cycle analysis and Western blot for Rb/cyclin D1/PCNA in gastric cancer cells","pmids":["22876838"],"confidence":"Medium","gaps":["Does not establish whether the effect requires PI3K catalytic activity","Upstream regulators unidentified"]},{"year":2014,"claim":"Defined PIK3R3 as a driver of EMT and metastasis and placed it within the TGF-β/NKX2.1 transcriptional circuit, identifying both a downstream effector (SNAI2) and an upstream control.","evidence":"OE/KD with migration/invasion and in vivo metastasis assays (colorectal); promoter-binding and rescue assays (lung adenocarcinoma)","pmids":["24837077","25371235"],"confidence":"Medium","gaps":["Direct mechanistic link from PIK3R3 to SNAI2 not resolved","Tissue-specific effectors not generalized"]},{"year":2018,"claim":"Extended PIK3R3 control of EMT/proliferation to multiple effectors (ERK1/2-ZEB1, NF-κB/TP) and identified transcriptional activators FOXM1, broadening its signaling reach beyond canonical AKT.","evidence":"ChIP, OE/KD, in vitro and in vivo assays across esophageal, pancreatic, and colorectal cancers","pmids":["29682174","29719293","29370570"],"confidence":"Medium","gaps":["Whether ERK and AKT branches are independent or convergent is unresolved","FOXM1 binding shown but functional specificity for PIK3R3 not isolated"]},{"year":2018,"claim":"Demonstrated a non-oncogenic physiological role, placing PIK3R3 in hepatic lipid handling via an HNF4α-PPARα axis using in vivo gain- and loss-of-function.","evidence":"Liver-specific knockout and overexpression mouse models with metabolic phenotyping","pmids":["29350678"],"confidence":"Medium","gaps":["Mechanism by which PIK3R3 induces HNF4α/PPARα is undefined","Relationship to canonical PI3K signaling unclear"]},{"year":2019,"claim":"Showed PIK3R3 abundance is post-transcriptionally tuned by non-coding RNA, linking 3'UTR-targeting miRNA machinery to AKT/NF-κB-driven malignancy.","evidence":"3'UTR binding assay, RIP-seq, functional assays, in vivo metastasis in cervical cancer","pmids":["31474757"],"confidence":"Medium","gaps":["GRSF1-dependent upregulation mechanism not fully resolved","Generality of miR-G-10 unknown"]},{"year":2020,"claim":"Revealed a moonlighting nuclear function: PIK3R3 binds p53 and blocks p21 promoter occupancy to suppress senescence, decoupling part of its activity from kinase-adaptor signaling.","evidence":"Co-IP, promoter occupancy assay, OE/KD with senescence markers in colorectal cancer","pmids":["32973127"],"confidence":"Medium","gaps":["Structural basis of PIK3R3-p53 binding unknown","Reciprocal validation and direct binding interface not mapped"]},{"year":2020,"claim":"Established PIK3R3 control of epithelial barrier integrity through NF-κB/ZO-1 and validated it as a therapeutic target with a peptide inhibitor in colitis.","evidence":"OE/KD in Caco-2, TEER, immunofluorescence, in vivo DSS colitis with TAT-N15 inhibitor","pmids":["32473571"],"confidence":"Medium","gaps":["Direct vs indirect NF-κB activation by PIK3R3 not separated","Off-target effects of TAT-N15 not excluded"]},{"year":2021,"claim":"Connected PIK3R3 to cancer stem-cell phenotypes through a PIK3R3/ERK/Nanog axis, implicating it in stemness and chemoresistance.","evidence":"shRNA, inhibitors, spheroid/CSC assays, xenograft in sarcoma","pmids":["34321458"],"confidence":"Medium","gaps":["How PIK3R3 selectively engages ERK vs AKT in CSCs is unclear","Direct regulation of Nanog not shown"]},{"year":2022,"claim":"Identified epigenetic transcriptional control of PIK3R3 by KMT2C-deposited H3K4 methylation, linking chromatin state to PIK3R3/AKT/NF-κB-driven inflammation.","evidence":"ChIP for H3K4me3/me1, KMT2C knockdown, in vivo psoriasis mouse model","pmids":["35870559"],"confidence":"Medium","gaps":["Whether KMT2C acts directly or via intermediate factors is not resolved","Generality beyond keratinocytes unknown"]},{"year":2023,"claim":"Refined the proliferative mechanism, showing PIK3R3 represses CDKN1C and supports SMC1A to sustain liver cancer growth, with rescue confirming causality.","evidence":"siRNA/OE, RNA-seq, IP, rescue assays, xenograft","pmids":["37212524"],"confidence":"Medium","gaps":["Interactions reported as indirect; direct effectors unmapped","Link to canonical PI3K activity not dissected"]},{"year":2024,"claim":"Established m6A as a major layer of PIK3R3 regulation, with VHL-orchestrated METTL3/METTL14 writing stabilizing the transcript and FTO demethylation modulating it, and revealed a tumor-suppressive arm in which PIK3R3 promotes p85 ubiquitination to restrain PI3K/AKT.","evidence":"MeRIP-seq, writer-complex assembly assays, p85 ubiquitination assay, FTO OE/KD rescue in ccRCC and cervical cancer","pmids":["38618953","39692250"],"confidence":"Medium","gaps":["Reconciliation of PIK3R3 oncogenic vs tumor-suppressive roles by context not resolved","Direct vs indirect role in p85 ubiquitination unclear"]},{"year":2024,"claim":"Demonstrated PIK3R3 forms a physical complex with PIK3R1 and that both are co-targeted by miR-29 cluster suppression, establishing a cooperative regulatory-subunit module in PI3K/AKT/mTOR signaling.","evidence":"Co-IP (PIK3R1-PIK3R3), luciferase 3'UTR assay, rescue, in vivo metastasis in gastric cancer","pmids":["39183556"],"confidence":"Medium","gaps":["Stoichiometry and functional consequence of the PIK3R1-PIK3R3 complex undefined","Whether they co-regulate the same catalytic subunit unknown"]},{"year":2025,"claim":"Extended PIK3R3 control of senescence to non-malignant stem cells through a FOXO1 axis, with epistasis confirming FOXO1 acts downstream.","evidence":"shRNA/OE, differentiation and senescence assays, FOXO1 siRNA rescue, in vivo aged rat model","pmids":["39862908"],"confidence":"Medium","gaps":["Mechanism by which PIK3R3 modulates FOXO1 expression not defined","Relationship to the p53/p21 senescence pathway unclear"]},{"year":null,"claim":"How PIK3R3 switches between oncogenic PI3K/AKT activation and tumor-suppressive p85 ubiquitination, and how its kinase-adaptor versus nuclear p53-binding functions are partitioned, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of PIK3R3 in complex with p110, PIK3R1, or p53","Context determinants of opposing PIK3R3 functions not defined","Direct enzymatic activity in p85 ubiquitination not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[4,18,19]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[9]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,18]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[1,19]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[9,20]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[5]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[3,4,13]}],"complexes":["PI3K class IA regulatory complex (with PIK3R1)"],"partners":["PIK3R1","TP53","LACTB"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92569","full_name":"Phosphatidylinositol 3-kinase regulatory subunit gamma","aliases":["Phosphatidylinositol 3-kinase 55 kDa regulatory subunit gamma","PI3-kinase subunit p55-gamma","PtdIns-3-kinase regulatory subunit p55-gamma","p55PIK"],"length_aa":461,"mass_kda":54.4,"function":"Binds to activated (phosphorylated) protein-tyrosine kinases through its SH2 domain and regulates their kinase activity. During insulin stimulation, it also binds to IRS-1","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q92569/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PIK3R3","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PIK3R1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PIK3R3","total_profiled":1310},"omim":[{"mim_id":"606076","title":"PHOSPHATIDYLINOSITOL 3-KINASE, REGULATORY SUBUNIT 3; PIK3R3","url":"https://www.omim.org/entry/606076"},{"mim_id":"171833","title":"PHOSPHATIDYLINOSITOL 3-KINASE, REGULATORY SUBUNIT 1; PIK3R1","url":"https://www.omim.org/entry/171833"},{"mim_id":"147670","title":"INSULIN RECEPTOR; INSR","url":"https://www.omim.org/entry/147670"},{"mim_id":"147370","title":"INSULIN-LIKE GROWTH FACTOR I RECEPTOR; IGF1R","url":"https://www.omim.org/entry/147370"},{"mim_id":"134934","title":"FIBROBLAST GROWTH FACTOR RECEPTOR 3; FGFR3","url":"https://www.omim.org/entry/134934"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Connecting piece","reliability":"Additional"},{"location":"Mid piece","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"},{"location":"End piece","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in many","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PIK3R3"},"hgnc":{"alias_symbol":["p55"],"prev_symbol":[]},"alphafold":{"accession":"Q92569","domains":[{"cath_id":"3.30.505.10","chopping":"61-162","consensus_level":"high","plddt":89.056,"start":61,"end":162},{"cath_id":"1.10.287.1490","chopping":"175-320","consensus_level":"high","plddt":93.6586,"start":175,"end":320},{"cath_id":"3.30.505.10","chopping":"353-452","consensus_level":"high","plddt":88.7293,"start":353,"end":452}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92569","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92569-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92569-F1-predicted_aligned_error_v6.png","plddt_mean":80.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PIK3R3","jax_strain_url":"https://www.jax.org/strain/search?query=PIK3R3"},"sequence":{"accession":"Q92569","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92569.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92569/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92569"}},"corpus_meta":[{"pmid":"24469061","id":"PMC_24469061","title":"MicroRNA-193a-3p 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\"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — clean KD with defined cellular phenotype (apoptosis), single lab, single method\",\n      \"pmids\": [\"17875760\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PIK3R3 knockdown in gastric cancer cells induced G0/G1 cell cycle arrest and decreased retinoblastoma protein (Rb) phosphorylation, cyclin D1, and PCNA expression, establishing PIK3R3 as a promoter of cell cycle progression.\",\n      \"method\": \"siRNA knockdown, FACS cell cycle analysis, crystal violet/BrdU proliferation assays, Western blot\",\n      \"journal\": \"BMC medical genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean KD with multiple orthogonal phenotypic readouts (cell cycle, proliferation, protein markers), single lab\",\n      \"pmids\": [\"22876838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"PIK3R3 overexpression induces epithelial-to-mesenchymal transition (EMT) dependent on SNAI2 expression, and its downregulation reverses EMT in colorectal cancer cells, promoting invasion and metastasis in vitro and in vivo.\",\n      \"method\": \"Overexpression and knockdown with in vitro migration/invasion assays and in vivo metastasis model, Western blot for EMT markers\",\n      \"journal\": \"Molecular cancer therapeutics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD/OE with defined cellular phenotype (EMT, invasion, metastasis) and pathway placement (SNAI2), single lab with multiple assays\",\n      \"pmids\": [\"24837077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"TGF-β downregulates PIK3R3 expression by attenuating the transcriptional activity of NKX2.1, a transcription factor that binds the PIK3R3 promoter; PIK3R3 overexpression attenuates TGF-β-induced inhibition of lung adenocarcinoma cell proliferation, placing PIK3R3 downstream of the TGF-β/NKX2.1 axis.\",\n      \"method\": \"Promoter-binding studies, overexpression rescue assay, Western blot, cell proliferation assays, correlation in clinical samples\",\n      \"journal\": \"Molecular carcinogenesis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter binding and rescue experiments establishing pathway position, single lab with multiple methods\",\n      \"pmids\": [\"25371235\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"FOXM1 directly binds the PIK3R3 promoter (confirmed by chromatin immunoprecipitation) and regulates its expression; FOXM1 overexpression activates PI3K/AKT signaling through PIK3R3-mediated AKT phosphorylation in esophageal squamous cell carcinoma cells.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), transcriptome analysis, overexpression experiments, Western blot for AKT phosphorylation\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP directly demonstrates FOXM1 binding to PIK3R3 promoter; AKT activation confirmed by Western blot; single lab\",\n      \"pmids\": [\"29682174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PIK3R3 overexpression promotes hepatic fatty acid β-oxidation by inducing PPARα expression in a HNF4α-dependent manner; hepatic PIK3R3 knockout increases hepatic triglyceride levels, and overexpression improves the fatty liver phenotype in high-fat diet mice, defining a novel PIK3R3-HNF4α-PPARα signaling axis in lipid metabolism.\",\n      \"method\": \"Overexpression and liver-specific knockout mouse models, gene expression analysis, phenotypic assessment of hepatosteatosis\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gain- and loss-of-function with defined metabolic phenotype and pathway placement, single lab\",\n      \"pmids\": [\"29350678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PIK3R3 promotes pancreatic cancer cell migration and invasion through the ERK1/2-ZEB1 pathway, triggering epithelial-mesenchymal transition; PIK3R3 overexpression or knockdown respectively promotes or suppresses metastasis in vitro and in vivo.\",\n      \"method\": \"RNAi knockdown, overexpression, in vitro migration/invasion assays, in vivo metastasis model, Western blot for ERK1/2-ZEB1 and EMT markers\",\n      \"journal\": \"Cellular physiology and biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD and OE with in vitro and in vivo phenotypes and pathway placement (ERK1/2-ZEB1-EMT), single lab\",\n      \"pmids\": [\"29719293\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PIK3R3 promotes chemotherapeutic sensitivity of colorectal cancer cells to 5-FU by enhancing 5-FU-induced apoptosis through upregulation of thymidine phosphorylase (TP) via the PIK3R3/NF-κB/TP pathway.\",\n      \"method\": \"Overexpression/knockdown, apoptosis assay, Western blot, clinical database analysis\",\n      \"journal\": \"Cancer biology & therapy\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, limited mechanistic follow-up of pathway placement\",\n      \"pmids\": [\"29370570\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A novel miRNA (miR-G-10) bound to the 3' UTR of PIK3R3 mRNA and upregulated its expression in a GRSF1-dependent manner, activating the AKT/NF-κB signaling pathway to promote cervical cancer cell migration, invasion, and anoikis resistance.\",\n      \"method\": \"3' UTR binding assay, RIP-seq, overexpression, in vitro functional assays (migration/invasion/anoikis), in vivo lung metastasis model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — 3'UTR binding validated, pathway activation confirmed, multiple functional readouts, single lab\",\n      \"pmids\": [\"31474757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PIK3R3 physically binds p53 and inhibits p53 binding to the p21 gene promoter region, thereby suppressing p21 transcriptional activity and inhibiting cellular senescence of colorectal cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (binding of PIK3R3 to p53), promoter binding assay (ChIP or reporter assay for p53-p21 interaction), overexpression/knockdown with senescence markers\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP demonstrates binding, promoter occupancy assay shows functional consequence, single lab\",\n      \"pmids\": [\"32973127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PIK3R3 overexpression activates the NF-κB pathway to downregulate ZO-1 expression, thereby disrupting epithelial tight junction integrity and increasing intestinal permeability; inhibition of PIK3R3 with TAT-N15 ameliorated DSS-induced intestinal permeability in mice.\",\n      \"method\": \"Overexpression and siRNA knockdown in Caco-2 cells, TEER measurement, immunoblot and immunofluorescence for tight junction proteins, in vivo DSS colitis model with PIK3R3 inhibitor\",\n      \"journal\": \"International immunopharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo experiments with defined pathway (NF-κB/ZO-1), multiple complementary methods, single lab\",\n      \"pmids\": [\"32473571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"LACTB regulates PIK3R3 activity (confirmed by immunoprecipitation) to influence PI3K/AKT/mTOR pathway activation; LACTB overexpression inhibits EMT and proliferation and promotes autophagy in colorectal cancer cells partly through PIK3R3.\",\n      \"method\": \"Immunoprecipitation, Western blot, RNA-seq, transwell/MTT assays, xenograft model\",\n      \"journal\": \"Cancer management and research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP establishing LACTB-PIK3R3 interaction, limited mechanistic follow-up, single lab\",\n      \"pmids\": [\"32636680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PIK3R3 activates both AKT and ERK signaling in sarcoma cancer stem-like cells; inhibition of PIK3R3 using shRNA reduced Nanog expression, spheroid formation, anchorage-independent growth, migration, invasion, MMP-2 secretion, and chemotherapy resistance, defining a PIK3R3/ERK/Nanog axis in sarcoma CSC phenotypes.\",\n      \"method\": \"shRNA knockdown, pharmacological inhibitors, spheroid/CSC assays, Western blot for AKT/ERK/Nanog, xenograft invasion assay, chemotherapy resistance assay\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal functional readouts with defined signaling pathway (PIK3R3/ERK/Nanog), single lab\",\n      \"pmids\": [\"34321458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"KMT2C promotes PIK3R3 transcription by regulating histone H3K4me3 enrichment at the PIK3R3 promoter and H3K4me1 at the enhancer; the resulting PIK3R3/AKT/NF-κB signaling drives keratinocyte hyperproliferation and cytokine secretion in psoriasiform inflammation.\",\n      \"method\": \"ChIP for histone marks at PIK3R3 promoter/enhancer, KMT2C knockdown with phenotypic and downstream signaling readouts, in vivo mouse psoriasis model\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — ChIP directly demonstrates epigenetic regulation of PIK3R3 promoter by KMT2C, in vitro and in vivo validation, single lab\",\n      \"pmids\": [\"35870559\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"PIK3R3 activates AKT signaling to control liver cancer cell growth; PIK3R3 knockdown upregulates CDKN1C (a cyclin-dependent kinase inhibitor) and reduces SMC1A; immunoprecipitation demonstrated indirect interactions between PIK3R3 and CDKN1C or SMC1A, and rescue of CDKN1C or SMC1A reversed PIK3R3 knockdown-induced growth inhibition.\",\n      \"method\": \"siRNA and lentivirus overexpression, colony formation/EdU/flow cytometry assays, xenograft model, RNA sequencing, rescue assays, immunoprecipitation\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, RNA-seq, and rescue experiments across multiple readouts; single lab\",\n      \"pmids\": [\"37212524\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"MCT4 overexpression promotes L929 fibroblast cell migration via activation of an IGF1/IGF1R/PIK3R3/SGK1 signaling axis; inhibition of IGF1R or SGK1 mitigated MCT4-promoted migration, placing PIK3R3 in this upstream signaling cascade.\",\n      \"method\": \"RNA sequencing, RT-qPCR, Western blot, wound healing assay, IGF1R/SGK1 inhibitor experiments\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement inferred from inhibitor experiments and expression, single lab, no direct PIK3R3 manipulation\",\n      \"pmids\": [\"37745980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"VHL governs m6A modification of PIK3R3 mRNA by orchestrating assembly of m6A writer proteins METTL3 and METTL14, stabilizing PIK3R3 mRNA; PIK3R3 contributes to p85 ubiquitination, which restrains PI3K/AKT signaling and impedes clear cell renal cell carcinoma (ccRCC) growth.\",\n      \"method\": \"m6A transcriptome profiling (MeRIP-seq), METTL3/METTL14 complex assembly assays, p85 ubiquitination assay, cell and mouse models (referenced study reviewed in this paper)\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — m6A profiling and mechanistic dissection of VHL-METTL3/14-PIK3R3-p85 axis with in vitro and in vivo validation; cited as a peer-reviewed finding in JCI commentary\",\n      \"pmids\": [\"38618953\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FTO demethylates m6A on PIK3R3 mRNA, decreasing its m6A level and affecting FoxO pathway activation; FTO knockdown increases PIK3R3 m6A modification (detected by MeRIP-seq/qPCR), and PIK3R3 upregulation restores cervical cancer cell malignancy reduced by FTO knockdown.\",\n      \"method\": \"MeRIP-seq and MeRIP-qPCR for m6A profiling, lentivirus-mediated FTO overexpression/knockdown, rescue assay with PIK3R3 overexpression, in vitro and in vivo functional assays\",\n      \"journal\": \"Cancer medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct m6A profiling links FTO to PIK3R3 mRNA modification; rescue experiment confirms mechanistic relevance; single lab\",\n      \"pmids\": [\"39692250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"POU2F1 binds the miR-29b1/a cluster promoter to suppress miR-29b-3p and miR-29a-3p expression; these miRNAs directly target PIK3R3 (and PIK3R1); PIK3R1 and PIK3R3 interact with each other (co-immunoprecipitation) and jointly regulate GC cell invasion/migration via PI3K/AKT/mTOR signaling.\",\n      \"method\": \"Co-immunoprecipitation (PIK3R1–PIK3R3 interaction), luciferase 3'-UTR assay, promoter analysis, rescue experiments, in vivo metastasis model, Western blot\",\n      \"journal\": \"Chinese medical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP demonstrates PIK3R1-PIK3R3 complex; 3'UTR luciferase validates miRNA targeting; in vivo confirmation; single lab\",\n      \"pmids\": [\"39183556\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"ZSTK474 (a PI3K inhibitor) targets PIK3R3 to induce G0/G1 phase arrest in Wilms' tumor cells; PIK3R3 knockdown confirmed that ZSTK474 acts by downregulating PIK3R3, reducing AKT phosphorylation, cyclin D, and CDK4 levels and elevating p21 expression.\",\n      \"method\": \"PIK3R3 siRNA knockdown, CCK-8, flow cytometry cell cycle assay, Western blot for AKT phosphorylation/cyclin D/CDK4/p21, in vivo xenograft model\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD confirms mechanism of drug action with defined downstream signaling (AKT/cyclin D/CDK4/p21), in vitro and in vivo, single lab\",\n      \"pmids\": [\"39466763\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"PIK3R3 regulates differentiation and senescence of human periodontal ligament stem cells (hPDLSCs) by modulating FOXO1 expression; PIK3R3 knockdown promotes senescence and inhibits multi-lineage differentiation, while PIK3R3 overexpression has opposite effects; FOXO1 knockdown promotes senescence and weakens the senescence-promoting effect of PIK3R3 knockdown, establishing PIK3R3–FOXO1 as a regulatory axis.\",\n      \"method\": \"shRNA knockdown and overexpression, osteogenic/adipogenic/chondrogenic differentiation assays, senescence markers, ROS and telomerase assays, FOXO1 siRNA rescue, in vivo aged rat alveolar bone loss model (micro-CT and histology)\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KD/OE with multiple differentiation/senescence assays, epistasis via FOXO1 siRNA rescue, in vivo validation; single lab\",\n      \"pmids\": [\"39862908\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PIK3R3 (p55γ), a class IA PI3K regulatory subunit, promotes cell proliferation and survival by activating AKT/mTOR signaling; it directly binds p53 to suppress p21 transcription and block senescence; its transcription is controlled by TGF-β/NKX2.1 and KMT2C-mediated H3K4 methylation, while its mRNA stability is regulated by VHL-orchestrated m6A writer assembly (METTL3/METTL14) and FTO-mediated demethylation; PIK3R3 drives EMT via SNAI2 in colorectal cancer and via ERK1/2-ZEB1 in pancreatic cancer, and activates a PIK3R3/ERK/Nanog axis in sarcoma stem cells; it also regulates hepatic lipid metabolism through a PIK3R3-HNF4α-PPARα axis, controls intestinal barrier integrity via NF-κB/ZO-1, modulates stem cell senescence through FOXO1, and forms a functional complex with PIK3R1 to regulate PI3K/AKT/mTOR signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PIK3R3 (p55γ), a class IA PI3K regulatory subunit, functions as a pro-proliferative, pro-survival node that drives cell cycle progression and tumor cell invasion across multiple tissues by activating PI3K/AKT and ERK signaling [#1, #4]. Loss of PIK3R3 promotes apoptosis and imposes G0/G1 arrest with reduced Rb phosphorylation, cyclin D1, and PCNA, while restoring p21/CDKN1C and CDK4 inhibition [#0, #1, #19]. Beyond its kinase-adaptor role, PIK3R3 acts in the nucleus by physically binding p53 and blocking its occupancy of the p21 promoter, thereby suppressing senescence [#9], and it controls stem-cell differentiation and senescence through a FOXO1 axis [#20]. PIK3R3 drives epithelial-to-mesenchymal transition through context-specific effectors — SNAI2 in colorectal cancer and an ERK1/2–ZEB1 cascade in pancreatic cancer — and sustains stemness via a PIK3R3/ERK/Nanog axis in sarcoma [#2, #6, #12]. It forms a functional complex with the regulatory subunit PIK3R1 to jointly regulate PI3K/AKT/mTOR signaling [#18]. Its expression is multiply controlled: transcriptionally by NKX2.1 (repressed by TGF-β), FOXM1, and KMT2C-mediated H3K4 methylation [#3, #4, #13], and post-transcriptionally by m6A dynamics in which VHL-orchestrated METTL3/METTL14 writing and FTO demethylation tune PIK3R3 mRNA stability [#16, #17]. Outside cancer, PIK3R3 governs hepatic lipid metabolism through an HNF4α–PPARα axis and intestinal barrier integrity via NF-κB/ZO-1 [#5, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established that PIK3R3 is required for cancer cell survival, defining its first cellular phenotype as a pro-survival regulatory subunit.\",\n      \"evidence\": \"siRNA knockdown with apoptosis readout in ovarian cancer cell lines\",\n      \"pmids\": [\"17875760\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No molecular mechanism linking PIK3R3 loss to apoptosis\", \"Single cancer type, single method\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected PIK3R3 to cell cycle machinery, showing it promotes G1/S progression rather than acting solely on survival.\",\n      \"evidence\": \"siRNA knockdown with FACS cell cycle analysis and Western blot for Rb/cyclin D1/PCNA in gastric cancer cells\",\n      \"pmids\": [\"22876838\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not establish whether the effect requires PI3K catalytic activity\", \"Upstream regulators unidentified\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Defined PIK3R3 as a driver of EMT and metastasis and placed it within the TGF-β/NKX2.1 transcriptional circuit, identifying both a downstream effector (SNAI2) and an upstream control.\",\n      \"evidence\": \"OE/KD with migration/invasion and in vivo metastasis assays (colorectal); promoter-binding and rescue assays (lung adenocarcinoma)\",\n      \"pmids\": [\"24837077\", \"25371235\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct mechanistic link from PIK3R3 to SNAI2 not resolved\", \"Tissue-specific effectors not generalized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Extended PIK3R3 control of EMT/proliferation to multiple effectors (ERK1/2-ZEB1, NF-κB/TP) and identified transcriptional activators FOXM1, broadening its signaling reach beyond canonical AKT.\",\n      \"evidence\": \"ChIP, OE/KD, in vitro and in vivo assays across esophageal, pancreatic, and colorectal cancers\",\n      \"pmids\": [\"29682174\", \"29719293\", \"29370570\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ERK and AKT branches are independent or convergent is unresolved\", \"FOXM1 binding shown but functional specificity for PIK3R3 not isolated\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Demonstrated a non-oncogenic physiological role, placing PIK3R3 in hepatic lipid handling via an HNF4α-PPARα axis using in vivo gain- and loss-of-function.\",\n      \"evidence\": \"Liver-specific knockout and overexpression mouse models with metabolic phenotyping\",\n      \"pmids\": [\"29350678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PIK3R3 induces HNF4α/PPARα is undefined\", \"Relationship to canonical PI3K signaling unclear\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showed PIK3R3 abundance is post-transcriptionally tuned by non-coding RNA, linking 3'UTR-targeting miRNA machinery to AKT/NF-κB-driven malignancy.\",\n      \"evidence\": \"3'UTR binding assay, RIP-seq, functional assays, in vivo metastasis in cervical cancer\",\n      \"pmids\": [\"31474757\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"GRSF1-dependent upregulation mechanism not fully resolved\", \"Generality of miR-G-10 unknown\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed a moonlighting nuclear function: PIK3R3 binds p53 and blocks p21 promoter occupancy to suppress senescence, decoupling part of its activity from kinase-adaptor signaling.\",\n      \"evidence\": \"Co-IP, promoter occupancy assay, OE/KD with senescence markers in colorectal cancer\",\n      \"pmids\": [\"32973127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of PIK3R3-p53 binding unknown\", \"Reciprocal validation and direct binding interface not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established PIK3R3 control of epithelial barrier integrity through NF-κB/ZO-1 and validated it as a therapeutic target with a peptide inhibitor in colitis.\",\n      \"evidence\": \"OE/KD in Caco-2, TEER, immunofluorescence, in vivo DSS colitis with TAT-N15 inhibitor\",\n      \"pmids\": [\"32473571\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect NF-κB activation by PIK3R3 not separated\", \"Off-target effects of TAT-N15 not excluded\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Connected PIK3R3 to cancer stem-cell phenotypes through a PIK3R3/ERK/Nanog axis, implicating it in stemness and chemoresistance.\",\n      \"evidence\": \"shRNA, inhibitors, spheroid/CSC assays, xenograft in sarcoma\",\n      \"pmids\": [\"34321458\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How PIK3R3 selectively engages ERK vs AKT in CSCs is unclear\", \"Direct regulation of Nanog not shown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified epigenetic transcriptional control of PIK3R3 by KMT2C-deposited H3K4 methylation, linking chromatin state to PIK3R3/AKT/NF-κB-driven inflammation.\",\n      \"evidence\": \"ChIP for H3K4me3/me1, KMT2C knockdown, in vivo psoriasis mouse model\",\n      \"pmids\": [\"35870559\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether KMT2C acts directly or via intermediate factors is not resolved\", \"Generality beyond keratinocytes unknown\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Refined the proliferative mechanism, showing PIK3R3 represses CDKN1C and supports SMC1A to sustain liver cancer growth, with rescue confirming causality.\",\n      \"evidence\": \"siRNA/OE, RNA-seq, IP, rescue assays, xenograft\",\n      \"pmids\": [\"37212524\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Interactions reported as indirect; direct effectors unmapped\", \"Link to canonical PI3K activity not dissected\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established m6A as a major layer of PIK3R3 regulation, with VHL-orchestrated METTL3/METTL14 writing stabilizing the transcript and FTO demethylation modulating it, and revealed a tumor-suppressive arm in which PIK3R3 promotes p85 ubiquitination to restrain PI3K/AKT.\",\n      \"evidence\": \"MeRIP-seq, writer-complex assembly assays, p85 ubiquitination assay, FTO OE/KD rescue in ccRCC and cervical cancer\",\n      \"pmids\": [\"38618953\", \"39692250\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation of PIK3R3 oncogenic vs tumor-suppressive roles by context not resolved\", \"Direct vs indirect role in p85 ubiquitination unclear\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Demonstrated PIK3R3 forms a physical complex with PIK3R1 and that both are co-targeted by miR-29 cluster suppression, establishing a cooperative regulatory-subunit module in PI3K/AKT/mTOR signaling.\",\n      \"evidence\": \"Co-IP (PIK3R1-PIK3R3), luciferase 3'UTR assay, rescue, in vivo metastasis in gastric cancer\",\n      \"pmids\": [\"39183556\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and functional consequence of the PIK3R1-PIK3R3 complex undefined\", \"Whether they co-regulate the same catalytic subunit unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Extended PIK3R3 control of senescence to non-malignant stem cells through a FOXO1 axis, with epistasis confirming FOXO1 acts downstream.\",\n      \"evidence\": \"shRNA/OE, differentiation and senescence assays, FOXO1 siRNA rescue, in vivo aged rat model\",\n      \"pmids\": [\"39862908\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which PIK3R3 modulates FOXO1 expression not defined\", \"Relationship to the p53/p21 senescence pathway unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How PIK3R3 switches between oncogenic PI3K/AKT activation and tumor-suppressive p85 ubiquitination, and how its kinase-adaptor versus nuclear p53-binding functions are partitioned, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of PIK3R3 in complex with p110, PIK3R1, or p53\", \"Context determinants of opposing PIK3R3 functions not defined\", \"Direct enzymatic activity in p85 ubiquitination not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [4, 18, 19]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 18]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [1, 19]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [9, 20]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [3, 4, 13]}\n    ],\n    \"complexes\": [\"PI3K class IA regulatory complex (with PIK3R1)\"],\n    \"partners\": [\"PIK3R1\", \"TP53\", \"LACTB\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"tie","faith_supported":7,"faith_total":7,"faith_pct":100.0}}