{"gene":"PIK3CD","run_date":"2026-06-10T06:43:35","timeline":{"discoveries":[{"year":2017,"finding":"APDS1 mutations in p110δ (N334K, E525K, E1021K) activate PI3Kδ via mechanisms analogous to oncogenic mutations in p110α. An APDS2 splice mutation in p85α (Δ434-475) causes >300-fold basal activation of p110δ by disrupting inhibitory interactions from the nSH2, iSH2, and cSH2 domains of p85α, while only minimally activating p110α (~2-fold). All APDS mutations were potently inhibited by idelalisib. Mechanism established by hydrogen-deuterium exchange mass spectrometry and biochemical assays.","method":"HDX-MS, biochemical kinase assays, active-site/domain mutagenesis analysis","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro biochemical assays combined with HDX-MS structural probing, multiple mutations tested, multiple orthogonal methods in a single rigorous study","pmids":["28167755"],"is_preprint":false},{"year":2018,"finding":"Germline gain-of-function mutations in PIK3CD cause intrinsic defects in B cell class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature. These defects were rescued by leniolisib, a specific p110δ inhibitor, establishing that hyperactive PI3Kδ signaling directly suppresses AID expression and CSR.","method":"CRISPR/Cas9 knock-in mouse model, ex vivo B cell functional assays, AID expression analysis, pharmacological inhibition with leniolisib","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — knock-in mouse model plus patient cohort, pharmacological rescue, multiple orthogonal methods across two species","pmids":["30018075"],"is_preprint":false},{"year":2018,"finding":"PIK3CD gain-of-function mutations cause CD8+ T and NK cells to adopt an exhausted/senescent phenotype with increased susceptibility to reactivation-induced cell death and reduced cytotoxic killing of EBV-infected B cells. GOF B cells showed increased expression of CD48, PD-L1/2, and CD70. These findings were recapitulated in a novel mouse model.","method":"Ex vivo phenotypic and functional analysis of patient T and NK cells, novel GOF mouse model, cytotoxicity assays","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — patient cohort plus mouse model, multiple cell types, functional cytotoxicity readouts, independently replicated across two species","pmids":["29800648"],"is_preprint":false},{"year":2019,"finding":"PIK3CD gain-of-function mutations cause intrinsic dysregulation of CD4+ T cells, specifically generating follicular helper T (TFH) cells with increased PD-1, CXCR3, and IFN-γ expression and impaired B-helper function. The increase in memory and TFH cell numbers was largely T cell extrinsic, while changes in cytokine production and TFH function were cell intrinsic. GOF CD4+ T cells provided poor help for germinal center reactions.","method":"Ex vivo and in vitro patient T cell analysis, Pik3cd GOF mouse model, mixed bone marrow chimeras, in vivo immunization experiments","journal":"The Journal of allergy and clinical immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — patient cohort plus mouse model with bone marrow chimeras distinguishing cell-intrinsic vs. extrinsic effects, multiple orthogonal methods","pmids":["30738173"],"is_preprint":false},{"year":2019,"finding":"Loss-of-function mutation in PIK3CD (significantly reducing kinase activity) results in reduced AKT signaling in T cells, while calcium flux, RAS-MAPK activation, and proliferation were increased, indicating an imbalance between PLCγ1 and PI3K pathways in T cells. This imbalance was associated with accumulation of EBV-infected T cells.","method":"Functional signaling assays in patient T cells, calcium flux, RAS-MAPK activation assays","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single patient with compound mutation, signaling assays performed but findings unique to this case","pmids":["31537641"],"is_preprint":false},{"year":2012,"finding":"PIK3CD has distinct promoters that can be dynamically activated by pro-inflammatory mediators. TNFα stimulation induces p110δ expression in human endothelial cells and synovial fibroblasts (but not in leukocytes) through transcription start sites in a novel promoter region. This isoform-selective induction is cell-type specific.","method":"Promoter cloning, transcription start site mapping, TNFα stimulation assays, biochemical and bioinformatic characterization","journal":"The Biochemical journal","confidence":"High","confidence_rationale":"Tier 1 / Moderate — direct promoter cloning and functional validation in multiple cell types, biochemical characterization in a single lab with multiple methods","pmids":["22375552"],"is_preprint":false},{"year":2019,"finding":"PIK3CD overexpression promotes colorectal cancer cell growth, migration, and invasion by activating AKT, reducing GSK-3β activity, and promoting nuclear translocation of β-catenin and TCF/LEF transcriptional activity. PIK3CD-mediated effects were reversed by blockade of AKT signaling or depletion of β-catenin, placing PIK3CD upstream of the AKT/GSK-3β/β-catenin axis.","method":"siRNA knockdown, idelalisib inhibition, overexpression, AKT inhibitor rescue, β-catenin knockdown rescue, in vitro and xenograft in vivo assays","journal":"Cancer science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established via rescue experiments, multiple genetic and pharmacological perturbations in one lab","pmids":["30618098"],"is_preprint":false},{"year":2021,"finding":"A somatic PIK3CD mutation (L666P) in lymphatic endothelial cells promotes cell proliferation and migration of HUVECs and induces hyperactivation of the mTOR pathway, indicating PIK3CD as a candidate causal gene for lymphatic malformations.","method":"In vitro functional studies in HUVECs, mTOR pathway activation assays, cell proliferation and migration assays","journal":"Orphanet journal of rare diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vitro functional validation with defined readouts in a single study, single mutation","pmids":["33964933"],"is_preprint":false},{"year":2017,"finding":"In T-ALL, IKAROS binds to the promoter region of PIK3CD and functions as a transcriptional repressor. CK2 phosphorylates IKAROS, impairing its DNA-binding ability and thus de-repressing PIK3CD expression. CK2 inhibition restores IKAROS binding to the PIK3CD promoter and represses PIK3CD transcription. miR-26b was shown to directly target PIK3CD and inhibit PI3K/AKT pathway activity.","method":"ChIP assay, promoter reporter assays, CK2 inhibitor treatment, shRNA knockdown, miR-26b overexpression with luciferase reporter","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assays demonstrate direct transcriptional regulation, pharmacological and genetic perturbations in multiple models","pmids":["28280276"],"is_preprint":false},{"year":2021,"finding":"IKAROS binds to the promoter regions of PIK3CD and represses its transcription in primary T-ALL. CK2 phosphorylates IKAROS to impair its DNA-binding ability, reducing PIK3CD repression. CK2 inhibition increases IKAROS binding at the PIK3CD promoter and decreases PIK3CD and PIKFYVE transcription.","method":"ChIP assay, CK2 inhibitor treatment, promoter binding assays in primary T-ALL","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP evidence for promoter binding, pharmacological and functional validation, single lab","pmids":["33467550"],"is_preprint":false},{"year":2022,"finding":"CRISPR/Cas9 knockout of PIK3CD in the GBM cell line U87-MG reduced migration, invasion, and colony formation. PIK3CD deficiency impaired activity of PAK3 and PLEK2, molecules involved in cancer cell migration and proliferation. RNAseq analysis suggested the interaction may occur through axonogenesis signaling pathway.","method":"CRISPR/Cas9 knockout, migration/invasion assays, RT2 profiler PCR array, RNAseq, xenograft tumorigenesis assay","journal":"Laboratory investigation; a journal of technical methods and pathology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complete gene knockout with multiple functional readouts and downstream gene expression analysis in a single lab","pmids":["35851857"],"is_preprint":false},{"year":2024,"finding":"FAM76B stabilizes PIK3CD mRNA, and its loss leads to increased PIK3CD mRNA and protein levels, enhanced PI3K/Akt/NF-κB pathway activity, and increased M1 macrophage polarization. FAM76B knockout promoted M1 polarization, and FAM76B protects against IBD by inhibiting M1 macrophage polarization through this pathway in vivo.","method":"FAM76B knockout in U937 cells, mRNA stability assays, western blot, in vivo IBD model","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO plus mRNA stability assay and functional rescue in vivo, single lab","pmids":["38421448"],"is_preprint":false},{"year":2023,"finding":"USP14 regulates ATF2 expression (shown by co-immunoprecipitation), and ATF2 directly promotes PIK3CD transcription (demonstrated by dual-luciferase reporter and ChIP assays). PIK3CD overexpression rescued the inhibitory effect of USP14 knockdown on proliferation, migration, and tube formation in HG-induced HRMECs, placing PIK3CD downstream of USP14/ATF2 in diabetic retinopathy pathogenesis.","method":"Co-immunoprecipitation, dual-luciferase reporter assay, ChIP assay, siRNA knockdown, overexpression rescue experiments","journal":"Biochemical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding shown by ChIP, protein interaction by Co-IP, epistasis by rescue experiment, single lab","pmids":["36939972"],"is_preprint":false},{"year":2024,"finding":"circZNF532 recruits TAF15 (shown by RIP and RNA pull-down) to stabilize PIK3CD mRNA in HG-treated retinal endothelial cells, elevating PIK3CD expression and p-AKT levels, thereby facilitating endothelial-to-mesenchymal transition. PIK3CD overexpression partially reversed the inhibitory effect of circZNF532 silencing on EndMT, migration, and angiogenesis.","method":"RNA immunoprecipitation (RIP), RNA pull-down, mRNA stability assay (actinomycin D), siRNA knockdown, overexpression rescue","journal":"Endocrine journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP and pull-down establish direct interaction, mRNA stability confirmed, functional rescue performed, single lab","pmids":["38811189"],"is_preprint":false},{"year":2023,"finding":"An oncogenic splice variant PIK3CD-S, generated by SRSF2-mediated exon 20 skipping, lacks core inhibitor-binding residues in the catalytic domain (confirmed by molecular docking and ATP-competitive assays), resulting in constitutively activated PI3K/AKT signaling and reduced affinity for PI3Kδ inhibitors including idelalisib. SRPIN340 (SRSF2 inhibitor) re-sensitizes PIK3CD-S-expressing prostate cancer cells to idelalisib.","method":"Molecular docking, ATP-competitive assay, PI3 kinase assay, RT-PCR, Western blot, SRPIN340 treatment, cell viability assays","journal":"Cancers","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro kinase assays plus structural docking, multiple biochemical methods, single lab","pmids":["36831678"],"is_preprint":false},{"year":2023,"finding":"Genome editing of Pik3cd in retinal vascular endothelial cells using a dual rAAV CRISPR/Cas9 system driven by an endothelial-specific promoter (pICAM2) achieved 80% indel rate and 70% depletion of p110δ expression, resulting in significant decrease in Akt activation and dramatic reduction in pathological retinal angiogenesis in an oxygen-induced retinopathy mouse model.","method":"Dual rAAV1 CRISPR/Cas9 delivery with endothelial-specific promoter, indel quantification, Western blot, OIR mouse model, retinal angiogenesis assessment","journal":"Human gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo gene editing with functional angiogenesis readout and downstream signaling validation, single study","pmids":["36515172"],"is_preprint":false},{"year":2023,"finding":"TALEN-mediated correction of the mutated PIK3CD gene in APDS1 patient T cells normalized phospho-AKT levels in basal and activated conditions and restored cytotoxic functions of edited CD8+ T cells. Single-cell RNA sequencing revealed corrected transcriptomic signatures of CD8+ effector memory and proliferating T cells.","method":"TALEN-mediated gene editing, phospho-AKT measurement, cytotoxicity assays, single-cell RNA sequencing","journal":"Molecular therapy. Methods & clinical development","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gene correction with functional restoration and transcriptomic validation in patient primary cells, single lab","pmids":["38152700"],"is_preprint":false},{"year":2024,"finding":"POU2F2 promotes PIK3CD transcription by binding to its promoter (demonstrated by ChIP and luciferase reporter assays) in B lymphocytes, activating the Akt/mTOR signaling pathway. Knockdown of POU2F2 suppressed B cell proliferation, and PIK3CD overexpression reversed these effects, establishing POU2F2 as an upstream transcriptional activator of PIK3CD.","method":"ChIP assay, luciferase reporter assay, lentiviral PIK3CD silencing, Akt activator rescue, flow cytometry","journal":"Nephrology (Carlton, Vic.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct promoter binding by ChIP, functional rescue confirms epistatic relationship, single lab","pmids":["39401868"],"is_preprint":false},{"year":2025,"finding":"The PIK3CD R512W gain-of-function variant increases PIP3 accumulation and AKT phosphorylation (kinase hyperactivation confirmed). However, T cells expressing R512W paradoxically exhibit reduced IL-2 production, impaired proliferation, increased PD-1 expression, and apoptosis (exhaustion-like state). Transcriptomic analysis revealed downregulation of polyamine biosynthesis genes (Odc1, Amd1, Smox) and reduced intracellular polyamine levels. Spermidine supplementation partially rescued proliferative defects. Structural modeling suggested R512W alters the helical domain conformation of p110δ.","method":"Overexpression in murine T cell line, PIP3 accumulation assay, AKT phosphorylation assay, transcriptomic analysis, intracellular polyamine measurement, spermidine rescue, in silico structural modeling","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional kinase assay plus transcriptomics plus metabolic rescue, multiple orthogonal methods, single lab","pmids":["40694900"],"is_preprint":false},{"year":2026,"finding":"CAR-adapted base-editing screen of PIK3CD identified specific point mutations with distinct functional effects: the PI3Kδ-activating substitution E81K enhanced proliferation, metabolic fitness, and effector function of 4-1BBz CAR T cells, promoting long-term functional persistence and enhanced therapeutic efficacy in vivo; the PI3Kδ-attenuating substitution L32P improved T cell memory formation and functionality of 28z CAR T cells.","method":"CAR-adapted base-editing screen, in vitro T cell functional assays (proliferation, metabolic fitness, effector function), in vivo therapeutic efficacy models","journal":"Nature cancer","confidence":"High","confidence_rationale":"Tier 1 / Moderate — systematic base-editing screen with in vitro and in vivo validation, distinct mutations with opposing effects in defined CAR contexts, multiple orthogonal readouts","pmids":["41495526"],"is_preprint":false},{"year":2025,"finding":"In APDS1, loss of naïve T cells is driven extrinsically by PI3K GOF T cells, while the increase in Tfh cells is mediated by dysregulated PI3K GOF B cells (not macrophages or DCs). PI3K GOF Tregs did not acquire an inflammatory phenotype driving T cell activation. This cell-type-specific epistasis was established using a mouse model of APDS1.","method":"Mouse model of APDS1, bone marrow transfer, cell-type-specific depletion/reconstitution experiments, in vivo T cell phenotyping","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis determined via cell-type-specific reconstitution in mouse model, preprint not yet peer-reviewed","pmids":["bio_10.1101_2024.08.04.606503"],"is_preprint":true},{"year":2001,"finding":"The mouse p110δ gene (PIK3CD ortholog) consists of 22 exons spanning over 13 kb and shares its exon structure with p110β, its closest PI3K family member at the amino acid level.","method":"Genomic library cloning, sequencing, and structural organization analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct genomic sequencing and structural determination, single study, foundational structural characterization","pmids":["11162674"],"is_preprint":false},{"year":2018,"finding":"Activated PIK3CD (E1021K GOF mutation) drives expansion of innate B1a and marginal zone B cells while causing bone marrow B lymphopenia. GOF B cells show increased pS6 and survival at multiple developmental stages. Mb1-aPIK3CD mice exhibited blunted T cell-independent immune responses and reduced class-switched antibodies following T cell-dependent immunization.","method":"Inducible mouse model with B cell-specific Cre lines (Mb1-Cre, CD21-Cre, AID-Cre), flow cytometry, immunization experiments, ELISA for Ig isotypes","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — inducible cell-type-specific mouse model with multiple Cre lines, multiple orthogonal functional readouts, in vivo immunization challenge","pmids":["30194267"],"is_preprint":false},{"year":2024,"finding":"PIK3CD transcription in gastric cancer is upregulated by the pro-inflammatory IL2/JAK3/STAT5 signaling axis and tumor-infiltrating lymphocytes. Genetic silencing of PIK3CD retards proliferation and migration in vitro and tumorigenicity and metastasis in vivo. PIK3CD, but not PIK3CA or PIK3CB, is selectively regulated by this inflammatory pathway.","method":"siRNA knockdown, overexpression, pharmacological PIK3CD inhibition, in vivo xenograft, STAT5 pathway inhibition, qRT-PCR, IHC","journal":"Journal of cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — isoform-selective transcriptional regulation shown by pathway inhibition and genetic perturbations, functional in vivo readout, single lab","pmids":["38545256"],"is_preprint":false},{"year":2026,"finding":"Hyperactive p110δ (PIK3CD GOF) increases the proportion of splenic marginal zone B cell precursors with enhanced surface ADAM10 levels as early as the T1 stage of B cell development. ADAM10 inhibition suppresses marginal zone B cell differentiation and partially reverses the T1/T2 stage imbalance, placing ADAM10 downstream of PIK3CD GOF in marginal zone B cell development.","method":"Mouse model of activated PI3Kδ syndrome, ADAM10 inhibitor treatment, single-cell RNA sequencing (scRNA-seq), flow cytometry","journal":"Inflammation research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pharmacological epistasis with scRNA-seq validation in mouse model, single lab","pmids":["42228175"],"is_preprint":false}],"current_model":"PIK3CD encodes p110δ, the catalytic subunit of class IA PI3Kδ, which is maintained in a basally inhibited state through interactions with p85α regulatory subunit domains (nSH2, iSH2, cSH2); gain-of-function mutations disrupt these inhibitory contacts to hyperactivate PI3Kδ, driving downstream AKT/mTOR signaling that governs lymphocyte development (B cell CSR via AID suppression, CD8+ T cell exhaustion, TFH dysregulation, marginal zone B cell expansion via ADAM10), while PIK3CD transcription is regulated by TNFα through a novel promoter, by IKAROS/CK2 in T-ALL, by JAK3/STAT5 in inflammation, and by POU2F2 in B cells; additionally, PIK3CD mRNA stability is regulated post-transcriptionally by FAM76B and TAF15/circZNF532, and specific point mutations in p110δ modulate CAR T cell metabolic fitness and memory in a CAR design-specific manner."},"narrative":{"mechanistic_narrative":"PIK3CD encodes p110δ, the catalytic subunit of class IA PI3Kδ, which generates PIP3 to drive AKT/mTOR signaling and governs lymphocyte development and function [PMID:28167755, PMID:30194267]. The enzyme is held in a basally inhibited state through inhibitory contacts from the nSH2, iSH2, and cSH2 domains of the p85α regulatory subunit; gain-of-function mutations in p110δ (N334K, E525K, E1021K) and a p85α splice variant (Δ434-475) disrupt these contacts to hyperactivate the kinase—isoform-selectively for p110δ—and all are inhibited by idelalisib [PMID:28167755]. Hyperactive PI3Kδ (activated PI3Kδ syndrome) produces broad immune dysregulation: it suppresses activation-induced cytidine deaminase to impair B cell class-switch recombination [PMID:30018075], drives CD8+ T and NK cells toward an exhausted/senescent phenotype with reduced cytotoxicity against EBV-infected cells [PMID:29800648], generates dysregulated follicular helper T cells with poor B-helper function [PMID:30738173], and expands innate B1a and marginal zone B cells—the latter via enhanced surface ADAM10 from early developmental stages [PMID:30194267, PMID:42228175]. Cell-type-specific reconstitution shows these effects are partitioned: GOF T cells drive naïve T cell loss while GOF B cells drive Tfh expansion [PMID:30738173, PMID:bio_10.1101_2024.08.04.606503]. Beyond immune cells, PIK3CD is overexpressed or hyperactivated in cancers where it promotes proliferation, migration, and invasion through the AKT/GSK-3β/β-catenin axis in colorectal cancer [PMID:30618098] and an SRSF2-generated inhibitor-resistant splice variant (PIK3CD-S) in prostate cancer [PMID:36831678]. PIK3CD transcription is controlled by multiple inputs—a TNFα-responsive promoter in non-leukocytes [PMID:22375552], IKAROS repression relieved by CK2 phosphorylation in T-ALL [PMID:28280276], the IL2/JAK3/STAT5 axis in gastric cancer [PMID:38545256], and POU2F2 in B cells [PMID:39401868]—while mRNA stability is regulated post-transcriptionally by FAM76B and by circZNF532/TAF15 [PMID:38421448, PMID:38811189]. Engineered p110δ point mutations tune CAR T cell metabolic fitness and memory in a CAR-design-specific manner [#20-context, #19].","teleology":[{"year":2001,"claim":"Establishing the genomic structure of the p110δ gene provided the foundation for understanding it as a distinct class IA PI3K catalytic subunit related to p110β.","evidence":"Genomic library cloning and structural organization analysis of the mouse ortholog","pmids":["11162674"],"confidence":"Medium","gaps":["Does not address protein function or regulation","Ortholog-based; human gene structure not directly characterized here"]},{"year":2012,"claim":"It was unknown how PIK3CD expression is induced in non-hematopoietic cells; this showed a distinct TNFα-responsive promoter drives isoform-selective p110δ induction in endothelial and synovial cells.","evidence":"Promoter cloning, transcription start site mapping, and TNFα stimulation in human cell types","pmids":["22375552"],"confidence":"High","gaps":["Downstream functional consequence of induced p110δ not established","Transcription factors acting at this promoter not identified"]},{"year":2017,"claim":"The biochemical basis of activated PI3Kδ syndrome was unresolved; this defined that APDS mutations disrupt p85α inhibitory domain contacts to hyperactivate p110δ isoform-selectively while remaining idelalisib-sensitive.","evidence":"HDX-MS, biochemical kinase assays, and domain mutagenesis of APDS1/APDS2 mutations","pmids":["28167755"],"confidence":"High","gaps":["Cellular/immune consequences not addressed in this biochemical study","Full structural model of activated complex not resolved"]},{"year":2017,"claim":"It was unclear how PIK3CD is transcriptionally controlled in leukemia; ChIP and reporter assays established IKAROS as a direct repressor relieved by CK2 phosphorylation, with miR-26b as an additional negative regulator.","evidence":"ChIP, promoter reporter assays, CK2 inhibition, and miR-26b luciferase reporter in T-ALL","pmids":["28280276"],"confidence":"Medium","gaps":["Relative contribution of IKAROS vs miR-26b to PIK3CD levels not quantified","Single disease context"]},{"year":2018,"claim":"How PIK3CD GOF impairs humoral immunity was unknown; a knock-in mouse showed hyperactive PI3Kδ suppresses AID induction and class-switch recombination, reversibly with leniolisib.","evidence":"CRISPR/Cas9 knock-in mouse, ex vivo B cell assays, AID analysis, pharmacological rescue","pmids":["30018075"],"confidence":"High","gaps":["Molecular link between AKT/mTOR and AID transcription not mapped","Plasmablast differentiation block mechanism not detailed"]},{"year":2018,"claim":"The cytotoxic-cell phenotype in APDS was undefined; patient and mouse data established that GOF drives CD8+ T/NK exhaustion and impaired killing of EBV-infected B cells.","evidence":"Patient T/NK cell phenotyping, GOF mouse model, cytotoxicity assays","pmids":["29800648"],"confidence":"High","gaps":["Mechanism linking PI3Kδ hyperactivity to senescence/exhaustion program not resolved","Reversibility not tested here"]},{"year":2018,"claim":"The effect of PIK3CD GOF on innate B cell compartments was unknown; an inducible model showed expansion of B1a and marginal zone B cells with developmental B lymphopenia and blunted antibody responses.","evidence":"Inducible B cell-specific Cre mouse models, flow cytometry, immunization, Ig ELISA","pmids":["30194267"],"confidence":"High","gaps":["Stage-specific signaling thresholds not defined","Effector mechanism downstream of pS6 not identified at this stage"]},{"year":2019,"claim":"Whether TFH defects in APDS were cell-intrinsic was unresolved; chimera experiments separated intrinsic cytokine/TFH-function defects from extrinsic expansion of memory/TFH numbers.","evidence":"Patient T cell analysis, GOF mouse, mixed bone marrow chimeras, in vivo immunization","pmids":["30738173"],"confidence":"High","gaps":["Molecular driver of impaired B-helper function not identified","Antigen-specific GC dynamics not fully resolved"]},{"year":2019,"claim":"The consequence of PIK3CD loss-of-function was unknown; a patient case showed reduced AKT signaling with compensatory increases in calcium flux and RAS-MAPK, indicating a PLCγ1/PI3K imbalance permitting EBV-infected T cell accumulation.","evidence":"Signaling assays in patient T cells, calcium flux, RAS-MAPK assays","pmids":["31537641"],"confidence":"Medium","gaps":["Single patient with compound mutation limits generalizability","Mechanism of pathway imbalance not reconstituted"]},{"year":2019,"claim":"A role for PIK3CD outside immunity was tested; in colorectal cancer it acts upstream of an AKT/GSK-3β/β-catenin axis to promote growth and invasion.","evidence":"siRNA, idelalisib, overexpression, AKT-inhibitor and β-catenin-knockdown rescue, xenografts","pmids":["30618098"],"confidence":"Medium","gaps":["Cause of PIK3CD overexpression in CRC not established here","Single tumor type"]},{"year":2021,"claim":"PIK3CD's candidacy in non-immune disease was extended; a somatic L666P variant in lymphatic endothelial cells hyperactivates mTOR and promotes proliferation/migration, implicating it in lymphatic malformations.","evidence":"In vitro HUVEC functional studies and mTOR activation assays","pmids":["33964933"],"confidence":"Medium","gaps":["Causality in patient tissue not demonstrated in vivo","Single mutation"]},{"year":2022,"claim":"A pro-tumorigenic function in glioma was tested; CRISPR knockout reduced migration/invasion/colony formation and impaired PAK3 and PLEK2 activity.","evidence":"CRISPR/Cas9 knockout, migration/invasion assays, PCR array, RNAseq, xenograft","pmids":["35851857"],"confidence":"Medium","gaps":["Direct molecular link to PAK3/PLEK2 not established","Axonogenesis pathway involvement only suggested by RNAseq"]},{"year":2023,"claim":"Post-transcriptional and transcriptional regulators of PIK3CD in vascular disease were identified, including circZNF532/TAF15 stabilizing mRNA and USP14/ATF2 driving transcription to promote pathological angiogenesis.","evidence":"RIP, RNA pull-down, mRNA stability assays, Co-IP, dual-luciferase, ChIP, rescue experiments","pmids":["38811189","36939972"],"confidence":"Medium","gaps":["Relative contribution of each regulatory layer not compared","Single disease models"]},{"year":2023,"claim":"Inhibitor-resistance mechanisms were uncovered; an SRSF2-driven exon-20-skipped variant (PIK3CD-S) lacks inhibitor-binding residues, is constitutively active, and resists idelalisib but is re-sensitized by SRSF2 inhibition.","evidence":"Molecular docking, ATP-competitive and PI3 kinase assays, RT-PCR, SRPIN340 treatment","pmids":["36831678"],"confidence":"Medium","gaps":["Prevalence of PIK3CD-S across tumors not established","In vivo validation limited"]},{"year":2023,"claim":"Therapeutic correction strategies were validated; TALEN gene correction of APDS1 T cells normalized phospho-AKT and restored CD8+ cytotoxicity and transcriptomes, and endothelial-targeted CRISPR depletion reduced retinal angiogenesis.","evidence":"TALEN editing of patient cells with scRNA-seq; dual rAAV CRISPR/Cas9 in OIR mouse model","pmids":["38152700","36515172"],"confidence":"Medium","gaps":["Long-term durability and off-target effects not fully assessed","Single labs/models"]},{"year":2024,"claim":"Additional regulatory inputs and disease contexts were defined: FAM76B stabilizes PIK3CD mRNA controlling macrophage polarization and IBD; IL2/JAK3/STAT5 selectively upregulates PIK3CD in gastric cancer; POU2F2 transactivates PIK3CD in B cells.","evidence":"Knockout/mRNA-stability assays, pathway inhibition, ChIP and luciferase reporters, in vivo models","pmids":["38421448","38545256","39401868"],"confidence":"Medium","gaps":["Isoform selectivity mechanism of upstream pathways not fully explained","Cross-talk among regulators not integrated"]},{"year":2025,"claim":"Paradoxical GOF phenotypes were dissected; the R512W variant hyperactivates kinase yet causes exhaustion-like T cell dysfunction via downregulated polyamine biosynthesis, partially rescued by spermidine, and APDS1 cell-type epistasis was mapped (GOF T cells drive naïve loss, GOF B cells drive Tfh expansion).","evidence":"Overexpression, PIP3/AKT assays, transcriptomics, polyamine measurement, spermidine rescue; mouse model with cell-type-specific reconstitution (preprint)","pmids":["40694900","bio_10.1101_2024.08.04.606503"],"confidence":"Medium","gaps":["Link between p110δ activity and polyamine gene regulation not mechanistically established","Preprint epistasis findings not peer-reviewed"]},{"year":2026,"claim":"Engineering and developmental detail were added; CAR-adapted base editing showed activating (E81K) and attenuating (L32P) p110δ substitutions tune CAR T fitness and memory in CAR-design-specific ways, and ADAM10 was placed downstream of PIK3CD GOF in marginal zone B cell development.","evidence":"CAR-adapted base-editing screen with in vivo efficacy; APDS mouse model with ADAM10 inhibition and scRNA-seq","pmids":["41495526","42228175"],"confidence":"High","gaps":["Mechanism linking p110δ activity to ADAM10 surface levels not defined","Generalizability of CAR-specific mutation effects across constructs not exhaustively mapped"]},{"year":null,"claim":"The mechanism connecting PI3Kδ hyperactivity to specific downstream transcriptional and metabolic programs (AID suppression, exhaustion, polyamine and ADAM10 regulation) remains incompletely resolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking AKT/mTOR output to each cell-type-specific phenotype","Structural model of how diverse GOF mutations converge on activation not complete","Integration of the multiple transcriptional/post-transcriptional regulators into one regulatory map lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,14,18]},{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,14]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,6,18]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,2,3,22]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,6,7,14]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,8,17,23]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[11,13]}],"complexes":["class IA PI3K (p110δ/p85α)"],"partners":["PIK3R1","ADAM10"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O00329","full_name":"Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform","aliases":["Phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit delta","PtdIns-3-kinase subunit p110-delta","p110delta"],"length_aa":1044,"mass_kda":119.5,"function":"Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides (PubMed:9235916). 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. Mediates immune responses. Plays a role in B-cell development, proliferation, migration, and function. Required for B-cell receptor (BCR) signaling. Mediates B-cell proliferation response to anti-IgM, anti-CD40 and IL4 stimulation. Promotes cytokine production in response to TLR4 and TLR9. Required for antibody class switch mediated by TLR9. Involved in the antigen presentation function of B-cells. Involved in B-cell chemotaxis in response to CXCL13 and sphingosine 1-phosphate (S1P). Required for proliferation, signaling and cytokine production of naive, effector and memory T-cells. Required for T-cell receptor (TCR) signaling. Mediates TCR signaling events at the immune synapse. Activation by TCR leads to antigen-dependent memory T-cell migration and retention to antigenic tissues. Together with PIK3CG participates in T-cell development. Contributes to T-helper cell expansion and differentiation. Required for T-cell migration mediated by homing receptors SELL/CD62L, CCR7 and S1PR1 and antigen dependent recruitment of T-cells. Together with PIK3CG is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in NK cell receptor activation. Plays a role in NK cell maturation and cytokine production. Together with PIK3CG is involved in neutrophil chemotaxis and extravasation. Together with PIK3CG participates in neutrophil respiratory burst. Plays important roles in mast-cell development and mast cell mediated allergic response. Involved in stem cell factor (SCF)-mediated proliferation, adhesion and migration. Required for allergen-IgE-induced degranulation and cytokine release. The lipid kinase activity is required for its biological function. Isoform 2 may be involved in stabilizing total RAS levels, resulting in increased ERK phosphorylation and increased PI3K activity","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/O00329/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PIK3CD","classification":"Not Classified","n_dependent_lines":81,"n_total_lines":1208,"dependency_fraction":0.06705298013245033},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"PIK3R1","stoichiometry":4.0}],"url":"https://opencell.sf.czbiohub.org/search/PIK3CD","total_profiled":1310},"omim":[{"mim_id":"619281","title":"IMMUNODEFICIENCY 14B, AUTOSOMAL RECESSIVE; IMD14B","url":"https://www.omim.org/entry/619281"},{"mim_id":"616005","title":"IMMUNODEFICIENCY 36 WITH LYMPHOPROLIFERATION; IMD36","url":"https://www.omim.org/entry/616005"},{"mim_id":"615513","title":"IMMUNODEFICIENCY 14A WITH LYMPHOPROLIFERATION, AUTOSOMAL DOMINANT; IMD14A","url":"https://www.omim.org/entry/615513"},{"mim_id":"614718","title":"KINETOCHORE-LOCALIZED ASTRIN/SPAG5-BINDING PROTEIN; KNSTRN","url":"https://www.omim.org/entry/614718"},{"mim_id":"613328","title":"ROIFMAN-CHITAYAT SYNDROME; ROCHIS","url":"https://www.omim.org/entry/613328"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Microtubules","reliability":"Additional"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Primary cilium tip","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":44.2},{"tissue":"lymphoid tissue","ntpm":44.5}],"url":"https://www.proteinatlas.org/search/PIK3CD"},"hgnc":{"alias_symbol":["p110D"],"prev_symbol":[]},"alphafold":{"accession":"O00329","domains":[{"cath_id":"3.10.20.90","chopping":"20-106","consensus_level":"high","plddt":91.2933,"start":20,"end":106},{"cath_id":"3.10.20.90","chopping":"166-290","consensus_level":"medium","plddt":85.3562,"start":166,"end":290},{"cath_id":"2.60.40.150","chopping":"330-401_427-464","consensus_level":"high","plddt":92.8683,"start":330,"end":464},{"cath_id":"1.25.40.70","chopping":"487-516_524-573","consensus_level":"medium","plddt":92.2594,"start":487,"end":573},{"cath_id":"1.10.1070.11","chopping":"831-1043","consensus_level":"high","plddt":82.9446,"start":831,"end":1043}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O00329","model_url":"https://alphafold.ebi.ac.uk/files/AF-O00329-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O00329-F1-predicted_aligned_error_v6.png","plddt_mean":87.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PIK3CD","jax_strain_url":"https://www.jax.org/strain/search?query=PIK3CD"},"sequence":{"accession":"O00329","fasta_url":"https://rest.uniprot.org/uniprotkb/O00329.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O00329/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O00329"}},"corpus_meta":[{"pmid":"24610295","id":"PMC_24610295","title":"Mutations 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immunology","url":"https://pubmed.ncbi.nlm.nih.gov/39253077","citation_count":2,"is_preprint":false},{"pmid":"41026257","id":"PMC_41026257","title":"Homozygous Loss of Function PIK3CD Mutation in Multiple Siblings Leading To B Cell Dysregulation and Autoimmunity.","date":"2025","source":"Journal of clinical immunology","url":"https://pubmed.ncbi.nlm.nih.gov/41026257","citation_count":1,"is_preprint":false},{"pmid":"39401868","id":"PMC_39401868","title":"POU2F2 activates the Akt/mTOR signalling pathway and enhances B lymphocyte function during diabetic kidney disease by promoting PIK3CD transcription.","date":"2024","source":"Nephrology (Carlton, Vic.)","url":"https://pubmed.ncbi.nlm.nih.gov/39401868","citation_count":1,"is_preprint":false},{"pmid":"39932361","id":"PMC_39932361","title":"Recurrent Panuveitis as a Manifestation of a Novel PIK3CD Gene Mutation: A Diagnostic and Management Challenge.","date":"2025","source":"Ocular immunology and 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41626283","citation_count":0,"is_preprint":false},{"pmid":"38507881","id":"PMC_38507881","title":"Establishment of a non-integrated iPSC (SDQLCHi068-A) line derived from a patient with autosomal dominant immunodeficiency-14A carrying a heterozygous mutation (c.3061G>A) in PIK3CD gene.","date":"2024","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/38507881","citation_count":0,"is_preprint":false},{"pmid":"39168413","id":"PMC_39168413","title":"A Case of Dysgerminoma in a Pediatric Patient With a PIK3CD Mutation.","date":"2024","source":"Urology","url":"https://pubmed.ncbi.nlm.nih.gov/39168413","citation_count":0,"is_preprint":false},{"pmid":"41845460","id":"PMC_41845460","title":"APDS in a 3-year-old boy presenting with EBV viremia and hodgkin lymphoma associated with a novel germline heterozygous variant in PIK3CD and with characteristic immune phenotype but no upregulation of the T cell mTOR 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[et al.]","url":"https://pubmed.ncbi.nlm.nih.gov/42228175","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2024.08.04.606503","title":"Both T and B cells contribute to dysregulated activation and differentiation of CD4  <sup>+</sup>  T cells in Activated PI3K delta syndrome 1","date":"2024-08-04","source":"bioRxiv","url":"https://doi.org/10.1101/2024.08.04.606503","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.09.602796","title":"Discovery and Repurposing of Multi-Target Senolytics through Structure-Based Virtual Screening","date":"2024-07-14","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.09.602796","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":35721,"output_tokens":6501,"usd":0.102339,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15671,"output_tokens":5865,"usd":0.11249,"stage2_stop_reason":"end_turn"},"total_usd":0.214829,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2017,\n      \"finding\": \"APDS1 mutations in p110δ (N334K, E525K, E1021K) activate PI3Kδ via mechanisms analogous to oncogenic mutations in p110α. An APDS2 splice mutation in p85α (Δ434-475) causes >300-fold basal activation of p110δ by disrupting inhibitory interactions from the nSH2, iSH2, and cSH2 domains of p85α, while only minimally activating p110α (~2-fold). All APDS mutations were potently inhibited by idelalisib. Mechanism established by hydrogen-deuterium exchange mass spectrometry and biochemical assays.\",\n      \"method\": \"HDX-MS, biochemical kinase assays, active-site/domain mutagenesis analysis\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro biochemical assays combined with HDX-MS structural probing, multiple mutations tested, multiple orthogonal methods in a single rigorous study\",\n      \"pmids\": [\"28167755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Germline gain-of-function mutations in PIK3CD cause intrinsic defects in B cell class-switch recombination (CSR) due to impaired induction of activation-induced cytidine deaminase (AID) and failure to acquire a plasmablast gene signature. These defects were rescued by leniolisib, a specific p110δ inhibitor, establishing that hyperactive PI3Kδ signaling directly suppresses AID expression and CSR.\",\n      \"method\": \"CRISPR/Cas9 knock-in mouse model, ex vivo B cell functional assays, AID expression analysis, pharmacological inhibition with leniolisib\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knock-in mouse model plus patient cohort, pharmacological rescue, multiple orthogonal methods across two species\",\n      \"pmids\": [\"30018075\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"PIK3CD gain-of-function mutations cause CD8+ T and NK cells to adopt an exhausted/senescent phenotype with increased susceptibility to reactivation-induced cell death and reduced cytotoxic killing of EBV-infected B cells. GOF B cells showed increased expression of CD48, PD-L1/2, and CD70. These findings were recapitulated in a novel mouse model.\",\n      \"method\": \"Ex vivo phenotypic and functional analysis of patient T and NK cells, novel GOF mouse model, cytotoxicity assays\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — patient cohort plus mouse model, multiple cell types, functional cytotoxicity readouts, independently replicated across two species\",\n      \"pmids\": [\"29800648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PIK3CD gain-of-function mutations cause intrinsic dysregulation of CD4+ T cells, specifically generating follicular helper T (TFH) cells with increased PD-1, CXCR3, and IFN-γ expression and impaired B-helper function. The increase in memory and TFH cell numbers was largely T cell extrinsic, while changes in cytokine production and TFH function were cell intrinsic. GOF CD4+ T cells provided poor help for germinal center reactions.\",\n      \"method\": \"Ex vivo and in vitro patient T cell analysis, Pik3cd GOF mouse model, mixed bone marrow chimeras, in vivo immunization experiments\",\n      \"journal\": \"The Journal of allergy and clinical immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — patient cohort plus mouse model with bone marrow chimeras distinguishing cell-intrinsic vs. extrinsic effects, multiple orthogonal methods\",\n      \"pmids\": [\"30738173\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss-of-function mutation in PIK3CD (significantly reducing kinase activity) results in reduced AKT signaling in T cells, while calcium flux, RAS-MAPK activation, and proliferation were increased, indicating an imbalance between PLCγ1 and PI3K pathways in T cells. This imbalance was associated with accumulation of EBV-infected T cells.\",\n      \"method\": \"Functional signaling assays in patient T cells, calcium flux, RAS-MAPK activation assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single patient with compound mutation, signaling assays performed but findings unique to this case\",\n      \"pmids\": [\"31537641\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"PIK3CD has distinct promoters that can be dynamically activated by pro-inflammatory mediators. TNFα stimulation induces p110δ expression in human endothelial cells and synovial fibroblasts (but not in leukocytes) through transcription start sites in a novel promoter region. This isoform-selective induction is cell-type specific.\",\n      \"method\": \"Promoter cloning, transcription start site mapping, TNFα stimulation assays, biochemical and bioinformatic characterization\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct promoter cloning and functional validation in multiple cell types, biochemical characterization in a single lab with multiple methods\",\n      \"pmids\": [\"22375552\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PIK3CD overexpression promotes colorectal cancer cell growth, migration, and invasion by activating AKT, reducing GSK-3β activity, and promoting nuclear translocation of β-catenin and TCF/LEF transcriptional activity. PIK3CD-mediated effects were reversed by blockade of AKT signaling or depletion of β-catenin, placing PIK3CD upstream of the AKT/GSK-3β/β-catenin axis.\",\n      \"method\": \"siRNA knockdown, idelalisib inhibition, overexpression, AKT inhibitor rescue, β-catenin knockdown rescue, in vitro and xenograft in vivo assays\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established via rescue experiments, multiple genetic and pharmacological perturbations in one lab\",\n      \"pmids\": [\"30618098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A somatic PIK3CD mutation (L666P) in lymphatic endothelial cells promotes cell proliferation and migration of HUVECs and induces hyperactivation of the mTOR pathway, indicating PIK3CD as a candidate causal gene for lymphatic malformations.\",\n      \"method\": \"In vitro functional studies in HUVECs, mTOR pathway activation assays, cell proliferation and migration assays\",\n      \"journal\": \"Orphanet journal of rare diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vitro functional validation with defined readouts in a single study, single mutation\",\n      \"pmids\": [\"33964933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In T-ALL, IKAROS binds to the promoter region of PIK3CD and functions as a transcriptional repressor. CK2 phosphorylates IKAROS, impairing its DNA-binding ability and thus de-repressing PIK3CD expression. CK2 inhibition restores IKAROS binding to the PIK3CD promoter and represses PIK3CD transcription. miR-26b was shown to directly target PIK3CD and inhibit PI3K/AKT pathway activity.\",\n      \"method\": \"ChIP assay, promoter reporter assays, CK2 inhibitor treatment, shRNA knockdown, miR-26b overexpression with luciferase reporter\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assays demonstrate direct transcriptional regulation, pharmacological and genetic perturbations in multiple models\",\n      \"pmids\": [\"28280276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IKAROS binds to the promoter regions of PIK3CD and represses its transcription in primary T-ALL. CK2 phosphorylates IKAROS to impair its DNA-binding ability, reducing PIK3CD repression. CK2 inhibition increases IKAROS binding at the PIK3CD promoter and decreases PIK3CD and PIKFYVE transcription.\",\n      \"method\": \"ChIP assay, CK2 inhibitor treatment, promoter binding assays in primary T-ALL\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP evidence for promoter binding, pharmacological and functional validation, single lab\",\n      \"pmids\": [\"33467550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CRISPR/Cas9 knockout of PIK3CD in the GBM cell line U87-MG reduced migration, invasion, and colony formation. PIK3CD deficiency impaired activity of PAK3 and PLEK2, molecules involved in cancer cell migration and proliferation. RNAseq analysis suggested the interaction may occur through axonogenesis signaling pathway.\",\n      \"method\": \"CRISPR/Cas9 knockout, migration/invasion assays, RT2 profiler PCR array, RNAseq, xenograft tumorigenesis assay\",\n      \"journal\": \"Laboratory investigation; a journal of technical methods and pathology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complete gene knockout with multiple functional readouts and downstream gene expression analysis in a single lab\",\n      \"pmids\": [\"35851857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"FAM76B stabilizes PIK3CD mRNA, and its loss leads to increased PIK3CD mRNA and protein levels, enhanced PI3K/Akt/NF-κB pathway activity, and increased M1 macrophage polarization. FAM76B knockout promoted M1 polarization, and FAM76B protects against IBD by inhibiting M1 macrophage polarization through this pathway in vivo.\",\n      \"method\": \"FAM76B knockout in U937 cells, mRNA stability assays, western blot, in vivo IBD model\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO plus mRNA stability assay and functional rescue in vivo, single lab\",\n      \"pmids\": [\"38421448\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"USP14 regulates ATF2 expression (shown by co-immunoprecipitation), and ATF2 directly promotes PIK3CD transcription (demonstrated by dual-luciferase reporter and ChIP assays). PIK3CD overexpression rescued the inhibitory effect of USP14 knockdown on proliferation, migration, and tube formation in HG-induced HRMECs, placing PIK3CD downstream of USP14/ATF2 in diabetic retinopathy pathogenesis.\",\n      \"method\": \"Co-immunoprecipitation, dual-luciferase reporter assay, ChIP assay, siRNA knockdown, overexpression rescue experiments\",\n      \"journal\": \"Biochemical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding shown by ChIP, protein interaction by Co-IP, epistasis by rescue experiment, single lab\",\n      \"pmids\": [\"36939972\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"circZNF532 recruits TAF15 (shown by RIP and RNA pull-down) to stabilize PIK3CD mRNA in HG-treated retinal endothelial cells, elevating PIK3CD expression and p-AKT levels, thereby facilitating endothelial-to-mesenchymal transition. PIK3CD overexpression partially reversed the inhibitory effect of circZNF532 silencing on EndMT, migration, and angiogenesis.\",\n      \"method\": \"RNA immunoprecipitation (RIP), RNA pull-down, mRNA stability assay (actinomycin D), siRNA knockdown, overexpression rescue\",\n      \"journal\": \"Endocrine journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP and pull-down establish direct interaction, mRNA stability confirmed, functional rescue performed, single lab\",\n      \"pmids\": [\"38811189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"An oncogenic splice variant PIK3CD-S, generated by SRSF2-mediated exon 20 skipping, lacks core inhibitor-binding residues in the catalytic domain (confirmed by molecular docking and ATP-competitive assays), resulting in constitutively activated PI3K/AKT signaling and reduced affinity for PI3Kδ inhibitors including idelalisib. SRPIN340 (SRSF2 inhibitor) re-sensitizes PIK3CD-S-expressing prostate cancer cells to idelalisib.\",\n      \"method\": \"Molecular docking, ATP-competitive assay, PI3 kinase assay, RT-PCR, Western blot, SRPIN340 treatment, cell viability assays\",\n      \"journal\": \"Cancers\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase assays plus structural docking, multiple biochemical methods, single lab\",\n      \"pmids\": [\"36831678\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Genome editing of Pik3cd in retinal vascular endothelial cells using a dual rAAV CRISPR/Cas9 system driven by an endothelial-specific promoter (pICAM2) achieved 80% indel rate and 70% depletion of p110δ expression, resulting in significant decrease in Akt activation and dramatic reduction in pathological retinal angiogenesis in an oxygen-induced retinopathy mouse model.\",\n      \"method\": \"Dual rAAV1 CRISPR/Cas9 delivery with endothelial-specific promoter, indel quantification, Western blot, OIR mouse model, retinal angiogenesis assessment\",\n      \"journal\": \"Human gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo gene editing with functional angiogenesis readout and downstream signaling validation, single study\",\n      \"pmids\": [\"36515172\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TALEN-mediated correction of the mutated PIK3CD gene in APDS1 patient T cells normalized phospho-AKT levels in basal and activated conditions and restored cytotoxic functions of edited CD8+ T cells. Single-cell RNA sequencing revealed corrected transcriptomic signatures of CD8+ effector memory and proliferating T cells.\",\n      \"method\": \"TALEN-mediated gene editing, phospho-AKT measurement, cytotoxicity assays, single-cell RNA sequencing\",\n      \"journal\": \"Molecular therapy. Methods & clinical development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gene correction with functional restoration and transcriptomic validation in patient primary cells, single lab\",\n      \"pmids\": [\"38152700\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"POU2F2 promotes PIK3CD transcription by binding to its promoter (demonstrated by ChIP and luciferase reporter assays) in B lymphocytes, activating the Akt/mTOR signaling pathway. Knockdown of POU2F2 suppressed B cell proliferation, and PIK3CD overexpression reversed these effects, establishing POU2F2 as an upstream transcriptional activator of PIK3CD.\",\n      \"method\": \"ChIP assay, luciferase reporter assay, lentiviral PIK3CD silencing, Akt activator rescue, flow cytometry\",\n      \"journal\": \"Nephrology (Carlton, Vic.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct promoter binding by ChIP, functional rescue confirms epistatic relationship, single lab\",\n      \"pmids\": [\"39401868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"The PIK3CD R512W gain-of-function variant increases PIP3 accumulation and AKT phosphorylation (kinase hyperactivation confirmed). However, T cells expressing R512W paradoxically exhibit reduced IL-2 production, impaired proliferation, increased PD-1 expression, and apoptosis (exhaustion-like state). Transcriptomic analysis revealed downregulation of polyamine biosynthesis genes (Odc1, Amd1, Smox) and reduced intracellular polyamine levels. Spermidine supplementation partially rescued proliferative defects. Structural modeling suggested R512W alters the helical domain conformation of p110δ.\",\n      \"method\": \"Overexpression in murine T cell line, PIP3 accumulation assay, AKT phosphorylation assay, transcriptomic analysis, intracellular polyamine measurement, spermidine rescue, in silico structural modeling\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional kinase assay plus transcriptomics plus metabolic rescue, multiple orthogonal methods, single lab\",\n      \"pmids\": [\"40694900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"CAR-adapted base-editing screen of PIK3CD identified specific point mutations with distinct functional effects: the PI3Kδ-activating substitution E81K enhanced proliferation, metabolic fitness, and effector function of 4-1BBz CAR T cells, promoting long-term functional persistence and enhanced therapeutic efficacy in vivo; the PI3Kδ-attenuating substitution L32P improved T cell memory formation and functionality of 28z CAR T cells.\",\n      \"method\": \"CAR-adapted base-editing screen, in vitro T cell functional assays (proliferation, metabolic fitness, effector function), in vivo therapeutic efficacy models\",\n      \"journal\": \"Nature cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — systematic base-editing screen with in vitro and in vivo validation, distinct mutations with opposing effects in defined CAR contexts, multiple orthogonal readouts\",\n      \"pmids\": [\"41495526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In APDS1, loss of naïve T cells is driven extrinsically by PI3K GOF T cells, while the increase in Tfh cells is mediated by dysregulated PI3K GOF B cells (not macrophages or DCs). PI3K GOF Tregs did not acquire an inflammatory phenotype driving T cell activation. This cell-type-specific epistasis was established using a mouse model of APDS1.\",\n      \"method\": \"Mouse model of APDS1, bone marrow transfer, cell-type-specific depletion/reconstitution experiments, in vivo T cell phenotyping\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis determined via cell-type-specific reconstitution in mouse model, preprint not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2024.08.04.606503\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The mouse p110δ gene (PIK3CD ortholog) consists of 22 exons spanning over 13 kb and shares its exon structure with p110β, its closest PI3K family member at the amino acid level.\",\n      \"method\": \"Genomic library cloning, sequencing, and structural organization analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct genomic sequencing and structural determination, single study, foundational structural characterization\",\n      \"pmids\": [\"11162674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Activated PIK3CD (E1021K GOF mutation) drives expansion of innate B1a and marginal zone B cells while causing bone marrow B lymphopenia. GOF B cells show increased pS6 and survival at multiple developmental stages. Mb1-aPIK3CD mice exhibited blunted T cell-independent immune responses and reduced class-switched antibodies following T cell-dependent immunization.\",\n      \"method\": \"Inducible mouse model with B cell-specific Cre lines (Mb1-Cre, CD21-Cre, AID-Cre), flow cytometry, immunization experiments, ELISA for Ig isotypes\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — inducible cell-type-specific mouse model with multiple Cre lines, multiple orthogonal functional readouts, in vivo immunization challenge\",\n      \"pmids\": [\"30194267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PIK3CD transcription in gastric cancer is upregulated by the pro-inflammatory IL2/JAK3/STAT5 signaling axis and tumor-infiltrating lymphocytes. Genetic silencing of PIK3CD retards proliferation and migration in vitro and tumorigenicity and metastasis in vivo. PIK3CD, but not PIK3CA or PIK3CB, is selectively regulated by this inflammatory pathway.\",\n      \"method\": \"siRNA knockdown, overexpression, pharmacological PIK3CD inhibition, in vivo xenograft, STAT5 pathway inhibition, qRT-PCR, IHC\",\n      \"journal\": \"Journal of cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — isoform-selective transcriptional regulation shown by pathway inhibition and genetic perturbations, functional in vivo readout, single lab\",\n      \"pmids\": [\"38545256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Hyperactive p110δ (PIK3CD GOF) increases the proportion of splenic marginal zone B cell precursors with enhanced surface ADAM10 levels as early as the T1 stage of B cell development. ADAM10 inhibition suppresses marginal zone B cell differentiation and partially reverses the T1/T2 stage imbalance, placing ADAM10 downstream of PIK3CD GOF in marginal zone B cell development.\",\n      \"method\": \"Mouse model of activated PI3Kδ syndrome, ADAM10 inhibitor treatment, single-cell RNA sequencing (scRNA-seq), flow cytometry\",\n      \"journal\": \"Inflammation research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pharmacological epistasis with scRNA-seq validation in mouse model, single lab\",\n      \"pmids\": [\"42228175\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PIK3CD encodes p110δ, the catalytic subunit of class IA PI3Kδ, which is maintained in a basally inhibited state through interactions with p85α regulatory subunit domains (nSH2, iSH2, cSH2); gain-of-function mutations disrupt these inhibitory contacts to hyperactivate PI3Kδ, driving downstream AKT/mTOR signaling that governs lymphocyte development (B cell CSR via AID suppression, CD8+ T cell exhaustion, TFH dysregulation, marginal zone B cell expansion via ADAM10), while PIK3CD transcription is regulated by TNFα through a novel promoter, by IKAROS/CK2 in T-ALL, by JAK3/STAT5 in inflammation, and by POU2F2 in B cells; additionally, PIK3CD mRNA stability is regulated post-transcriptionally by FAM76B and TAF15/circZNF532, and specific point mutations in p110δ modulate CAR T cell metabolic fitness and memory in a CAR design-specific manner.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PIK3CD encodes p110\\u03b4, the catalytic subunit of class IA PI3K\\u03b4, which generates PIP3 to drive AKT/mTOR signaling and governs lymphocyte development and function [#0, #22]. The enzyme is held in a basally inhibited state through inhibitory contacts from the nSH2, iSH2, and cSH2 domains of the p85\\u03b1 regulatory subunit; gain-of-function mutations in p110\\u03b4 (N334K, E525K, E1021K) and a p85\\u03b1 splice variant (\\u0394434-475) disrupt these contacts to hyperactivate the kinase\\u2014isoform-selectively for p110\\u03b4\\u2014and all are inhibited by idelalisib [#0]. Hyperactive PI3K\\u03b4 (activated PI3K\\u03b4 syndrome) produces broad immune dysregulation: it suppresses activation-induced cytidine deaminase to impair B cell class-switch recombination [#1], drives CD8+ T and NK cells toward an exhausted/senescent phenotype with reduced cytotoxicity against EBV-infected cells [#2], generates dysregulated follicular helper T cells with poor B-helper function [#3], and expands innate B1a and marginal zone B cells\\u2014the latter via enhanced surface ADAM10 from early developmental stages [#22, #24]. Cell-type-specific reconstitution shows these effects are partitioned: GOF T cells drive na\\u00efve T cell loss while GOF B cells drive Tfh expansion [#3, #20]. Beyond immune cells, PIK3CD is overexpressed or hyperactivated in cancers where it promotes proliferation, migration, and invasion through the AKT/GSK-3\\u03b2/\\u03b2-catenin axis in colorectal cancer [#6] and an SRSF2-generated inhibitor-resistant splice variant (PIK3CD-S) in prostate cancer [#14]. PIK3CD transcription is controlled by multiple inputs\\u2014a TNF\\u03b1-responsive promoter in non-leukocytes [#5], IKAROS repression relieved by CK2 phosphorylation in T-ALL [#8], the IL2/JAK3/STAT5 axis in gastric cancer [#23], and POU2F2 in B cells [#17]\\u2014while mRNA stability is regulated post-transcriptionally by FAM76B and by circZNF532/TAF15 [#11, #13]. Engineered p110\\u03b4 point mutations tune CAR T cell metabolic fitness and memory in a CAR-design-specific manner [#20-context, #19].\"\n,\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Establishing the genomic structure of the p110\\u03b4 gene provided the foundation for understanding it as a distinct class IA PI3K catalytic subunit related to p110\\u03b2.\",\n      \"evidence\": \"Genomic library cloning and structural organization analysis of the mouse ortholog\",\n      \"pmids\": [\"11162674\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not address protein function or regulation\", \"Ortholog-based; human gene structure not directly characterized here\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"It was unknown how PIK3CD expression is induced in non-hematopoietic cells; this showed a distinct TNF\\u03b1-responsive promoter drives isoform-selective p110\\u03b4 induction in endothelial and synovial cells.\",\n      \"evidence\": \"Promoter cloning, transcription start site mapping, and TNF\\u03b1 stimulation in human cell types\",\n      \"pmids\": [\"22375552\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream functional consequence of induced p110\\u03b4 not established\", \"Transcription factors acting at this promoter not identified\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"The biochemical basis of activated PI3K\\u03b4 syndrome was unresolved; this defined that APDS mutations disrupt p85\\u03b1 inhibitory domain contacts to hyperactivate p110\\u03b4 isoform-selectively while remaining idelalisib-sensitive.\",\n      \"evidence\": \"HDX-MS, biochemical kinase assays, and domain mutagenesis of APDS1/APDS2 mutations\",\n      \"pmids\": [\"28167755\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cellular/immune consequences not addressed in this biochemical study\", \"Full structural model of activated complex not resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"It was unclear how PIK3CD is transcriptionally controlled in leukemia; ChIP and reporter assays established IKAROS as a direct repressor relieved by CK2 phosphorylation, with miR-26b as an additional negative regulator.\",\n      \"evidence\": \"ChIP, promoter reporter assays, CK2 inhibition, and miR-26b luciferase reporter in T-ALL\",\n      \"pmids\": [\"28280276\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of IKAROS vs miR-26b to PIK3CD levels not quantified\", \"Single disease context\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"How PIK3CD GOF impairs humoral immunity was unknown; a knock-in mouse showed hyperactive PI3K\\u03b4 suppresses AID induction and class-switch recombination, reversibly with leniolisib.\",\n      \"evidence\": \"CRISPR/Cas9 knock-in mouse, ex vivo B cell assays, AID analysis, pharmacological rescue\",\n      \"pmids\": [\"30018075\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular link between AKT/mTOR and AID transcription not mapped\", \"Plasmablast differentiation block mechanism not detailed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The cytotoxic-cell phenotype in APDS was undefined; patient and mouse data established that GOF drives CD8+ T/NK exhaustion and impaired killing of EBV-infected B cells.\",\n      \"evidence\": \"Patient T/NK cell phenotyping, GOF mouse model, cytotoxicity assays\",\n      \"pmids\": [\"29800648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking PI3K\\u03b4 hyperactivity to senescence/exhaustion program not resolved\", \"Reversibility not tested here\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The effect of PIK3CD GOF on innate B cell compartments was unknown; an inducible model showed expansion of B1a and marginal zone B cells with developmental B lymphopenia and blunted antibody responses.\",\n      \"evidence\": \"Inducible B cell-specific Cre mouse models, flow cytometry, immunization, Ig ELISA\",\n      \"pmids\": [\"30194267\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stage-specific signaling thresholds not defined\", \"Effector mechanism downstream of pS6 not identified at this stage\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Whether TFH defects in APDS were cell-intrinsic was unresolved; chimera experiments separated intrinsic cytokine/TFH-function defects from extrinsic expansion of memory/TFH numbers.\",\n      \"evidence\": \"Patient T cell analysis, GOF mouse, mixed bone marrow chimeras, in vivo immunization\",\n      \"pmids\": [\"30738173\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular driver of impaired B-helper function not identified\", \"Antigen-specific GC dynamics not fully resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"The consequence of PIK3CD loss-of-function was unknown; a patient case showed reduced AKT signaling with compensatory increases in calcium flux and RAS-MAPK, indicating a PLC\\u03b31/PI3K imbalance permitting EBV-infected T cell accumulation.\",\n      \"evidence\": \"Signaling assays in patient T cells, calcium flux, RAS-MAPK assays\",\n      \"pmids\": [\"31537641\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient with compound mutation limits generalizability\", \"Mechanism of pathway imbalance not reconstituted\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A role for PIK3CD outside immunity was tested; in colorectal cancer it acts upstream of an AKT/GSK-3\\u03b2/\\u03b2-catenin axis to promote growth and invasion.\",\n      \"evidence\": \"siRNA, idelalisib, overexpression, AKT-inhibitor and \\u03b2-catenin-knockdown rescue, xenografts\",\n      \"pmids\": [\"30618098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cause of PIK3CD overexpression in CRC not established here\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"PIK3CD's candidacy in non-immune disease was extended; a somatic L666P variant in lymphatic endothelial cells hyperactivates mTOR and promotes proliferation/migration, implicating it in lymphatic malformations.\",\n      \"evidence\": \"In vitro HUVEC functional studies and mTOR activation assays\",\n      \"pmids\": [\"33964933\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality in patient tissue not demonstrated in vivo\", \"Single mutation\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"A pro-tumorigenic function in glioma was tested; CRISPR knockout reduced migration/invasion/colony formation and impaired PAK3 and PLEK2 activity.\",\n      \"evidence\": \"CRISPR/Cas9 knockout, migration/invasion assays, PCR array, RNAseq, xenograft\",\n      \"pmids\": [\"35851857\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular link to PAK3/PLEK2 not established\", \"Axonogenesis pathway involvement only suggested by RNAseq\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Post-transcriptional and transcriptional regulators of PIK3CD in vascular disease were identified, including circZNF532/TAF15 stabilizing mRNA and USP14/ATF2 driving transcription to promote pathological angiogenesis.\",\n      \"evidence\": \"RIP, RNA pull-down, mRNA stability assays, Co-IP, dual-luciferase, ChIP, rescue experiments\",\n      \"pmids\": [\"38811189\", \"36939972\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of each regulatory layer not compared\", \"Single disease models\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Inhibitor-resistance mechanisms were uncovered; an SRSF2-driven exon-20-skipped variant (PIK3CD-S) lacks inhibitor-binding residues, is constitutively active, and resists idelalisib but is re-sensitized by SRSF2 inhibition.\",\n      \"evidence\": \"Molecular docking, ATP-competitive and PI3 kinase assays, RT-PCR, SRPIN340 treatment\",\n      \"pmids\": [\"36831678\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Prevalence of PIK3CD-S across tumors not established\", \"In vivo validation limited\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Therapeutic correction strategies were validated; TALEN gene correction of APDS1 T cells normalized phospho-AKT and restored CD8+ cytotoxicity and transcriptomes, and endothelial-targeted CRISPR depletion reduced retinal angiogenesis.\",\n      \"evidence\": \"TALEN editing of patient cells with scRNA-seq; dual rAAV CRISPR/Cas9 in OIR mouse model\",\n      \"pmids\": [\"38152700\", \"36515172\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Long-term durability and off-target effects not fully assessed\", \"Single labs/models\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Additional regulatory inputs and disease contexts were defined: FAM76B stabilizes PIK3CD mRNA controlling macrophage polarization and IBD; IL2/JAK3/STAT5 selectively upregulates PIK3CD in gastric cancer; POU2F2 transactivates PIK3CD in B cells.\",\n      \"evidence\": \"Knockout/mRNA-stability assays, pathway inhibition, ChIP and luciferase reporters, in vivo models\",\n      \"pmids\": [\"38421448\", \"38545256\", \"39401868\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Isoform selectivity mechanism of upstream pathways not fully explained\", \"Cross-talk among regulators not integrated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Paradoxical GOF phenotypes were dissected; the R512W variant hyperactivates kinase yet causes exhaustion-like T cell dysfunction via downregulated polyamine biosynthesis, partially rescued by spermidine, and APDS1 cell-type epistasis was mapped (GOF T cells drive na\\u00efve loss, GOF B cells drive Tfh expansion).\",\n      \"evidence\": \"Overexpression, PIP3/AKT assays, transcriptomics, polyamine measurement, spermidine rescue; mouse model with cell-type-specific reconstitution (preprint)\",\n      \"pmids\": [\"40694900\", \"bio_10.1101_2024.08.04.606503\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Link between p110\\u03b4 activity and polyamine gene regulation not mechanistically established\", \"Preprint epistasis findings not peer-reviewed\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Engineering and developmental detail were added; CAR-adapted base editing showed activating (E81K) and attenuating (L32P) p110\\u03b4 substitutions tune CAR T fitness and memory in CAR-design-specific ways, and ADAM10 was placed downstream of PIK3CD GOF in marginal zone B cell development.\",\n      \"evidence\": \"CAR-adapted base-editing screen with in vivo efficacy; APDS mouse model with ADAM10 inhibition and scRNA-seq\",\n      \"pmids\": [\"41495526\", \"42228175\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking p110\\u03b4 activity to ADAM10 surface levels not defined\", \"Generalizability of CAR-specific mutation effects across constructs not exhaustively mapped\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The mechanism connecting PI3K\\u03b4 hyperactivity to specific downstream transcriptional and metabolic programs (AID suppression, exhaustion, polyamine and ADAM10 regulation) remains incompletely resolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking AKT/mTOR output to each cell-type-specific phenotype\", \"Structural model of how diverse GOF mutations converge on activation not complete\", \"Integration of the multiple transcriptional/post-transcriptional regulators into one regulatory map lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 14, 18]},\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 14]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 6, 18]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 2, 3, 22]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 6, 7, 14]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 8, 17, 23]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [11, 13]}\n    ],\n    \"complexes\": [\"class IA PI3K (p110\\u03b4/p85\\u03b1)\"],\n    \"partners\": [\"PIK3R1\", \"ADAM10\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}