{"gene":"PIK3CB","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2008,"finding":"In PTEN-deficient cancer cells, PIK3CB (p110β) but not PIK3CA (p110α) is required to sustain PI3K pathway activation and cell growth; this essential function requires the lipid kinase activity of p110β, established by shRNA-mediated selective knockdown and kinase-dead rescue in cell-based and in vivo xenograft models.","method":"Inducible shRNA knockdown (lentiviral), cell growth assays, in vivo xenograft models, kinase-dead mutant rescue","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean isoform-specific knockdown with multiple cell lines, in vivo validation, and kinase-dead mutant rescue; replicated in subsequent studies","pmids":["18755892"],"is_preprint":false},{"year":2016,"finding":"A PIK3CB D1067Y activating mutation confers resistance to pan-PI3K inhibition by elevating PIP3 levels at the cell membrane, promoting AKT and PDK1 membrane localization/activation; this mutant behaves as an oncogene and transforms normal cells, and resistance can be overcome by downstream AKT or mTORC1/2 inhibitors.","method":"Stable expression of mutant PIK3CB variants, PIP3 membrane imaging, AKT/PDK1 localization assays, cell transformation assays, pharmacological rescue with AKT/mTORC1/2 inhibitors","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (PIP3 quantification, membrane localization, transformation assay, pharmacological rescue) in a single focused study","pmids":["26759240"],"is_preprint":false},{"year":2017,"finding":"The PIK3CB catalytic domain mutant p110βE1051K (first identified in castrate-resistant prostate cancer) is a gain-of-function oncogenic mutation that drives PI3K signaling, tumorigenic cell growth, and migration; tumor cells expressing this mutant are sensitive to p110β-selective inhibition.","method":"Expression of mutant PIK3CB in cells, PI3K signaling assays, cell growth and migration assays, p110β-selective inhibitor treatment","journal":"Signal transduction and targeted therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional readouts (signaling, growth, migration, inhibitor sensitivity) in a single lab study","pmids":["29279775"],"is_preprint":false},{"year":2021,"finding":"PIK3CB (p110β) wild-type overexpression transforms MCF-10A epithelial cells through a signaling loop requiring direct binding to RAC1; p110β-induced transformation involves RAC1 hyperactivation, lamellipodia formation, and a partial EMT (E-cadherin maintained, delamination occurs), distinct from the PIK3CA H1047R-induced phenotype; a Rac1-binding mutant of p110β abolished transformation.","method":"MCF-10A overexpression model, Rac1-binding mutant of p110β (loss-of-function mutagenesis), morphological and migration assays, immunofluorescence for lamellipodia/filopodia, RAC1 activation assay, PI3K-AKT signaling assays","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — structure-function mutagenesis (Rac1-binding mutant) combined with multiple orthogonal phenotypic and biochemical readouts in a single focused study","pmids":["33526718"],"is_preprint":false},{"year":2020,"finding":"m6A methylation of PIK3CB mRNA by the METTL3/METTL14/WTAP writer complex is read by YTHDF2, suppressing PIK3CB mRNA and protein expression; a missense variant rs142933486 in PIK3CB reduces this m6A modification, elevating PIK3CB expression and activating AKT signaling to promote PTEN-deficient PDAC progression.","method":"m6A methylation assays, METTL3/METTL14/WTAP and YTHDF2 functional studies, in vitro and in vivo PDAC models, PIK3CB-selective inhibitor KIN-193 treatment","journal":"Gut","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple biochemical experiments (m6A quantification, writer/reader manipulation, in vivo) in a single lab","pmids":["32312789"],"is_preprint":false},{"year":2007,"finding":"A C/T variant (rs361072) in the PIK3CB promoter creates a GATA-binding site; the C allele drives increased PIK3CB transcription as shown by GATA-binding assays and reporter transfection, and is associated with reduced insulin resistance (lower HOMA-IR) in obese children, identifying PIK3CB as a cis-acting eQTL for insulin sensitivity.","method":"GATA-binding assays, promoter-reporter transfection in cell lines, lymphocyte expression quantification, population genetic association (HOMA-IR measurement)","journal":"Diabetes","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — functional promoter assay combined with population replication; single lab but multiple cohorts","pmids":["17977952"],"is_preprint":false},{"year":2017,"finding":"In a rat subarachnoid hemorrhage model, ErbB4 activation increases YAP expression, which in turn elevates PIK3CB levels; YAP knockdown reduces PIK3CB expression and abolishes the anti-apoptotic effect of ErbB4 activation, placing PIK3CB downstream of ErbB4/YAP in a neuroprotective signaling pathway.","method":"ErbB4 siRNA, YAP siRNA, ErbB4 activator (Nrg1β1), immunofluorescence, neurological scoring, rat SAH model","journal":"Experimental neurology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — pathway placement by siRNA epistasis in a single in vivo rat model; paper later associated with a retracted companion study (PMID:40584880) raising some concern, though this specific paper (PMID:28756200) has not been retracted","pmids":["28756200"],"is_preprint":false},{"year":2024,"finding":"PDCD4 binds to the IRES element in the 5' UTR of PIK3CB mRNA (confirmed by RNA pull-down and dual luciferase reporter assay), inhibiting PIK3CB translation; PDCD4 knockdown reduces apoptosis in multiple myeloma cells, which is rescued by PIK3CB inhibitors, indicating PDCD4 suppresses PIK3CB protein production to promote apoptosis.","method":"RNA-binding protein immunoprecipitation sequencing, dual luciferase IRES reporter assay, RNA pull-down assay, PDCD4 knockdown/overexpression, in vitro and in vivo apoptosis assays","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dual luciferase reporter + RNA pull-down + functional rescue in a single focused study with multiple orthogonal methods","pmids":["39190024"],"is_preprint":false},{"year":2024,"finding":"SP1 transcription factor binds the -771 to -605 region of the PIK3CB promoter (confirmed by ChIP and dual-luciferase assay), activating PIK3CB transcription and driving AKT activation to promote gastric cancer cell proliferation and migration.","method":"Chromatin immunoprecipitation (ChIP), dual-luciferase promoter reporter assay, PIK3CB knockdown/overexpression, SP1 knockdown, AKT phosphorylation assays, PIK3CB inhibitor TGX-221","journal":"Journal of Cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay confirm direct SP1-PIK3CB promoter binding; single lab with two orthogonal methods","pmids":["38356702"],"is_preprint":false},{"year":2021,"finding":"PIK3CB depletion inhibits invasion specifically by suppressing cell adhesion to collagen I in pancreatic cancer cells, and significantly reduces metastatic potential in vivo in nude mice.","method":"PIK3CB knockdown, collagen I adhesion assays, invasion assays, in vivo metastasis model (nude mice), bioinformatic pathway analysis","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — specific adhesion assay identifies collagen I as the substrate; in vivo validation; single lab","pmids":["34603784"],"is_preprint":false},{"year":2021,"finding":"LukS-PV induces apoptosis in AML cells by downregulating the histone methyltransferase SET8 and its product H4K20me1; ChIP-seq identified PIK3CB as a downstream transcriptional target of the SET8/H4K20me1 mark, placing PIK3CB in a SET8→H4K20me1→PIK3CB→AKT→FOXO1 apoptosis signaling axis.","method":"ChIP-seq, SET8 knockdown, H4K20me1 ChIP-PCR, LukS-PV treatment, AKT/FOXO1 signaling assays, apoptosis assays","journal":"Frontiers in oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq links H4K20me1 mark to PIK3CB promoter; multiple biochemical readouts; single lab","pmids":["34745943"],"is_preprint":false},{"year":2024,"finding":"PTK7 physically interacts with PIK3CB (confirmed by Co-IP), and USP8-mediated deubiquitination of PTK7 stabilizes PTK7 protein, which in turn positively regulates PIK3CB expression to activate the PI3K/AKT pathway and promote NSCLC malignant progression.","method":"Co-immunoprecipitation (Co-IP), PTK7/USP8 knockdown, PIK3CB overexpression rescue, western blot (PI3K/AKT), in vivo xenograft","journal":"Thoracic cancer","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP confirms interaction; functional pathway placement by rescue experiment; single lab, single Co-IP method","pmids":["39552193"],"is_preprint":false},{"year":2025,"finding":"hnRNPL forms phase-separated condensates at the PIK3CB promoter to activate PIK3CB transcription; this drives glycolysis and ovarian cancer progression. A non-coding RNA transcribed from the PIK3CB promoter itself interacts with hnRNPL and promotes hnRNPL condensation, creating a positive feedback loop.","method":"ChIP, phase separation assays, hnRNPL knockdown/overexpression, PIK3CB promoter reporter, RNA–protein interaction assays, glycolysis measurement, cell-derived xenograft and patient-derived organoid models","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (ChIP, phase separation, RNA-protein interaction, organoid) in a single lab; novel mechanism with functional consequence","pmids":["40413189"],"is_preprint":false},{"year":2018,"finding":"PIK3CB (p110β) is the dominant PI3K isoform controlling PI3K signaling in GBM cells; blocking p110β with shRNA or isoform-selective inhibitors deactivates PI3K signaling and suppresses GBM cell viability, growth, and xenograft tumor growth, whereas inhibition of other PI3K isoforms had no effect.","method":"shRNA knockdown, isoform-selective inhibitors, MTS/trypan blue viability assays, caspase activity assay, mouse xenograft models, immunoblotting","journal":"Neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic (shRNA) and pharmacological (isoform-selective inhibitor) concordance with in vivo validation; single lab","pmids":["29016844"],"is_preprint":false},{"year":2010,"finding":"In PTEN-deficient glioblastoma cells, PIK3CB knockdown (but not PIK3CA knockdown) reduces pAKT levels, inhibits proliferation, arrests cell cycle at G0/G1, and promotes caspase-dependent apoptosis; combined PTEN restoration and PIK3CB knockdown shows strong synergy in vitro and completely suppresses xenograft tumor growth.","method":"siRNA knockdown of PIK3CB vs. PIK3CA, PTEN restoration, AKT phosphorylation western blot, cell cycle analysis, apoptosis assay, nude mouse xenograft","journal":"Journal of neuro-oncology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-specific genetic epistasis with multiple functional readouts and in vivo validation; single lab","pmids":["21188471"],"is_preprint":false}],"current_model":"PIK3CB encodes the p110β catalytic subunit of class IA PI3K, which is the dominant driver of PI3K/AKT pathway activation in PTEN-deficient tumors (requiring its lipid kinase activity), can be activated by oncogenic point mutations (e.g., D1067Y, E1051K) that elevate PIP3, promote AKT/PDK1 membrane recruitment, and confer resistance to PI3K inhibitors; p110β drives a RAC1-dependent transformed phenotype distinct from p110α, its transcription is regulated by SP1 and hnRNPL phase separation, its mRNA translation is regulated by m6A methylation (METTL3/METTL14/WTAP–YTHDF2 axis) and PDCD4-mediated IRES suppression, and it signals downstream through AKT/mTOR to control cell proliferation, survival, adhesion to collagen I, and glycolysis across multiple cancer contexts."},"narrative":{"mechanistic_narrative":"PIK3CB encodes the p110β catalytic subunit of class IA PI3K and is the dominant PI3K isoform sustaining PI3K/AKT pathway activation in PTEN-deficient tumors, where its lipid kinase activity is selectively required for signaling and growth in a manner that p110α cannot substitute for [PMID:18755892, PMID:21188471]. This isoform dependence extends across cancer contexts including glioblastoma, where genetic or pharmacologic p110β blockade collapses PI3K signaling, viability, and xenograft growth [PMID:29016844, PMID:21188471]. Beyond its catalytic role, p110β drives a distinct transformed phenotype through direct binding to RAC1, producing RAC1 hyperactivation, lamellipodia, and partial EMT that diverges from the p110α H1047R program [PMID:33526718], and PIK3CB depletion blocks invasion by suppressing cell adhesion to collagen I and reduces metastasis in vivo [PMID:34603784]. Oncogenic point mutations activate the kinase: D1067Y elevates membrane PIP3 to recruit and activate AKT and PDK1, behaving as an oncogene and conferring resistance to pan-PI3K inhibition that is reversible by downstream AKT or mTORC1/2 inhibition [PMID:26759240], while the catalytic-domain E1051K mutant confers gain-of-function signaling, growth, and migration with sensitivity to p110β-selective inhibitors [PMID:29279775]. PIK3CB expression is tightly controlled at multiple layers: transcriptionally by SP1 binding the promoter [PMID:38356702] and by hnRNPL phase-separated condensates that drive glycolysis through a promoter-derived non-coding RNA feedback loop [PMID:40413189]; and translationally by m6A methylation via the METTL3/METTL14/WTAP–YTHDF2 axis [PMID:32312789] and by PDCD4 binding the PIK3CB 5'UTR IRES to suppress translation and promote apoptosis [PMID:39190024]. Downstream, p110β signals through AKT to FOXO1 and mTOR to control proliferation, survival, adhesion, and glycolysis [PMID:34745943, PMID:40413189].","teleology":[{"year":2008,"claim":"Established that PIK3CB, not PIK3CA, is the catalytically essential PI3K isoform in PTEN-deficient cancers, defining the isoform-specific therapeutic target rationale.","evidence":"Inducible isoform-specific shRNA knockdown with kinase-dead rescue in cell and xenograft models","pmids":["18755892"],"confidence":"High","gaps":["Does not resolve the structural basis of p110β preferential activation in the PTEN-null state","Mechanism of how PTEN loss shifts dependence from p110α to p110β not defined"]},{"year":2010,"claim":"Confirmed the isoform-specific p110β dependence in PTEN-deficient glioblastoma and showed synergy of PIK3CB knockdown with PTEN restoration, extending the dependence to a second tumor context with downstream cell-cycle and apoptotic readouts.","evidence":"siRNA knockdown of PIK3CB vs PIK3CA, PTEN restoration, cell cycle and apoptosis assays, nude mouse xenograft","pmids":["21188471"],"confidence":"Medium","gaps":["Single tumor type","Does not address resistance mechanisms"]},{"year":2016,"claim":"Identified PIK3CB activating mutation D1067Y as an oncogenic driver that elevates membrane PIP3 and recruits AKT/PDK1, explaining a mechanism of pan-PI3K inhibitor resistance and pointing to downstream inhibitors as a rescue strategy.","evidence":"Stable mutant expression, PIP3 membrane imaging, AKT/PDK1 localization, transformation assays, pharmacological rescue","pmids":["26759240"],"confidence":"High","gaps":["Clinical frequency of D1067Y not established by this study","Structural mechanism of constitutive activation not resolved"]},{"year":2017,"claim":"Showed the catalytic-domain mutant E1051K from castrate-resistant prostate cancer is gain-of-function and remains sensitive to p110β-selective inhibition, distinguishing it pharmacologically from pan-PI3K-resistant mutants.","evidence":"Mutant expression, PI3K signaling, growth and migration assays, p110β-selective inhibitor treatment","pmids":["29279775"],"confidence":"Medium","gaps":["Single lab study","Comparison to D1067Y resistance profile not directly addressed"]},{"year":2021,"claim":"Defined a kinase-activity-independent oncogenic mechanism: direct p110β–RAC1 binding drives a RAC1-dependent transformation program distinct from p110α H1047R, revealing functional divergence between PI3K isoforms.","evidence":"MCF-10A overexpression, Rac1-binding mutant mutagenesis, RAC1 activation and morphology assays","pmids":["33526718"],"confidence":"High","gaps":["Whether RAC1 binding cooperates with or is independent of lipid kinase activity in tumors not fully resolved","In vivo requirement of the RAC1-binding interface not tested"]},{"year":2021,"claim":"Linked PIK3CB to invasion and metastasis through a specific cell-biological output—adhesion to collagen I—rather than generic growth, identifying the relevant matrix substrate.","evidence":"PIK3CB knockdown, collagen I adhesion and invasion assays, in vivo metastasis model","pmids":["34603784"],"confidence":"Medium","gaps":["Receptor/integrin link between p110β and collagen I adhesion not defined","Single tumor type"]},{"year":2007,"claim":"First evidence for cis-regulation of PIK3CB transcription, showing a promoter variant creating a GATA site alters expression and links PIK3CB to insulin sensitivity, establishing it as a physiologically regulated eQTL beyond cancer.","evidence":"GATA-binding assays, promoter-reporter transfection, lymphocyte expression, population HOMA-IR association","pmids":["17977952"],"confidence":"Medium","gaps":["Mechanistic link between expression change and insulin signaling not dissected","Association cohort-based"]},{"year":2020,"claim":"Revealed translational/post-transcriptional control of PIK3CB by m6A methylation, with a variant that reduces methylation elevating PIK3CB and driving PTEN-deficient PDAC, connecting epitranscriptomic regulation to PI3K output.","evidence":"m6A assays, METTL3/METTL14/WTAP–YTHDF2 manipulation, in vivo PDAC models, KIN-193 treatment","pmids":["32312789"],"confidence":"Medium","gaps":["Whether m6A regulates stability vs translation not fully separated","Single lab"]},{"year":2021,"claim":"Placed PIK3CB downstream of an epigenetic SET8/H4K20me1 mark in an apoptosis axis, identifying chromatin-level transcriptional control of PIK3CB feeding AKT/FOXO1 signaling.","evidence":"ChIP-seq, SET8 knockdown, H4K20me1 ChIP-PCR, LukS-PV treatment, AKT/FOXO1 and apoptosis assays","pmids":["34745943"],"confidence":"Medium","gaps":["Direct vs indirect regulation by H4K20me1 not fully disentangled","Single cell context (AML)"]},{"year":2024,"claim":"Identified SP1 as a direct transcriptional activator binding a defined PIK3CB promoter region, providing a transcription-factor mechanism for elevated PIK3CB in gastric cancer.","evidence":"ChIP, dual-luciferase promoter reporter, SP1/PIK3CB knockdown, AKT phosphorylation, TGX-221 inhibitor","pmids":["38356702"],"confidence":"Medium","gaps":["Upstream signals regulating SP1 occupancy not defined","Single tumor type"]},{"year":2024,"claim":"Established translational repression of PIK3CB by PDCD4 binding its 5'UTR IRES, defining a tumor-suppressor brake on p110β protein production whose loss reduces apoptosis.","evidence":"RIP-seq, dual-luciferase IRES reporter, RNA pull-down, PDCD4 manipulation, apoptosis rescue with PIK3CB inhibitors","pmids":["39190024"],"confidence":"Medium","gaps":["IRES element boundaries and trans-acting factors not fully mapped","Single cell context (multiple myeloma)"]},{"year":2025,"claim":"Uncovered phase-separation-based transcriptional activation of PIK3CB by hnRNPL condensates with a promoter-derived ncRNA feedback loop, coupling PIK3CB expression to glycolytic reprogramming.","evidence":"ChIP, phase separation assays, RNA–protein interaction, glycolysis measurement, xenograft and patient-derived organoid models","pmids":["40413189"],"confidence":"Medium","gaps":["Generality of condensate mechanism beyond ovarian cancer unknown","How the ncRNA is itself regulated not defined"]},{"year":null,"claim":"How the diverse transcriptional, epitranscriptomic, and translational regulatory inputs onto PIK3CB are integrated, and how its kinase-dependent versus RAC1-binding oncogenic outputs are partitioned in vivo, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model integrating SP1, hnRNPL, m6A, and PDCD4 control of PIK3CB levels","Structural basis of p110β isoform-specific activation in PTEN-null cells not defined","Relative in vivo contribution of lipid kinase vs RAC1-binding functions unclear"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[0,1]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,8,14]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[1,2,4]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[7,10,14]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[12]}],"complexes":["class IA PI3K"],"partners":["RAC1","AKT1","PDK1","PTK7","PDCD4","HNRNPL","YTHDF2","SP1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P42338","full_name":"Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform","aliases":["Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit beta","PtdIns-3-kinase subunit p110-beta","p110beta","Serine/threonine protein kinase PIK3CB"],"length_aa":1070,"mass_kda":122.8,"function":"Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol derivatives at position 3 of the inositol ring to produce 3-phosphoinositides (PubMed:15135396). Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) (PubMed:15135396). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Involved in the activation of AKT1 upon stimulation by G-protein coupled receptors (GPCRs) ligands such as CXCL12, sphingosine 1-phosphate, and lysophosphatidic acid. May also act downstream receptor tyrosine kinases. Required in different signaling pathways for stable platelet adhesion and aggregation. Plays a role in platelet activation signaling triggered by GPCRs, alpha-IIb/beta-3 integrins (ITGA2B/ ITGB3) and ITAM (immunoreceptor tyrosine-based activation motif)-bearing receptors such as GP6. Regulates the strength of adhesion of ITGA2B/ ITGB3 activated receptors necessary for the cellular transmission of contractile forces. Required for platelet aggregation induced by F2 (thrombin) and thromboxane A2 (TXA2). Has a role in cell survival. May have a role in cell migration. Involved in the early stage of autophagosome formation. Modulates the intracellular level of PtdIns3P (phosphatidylinositol 3-phosphate) and activates PIK3C3 kinase activity. May act as a scaffold, independently of its lipid kinase activity to positively regulate autophagy. May have a role in insulin signaling as scaffolding protein in which the lipid kinase activity is not required. May have a kinase-independent function in regulating cell proliferation and in clathrin-mediated endocytosis. Mediator of oncogenic signal in cell lines lacking PTEN. The lipid kinase activity is necessary for its role in oncogenic transformation. Required for the growth of ERBB2 and RAS driven tumors. Also has a protein kinase activity showing autophosphorylation (PubMed:12502714)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P42338/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PIK3CB","classification":"Not Classified","n_dependent_lines":63,"n_total_lines":1208,"dependency_fraction":0.052152317880794705},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PIK3R1","stoichiometry":10.0},{"gene":"TPR","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/PIK3CB","total_profiled":1310},"omim":[{"mim_id":"615513","title":"IMMUNODEFICIENCY 14A WITH LYMPHOPROLIFERATION, AUTOSOMAL DOMINANT; IMD14A","url":"https://www.omim.org/entry/615513"},{"mim_id":"610235","title":"MITOCHONDRIAL FISSION PROCESS 1; MTFP1","url":"https://www.omim.org/entry/610235"},{"mim_id":"602925","title":"PHOSPHATIDYLINOSITOL 3-KINASE, CATALYTIC, BETA; PIK3CB","url":"https://www.omim.org/entry/602925"},{"mim_id":"602839","title":"PHOSPHATIDYLINOSITOL 3-KINASE, CATALYTIC, DELTA; PIK3CD","url":"https://www.omim.org/entry/602839"},{"mim_id":"188550","title":"THYROID CANCER, NONMEDULLARY, 1; NMTC1","url":"https://www.omim.org/entry/188550"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Midbody","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/PIK3CB"},"hgnc":{"alias_symbol":[],"prev_symbol":["PIK3C1"]},"alphafold":{"accession":"P42338","domains":[{"cath_id":"3.10.20.770","chopping":"1-116","consensus_level":"medium","plddt":77.2097,"start":1,"end":116},{"cath_id":"3.10.20.90","chopping":"177-294","consensus_level":"high","plddt":86.1796,"start":177,"end":294},{"cath_id":"2.60.40.150","chopping":"333-410_428-503","consensus_level":"high","plddt":88.4462,"start":333,"end":503},{"cath_id":"1.25.40.70","chopping":"506-520_537-629","consensus_level":"medium","plddt":94.2554,"start":506,"end":629},{"cath_id":"1.10.1070.11","chopping":"855-1065","consensus_level":"high","plddt":88.675,"start":855,"end":1065}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P42338","model_url":"https://alphafold.ebi.ac.uk/files/AF-P42338-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P42338-F1-predicted_aligned_error_v6.png","plddt_mean":86.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PIK3CB","jax_strain_url":"https://www.jax.org/strain/search?query=PIK3CB"},"sequence":{"accession":"P42338","fasta_url":"https://rest.uniprot.org/uniprotkb/P42338.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P42338/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P42338"}},"corpus_meta":[{"pmid":"18755892","id":"PMC_18755892","title":"PTEN-deficient cancers depend on PIK3CB.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18755892","citation_count":472,"is_preprint":false},{"pmid":"19366795","id":"PMC_19366795","title":"PIK3CA and PIK3CB inhibition produce synthetic lethality when combined with estrogen deprivation in estrogen receptor-positive breast cancer.","date":"2009","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/19366795","citation_count":176,"is_preprint":false},{"pmid":"32312789","id":"PMC_32312789","title":"N6-methyladenosine mRNA methylation of PIK3CB regulates AKT signalling to promote PTEN-deficient pancreatic cancer progression.","date":"2020","source":"Gut","url":"https://pubmed.ncbi.nlm.nih.gov/32312789","citation_count":72,"is_preprint":false},{"pmid":"16380997","id":"PMC_16380997","title":"Mutation analysis of PIK3CA and PIK3CB in esophageal cancer and Barrett's esophagus.","date":"2006","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/16380997","citation_count":70,"is_preprint":false},{"pmid":"26759240","id":"PMC_26759240","title":"Activating Mutations in PIK3CB Confer Resistance to PI3K Inhibition and Define a Novel Oncogenic Role for p110β.","date":"2016","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/26759240","citation_count":58,"is_preprint":false},{"pmid":"31629932","id":"PMC_31629932","title":"MiR-337-3p suppresses proliferation of epithelial ovarian cancer by targeting PIK3CA and PIK3CB.","date":"2019","source":"Cancer letters","url":"https://pubmed.ncbi.nlm.nih.gov/31629932","citation_count":57,"is_preprint":false},{"pmid":"29016844","id":"PMC_29016844","title":"PIK3CB/p110β is a selective survival factor for glioblastoma.","date":"2018","source":"Neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29016844","citation_count":55,"is_preprint":false},{"pmid":"16700623","id":"PMC_16700623","title":"Downregulation of PIK3CB by siRNA suppresses malignant glioma cell growth in vitro and in vivo.","date":"2006","source":"Technology in cancer research & treatment","url":"https://pubmed.ncbi.nlm.nih.gov/16700623","citation_count":47,"is_preprint":false},{"pmid":"30544563","id":"PMC_30544563","title":"Class I Phosphoinositide 3-Kinase PIK3CA/p110α and PIK3CB/p110β Isoforms in Endometrial Cancer.","date":"2018","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/30544563","citation_count":43,"is_preprint":false},{"pmid":"21188471","id":"PMC_21188471","title":"PTEN restoration and PIK3CB knockdown synergistically suppress glioblastoma growth in vitro and in xenografts.","date":"2010","source":"Journal of 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knockdown (lentiviral), cell growth assays, in vivo xenograft models, kinase-dead mutant rescue\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean isoform-specific knockdown with multiple cell lines, in vivo validation, and kinase-dead mutant rescue; replicated in subsequent studies\",\n      \"pmids\": [\"18755892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"A PIK3CB D1067Y activating mutation confers resistance to pan-PI3K inhibition by elevating PIP3 levels at the cell membrane, promoting AKT and PDK1 membrane localization/activation; this mutant behaves as an oncogene and transforms normal cells, and resistance can be overcome by downstream AKT or mTORC1/2 inhibitors.\",\n      \"method\": \"Stable expression of mutant PIK3CB variants, PIP3 membrane imaging, AKT/PDK1 localization assays, cell transformation assays, pharmacological rescue with AKT/mTORC1/2 inhibitors\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (PIP3 quantification, membrane localization, transformation assay, pharmacological rescue) in a single focused study\",\n      \"pmids\": [\"26759240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The PIK3CB catalytic domain mutant p110βE1051K (first identified in castrate-resistant prostate cancer) is a gain-of-function oncogenic mutation that drives PI3K signaling, tumorigenic cell growth, and migration; tumor cells expressing this mutant are sensitive to p110β-selective inhibition.\",\n      \"method\": \"Expression of mutant PIK3CB in cells, PI3K signaling assays, cell growth and migration assays, p110β-selective inhibitor treatment\",\n      \"journal\": \"Signal transduction and targeted therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional readouts (signaling, growth, migration, inhibitor sensitivity) in a single lab study\",\n      \"pmids\": [\"29279775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PIK3CB (p110β) wild-type overexpression transforms MCF-10A epithelial cells through a signaling loop requiring direct binding to RAC1; p110β-induced transformation involves RAC1 hyperactivation, lamellipodia formation, and a partial EMT (E-cadherin maintained, delamination occurs), distinct from the PIK3CA H1047R-induced phenotype; a Rac1-binding mutant of p110β abolished transformation.\",\n      \"method\": \"MCF-10A overexpression model, Rac1-binding mutant of p110β (loss-of-function mutagenesis), morphological and migration assays, immunofluorescence for lamellipodia/filopodia, RAC1 activation assay, PI3K-AKT signaling assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — structure-function mutagenesis (Rac1-binding mutant) combined with multiple orthogonal phenotypic and biochemical readouts in a single focused study\",\n      \"pmids\": [\"33526718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"m6A methylation of PIK3CB mRNA by the METTL3/METTL14/WTAP writer complex is read by YTHDF2, suppressing PIK3CB mRNA and protein expression; a missense variant rs142933486 in PIK3CB reduces this m6A modification, elevating PIK3CB expression and activating AKT signaling to promote PTEN-deficient PDAC progression.\",\n      \"method\": \"m6A methylation assays, METTL3/METTL14/WTAP and YTHDF2 functional studies, in vitro and in vivo PDAC models, PIK3CB-selective inhibitor KIN-193 treatment\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple biochemical experiments (m6A quantification, writer/reader manipulation, in vivo) in a single lab\",\n      \"pmids\": [\"32312789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A C/T variant (rs361072) in the PIK3CB promoter creates a GATA-binding site; the C allele drives increased PIK3CB transcription as shown by GATA-binding assays and reporter transfection, and is associated with reduced insulin resistance (lower HOMA-IR) in obese children, identifying PIK3CB as a cis-acting eQTL for insulin sensitivity.\",\n      \"method\": \"GATA-binding assays, promoter-reporter transfection in cell lines, lymphocyte expression quantification, population genetic association (HOMA-IR measurement)\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — functional promoter assay combined with population replication; single lab but multiple cohorts\",\n      \"pmids\": [\"17977952\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In a rat subarachnoid hemorrhage model, ErbB4 activation increases YAP expression, which in turn elevates PIK3CB levels; YAP knockdown reduces PIK3CB expression and abolishes the anti-apoptotic effect of ErbB4 activation, placing PIK3CB downstream of ErbB4/YAP in a neuroprotective signaling pathway.\",\n      \"method\": \"ErbB4 siRNA, YAP siRNA, ErbB4 activator (Nrg1β1), immunofluorescence, neurological scoring, rat SAH model\",\n      \"journal\": \"Experimental neurology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — pathway placement by siRNA epistasis in a single in vivo rat model; paper later associated with a retracted companion study (PMID:40584880) raising some concern, though this specific paper (PMID:28756200) has not been retracted\",\n      \"pmids\": [\"28756200\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PDCD4 binds to the IRES element in the 5' UTR of PIK3CB mRNA (confirmed by RNA pull-down and dual luciferase reporter assay), inhibiting PIK3CB translation; PDCD4 knockdown reduces apoptosis in multiple myeloma cells, which is rescued by PIK3CB inhibitors, indicating PDCD4 suppresses PIK3CB protein production to promote apoptosis.\",\n      \"method\": \"RNA-binding protein immunoprecipitation sequencing, dual luciferase IRES reporter assay, RNA pull-down assay, PDCD4 knockdown/overexpression, in vitro and in vivo apoptosis assays\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dual luciferase reporter + RNA pull-down + functional rescue in a single focused study with multiple orthogonal methods\",\n      \"pmids\": [\"39190024\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SP1 transcription factor binds the -771 to -605 region of the PIK3CB promoter (confirmed by ChIP and dual-luciferase assay), activating PIK3CB transcription and driving AKT activation to promote gastric cancer cell proliferation and migration.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), dual-luciferase promoter reporter assay, PIK3CB knockdown/overexpression, SP1 knockdown, AKT phosphorylation assays, PIK3CB inhibitor TGX-221\",\n      \"journal\": \"Journal of Cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay confirm direct SP1-PIK3CB promoter binding; single lab with two orthogonal methods\",\n      \"pmids\": [\"38356702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"PIK3CB depletion inhibits invasion specifically by suppressing cell adhesion to collagen I in pancreatic cancer cells, and significantly reduces metastatic potential in vivo in nude mice.\",\n      \"method\": \"PIK3CB knockdown, collagen I adhesion assays, invasion assays, in vivo metastasis model (nude mice), bioinformatic pathway analysis\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — specific adhesion assay identifies collagen I as the substrate; in vivo validation; single lab\",\n      \"pmids\": [\"34603784\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LukS-PV induces apoptosis in AML cells by downregulating the histone methyltransferase SET8 and its product H4K20me1; ChIP-seq identified PIK3CB as a downstream transcriptional target of the SET8/H4K20me1 mark, placing PIK3CB in a SET8→H4K20me1→PIK3CB→AKT→FOXO1 apoptosis signaling axis.\",\n      \"method\": \"ChIP-seq, SET8 knockdown, H4K20me1 ChIP-PCR, LukS-PV treatment, AKT/FOXO1 signaling assays, apoptosis assays\",\n      \"journal\": \"Frontiers in oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq links H4K20me1 mark to PIK3CB promoter; multiple biochemical readouts; single lab\",\n      \"pmids\": [\"34745943\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PTK7 physically interacts with PIK3CB (confirmed by Co-IP), and USP8-mediated deubiquitination of PTK7 stabilizes PTK7 protein, which in turn positively regulates PIK3CB expression to activate the PI3K/AKT pathway and promote NSCLC malignant progression.\",\n      \"method\": \"Co-immunoprecipitation (Co-IP), PTK7/USP8 knockdown, PIK3CB overexpression rescue, western blot (PI3K/AKT), in vivo xenograft\",\n      \"journal\": \"Thoracic cancer\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP confirms interaction; functional pathway placement by rescue experiment; single lab, single Co-IP method\",\n      \"pmids\": [\"39552193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"hnRNPL forms phase-separated condensates at the PIK3CB promoter to activate PIK3CB transcription; this drives glycolysis and ovarian cancer progression. A non-coding RNA transcribed from the PIK3CB promoter itself interacts with hnRNPL and promotes hnRNPL condensation, creating a positive feedback loop.\",\n      \"method\": \"ChIP, phase separation assays, hnRNPL knockdown/overexpression, PIK3CB promoter reporter, RNA–protein interaction assays, glycolysis measurement, cell-derived xenograft and patient-derived organoid models\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (ChIP, phase separation, RNA-protein interaction, organoid) in a single lab; novel mechanism with functional consequence\",\n      \"pmids\": [\"40413189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PIK3CB (p110β) is the dominant PI3K isoform controlling PI3K signaling in GBM cells; blocking p110β with shRNA or isoform-selective inhibitors deactivates PI3K signaling and suppresses GBM cell viability, growth, and xenograft tumor growth, whereas inhibition of other PI3K isoforms had no effect.\",\n      \"method\": \"shRNA knockdown, isoform-selective inhibitors, MTS/trypan blue viability assays, caspase activity assay, mouse xenograft models, immunoblotting\",\n      \"journal\": \"Neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic (shRNA) and pharmacological (isoform-selective inhibitor) concordance with in vivo validation; single lab\",\n      \"pmids\": [\"29016844\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In PTEN-deficient glioblastoma cells, PIK3CB knockdown (but not PIK3CA knockdown) reduces pAKT levels, inhibits proliferation, arrests cell cycle at G0/G1, and promotes caspase-dependent apoptosis; combined PTEN restoration and PIK3CB knockdown shows strong synergy in vitro and completely suppresses xenograft tumor growth.\",\n      \"method\": \"siRNA knockdown of PIK3CB vs. PIK3CA, PTEN restoration, AKT phosphorylation western blot, cell cycle analysis, apoptosis assay, nude mouse xenograft\",\n      \"journal\": \"Journal of neuro-oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-specific genetic epistasis with multiple functional readouts and in vivo validation; single lab\",\n      \"pmids\": [\"21188471\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PIK3CB encodes the p110β catalytic subunit of class IA PI3K, which is the dominant driver of PI3K/AKT pathway activation in PTEN-deficient tumors (requiring its lipid kinase activity), can be activated by oncogenic point mutations (e.g., D1067Y, E1051K) that elevate PIP3, promote AKT/PDK1 membrane recruitment, and confer resistance to PI3K inhibitors; p110β drives a RAC1-dependent transformed phenotype distinct from p110α, its transcription is regulated by SP1 and hnRNPL phase separation, its mRNA translation is regulated by m6A methylation (METTL3/METTL14/WTAP–YTHDF2 axis) and PDCD4-mediated IRES suppression, and it signals downstream through AKT/mTOR to control cell proliferation, survival, adhesion to collagen I, and glycolysis across multiple cancer contexts.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PIK3CB encodes the p110β catalytic subunit of class IA PI3K and is the dominant PI3K isoform sustaining PI3K/AKT pathway activation in PTEN-deficient tumors, where its lipid kinase activity is selectively required for signaling and growth in a manner that p110α cannot substitute for [#0, #14]. This isoform dependence extends across cancer contexts including glioblastoma, where genetic or pharmacologic p110β blockade collapses PI3K signaling, viability, and xenograft growth [#13, #14]. Beyond its catalytic role, p110β drives a distinct transformed phenotype through direct binding to RAC1, producing RAC1 hyperactivation, lamellipodia, and partial EMT that diverges from the p110α H1047R program [#3], and PIK3CB depletion blocks invasion by suppressing cell adhesion to collagen I and reduces metastasis in vivo [#9]. Oncogenic point mutations activate the kinase: D1067Y elevates membrane PIP3 to recruit and activate AKT and PDK1, behaving as an oncogene and conferring resistance to pan-PI3K inhibition that is reversible by downstream AKT or mTORC1/2 inhibition [#1], while the catalytic-domain E1051K mutant confers gain-of-function signaling, growth, and migration with sensitivity to p110β-selective inhibitors [#2]. PIK3CB expression is tightly controlled at multiple layers: transcriptionally by SP1 binding the promoter [#8] and by hnRNPL phase-separated condensates that drive glycolysis through a promoter-derived non-coding RNA feedback loop [#12]; and translationally by m6A methylation via the METTL3/METTL14/WTAP–YTHDF2 axis [#4] and by PDCD4 binding the PIK3CB 5'UTR IRES to suppress translation and promote apoptosis [#7]. Downstream, p110β signals through AKT to FOXO1 and mTOR to control proliferation, survival, adhesion, and glycolysis [#10, #12].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established that PIK3CB, not PIK3CA, is the catalytically essential PI3K isoform in PTEN-deficient cancers, defining the isoform-specific therapeutic target rationale.\",\n      \"evidence\": \"Inducible isoform-specific shRNA knockdown with kinase-dead rescue in cell and xenograft models\",\n      \"pmids\": [\"18755892\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not resolve the structural basis of p110β preferential activation in the PTEN-null state\", \"Mechanism of how PTEN loss shifts dependence from p110α to p110β not defined\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Confirmed the isoform-specific p110β dependence in PTEN-deficient glioblastoma and showed synergy of PIK3CB knockdown with PTEN restoration, extending the dependence to a second tumor context with downstream cell-cycle and apoptotic readouts.\",\n      \"evidence\": \"siRNA knockdown of PIK3CB vs PIK3CA, PTEN restoration, cell cycle and apoptosis assays, nude mouse xenograft\",\n      \"pmids\": [\"21188471\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single tumor type\", \"Does not address resistance mechanisms\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified PIK3CB activating mutation D1067Y as an oncogenic driver that elevates membrane PIP3 and recruits AKT/PDK1, explaining a mechanism of pan-PI3K inhibitor resistance and pointing to downstream inhibitors as a rescue strategy.\",\n      \"evidence\": \"Stable mutant expression, PIP3 membrane imaging, AKT/PDK1 localization, transformation assays, pharmacological rescue\",\n      \"pmids\": [\"26759240\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Clinical frequency of D1067Y not established by this study\", \"Structural mechanism of constitutive activation not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed the catalytic-domain mutant E1051K from castrate-resistant prostate cancer is gain-of-function and remains sensitive to p110β-selective inhibition, distinguishing it pharmacologically from pan-PI3K-resistant mutants.\",\n      \"evidence\": \"Mutant expression, PI3K signaling, growth and migration assays, p110β-selective inhibitor treatment\",\n      \"pmids\": [\"29279775\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab study\", \"Comparison to D1067Y resistance profile not directly addressed\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a kinase-activity-independent oncogenic mechanism: direct p110β–RAC1 binding drives a RAC1-dependent transformation program distinct from p110α H1047R, revealing functional divergence between PI3K isoforms.\",\n      \"evidence\": \"MCF-10A overexpression, Rac1-binding mutant mutagenesis, RAC1 activation and morphology assays\",\n      \"pmids\": [\"33526718\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether RAC1 binding cooperates with or is independent of lipid kinase activity in tumors not fully resolved\", \"In vivo requirement of the RAC1-binding interface not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked PIK3CB to invasion and metastasis through a specific cell-biological output—adhesion to collagen I—rather than generic growth, identifying the relevant matrix substrate.\",\n      \"evidence\": \"PIK3CB knockdown, collagen I adhesion and invasion assays, in vivo metastasis model\",\n      \"pmids\": [\"34603784\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Receptor/integrin link between p110β and collagen I adhesion not defined\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"First evidence for cis-regulation of PIK3CB transcription, showing a promoter variant creating a GATA site alters expression and links PIK3CB to insulin sensitivity, establishing it as a physiologically regulated eQTL beyond cancer.\",\n      \"evidence\": \"GATA-binding assays, promoter-reporter transfection, lymphocyte expression, population HOMA-IR association\",\n      \"pmids\": [\"17977952\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between expression change and insulin signaling not dissected\", \"Association cohort-based\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Revealed translational/post-transcriptional control of PIK3CB by m6A methylation, with a variant that reduces methylation elevating PIK3CB and driving PTEN-deficient PDAC, connecting epitranscriptomic regulation to PI3K output.\",\n      \"evidence\": \"m6A assays, METTL3/METTL14/WTAP–YTHDF2 manipulation, in vivo PDAC models, KIN-193 treatment\",\n      \"pmids\": [\"32312789\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether m6A regulates stability vs translation not fully separated\", \"Single lab\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Placed PIK3CB downstream of an epigenetic SET8/H4K20me1 mark in an apoptosis axis, identifying chromatin-level transcriptional control of PIK3CB feeding AKT/FOXO1 signaling.\",\n      \"evidence\": \"ChIP-seq, SET8 knockdown, H4K20me1 ChIP-PCR, LukS-PV treatment, AKT/FOXO1 and apoptosis assays\",\n      \"pmids\": [\"34745943\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs indirect regulation by H4K20me1 not fully disentangled\", \"Single cell context (AML)\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified SP1 as a direct transcriptional activator binding a defined PIK3CB promoter region, providing a transcription-factor mechanism for elevated PIK3CB in gastric cancer.\",\n      \"evidence\": \"ChIP, dual-luciferase promoter reporter, SP1/PIK3CB knockdown, AKT phosphorylation, TGX-221 inhibitor\",\n      \"pmids\": [\"38356702\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Upstream signals regulating SP1 occupancy not defined\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Established translational repression of PIK3CB by PDCD4 binding its 5'UTR IRES, defining a tumor-suppressor brake on p110β protein production whose loss reduces apoptosis.\",\n      \"evidence\": \"RIP-seq, dual-luciferase IRES reporter, RNA pull-down, PDCD4 manipulation, apoptosis rescue with PIK3CB inhibitors\",\n      \"pmids\": [\"39190024\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"IRES element boundaries and trans-acting factors not fully mapped\", \"Single cell context (multiple myeloma)\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Uncovered phase-separation-based transcriptional activation of PIK3CB by hnRNPL condensates with a promoter-derived ncRNA feedback loop, coupling PIK3CB expression to glycolytic reprogramming.\",\n      \"evidence\": \"ChIP, phase separation assays, RNA–protein interaction, glycolysis measurement, xenograft and patient-derived organoid models\",\n      \"pmids\": [\"40413189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of condensate mechanism beyond ovarian cancer unknown\", \"How the ncRNA is itself regulated not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse transcriptional, epitranscriptomic, and translational regulatory inputs onto PIK3CB are integrated, and how its kinase-dependent versus RAC1-binding oncogenic outputs are partitioned in vivo, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model integrating SP1, hnRNPL, m6A, and PDCD4 control of PIK3CB levels\", \"Structural basis of p110β isoform-specific activation in PTEN-null cells not defined\", \"Relative in vivo contribution of lipid kinase vs RAC1-binding functions unclear\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 8, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [1, 2, 4]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [7, 10, 14]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [12]}\n    ],\n    \"complexes\": [\"class IA PI3K\"],\n    \"partners\": [\"RAC1\", \"AKT1\", \"PDK1\", \"PTK7\", \"PDCD4\", \"hnRNPL\", \"YTHDF2\", \"SP1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}