Affinage

PIK3CD

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform · UniProt O00329

Length
1044 aa
Mass
119.5 kDa
Annotated
2026-06-10
68 papers in source corpus 25 papers cited in narrative 25 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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].

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 2001 Medium

    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

    PMID:11162674

    Open questions at the time
    • Does not address protein function or regulation
    • Ortholog-based; human gene structure not directly characterized here
  2. 2012 High

    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

    PMID:22375552

    Open questions at the time
    • Downstream functional consequence of induced p110δ not established
    • Transcription factors acting at this promoter not identified
  3. 2017 High

    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

    PMID:28167755

    Open questions at the time
    • Cellular/immune consequences not addressed in this biochemical study
    • Full structural model of activated complex not resolved
  4. 2017 Medium

    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

    PMID:28280276

    Open questions at the time
    • Relative contribution of IKAROS vs miR-26b to PIK3CD levels not quantified
    • Single disease context
  5. 2018 High

    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

    PMID:30018075

    Open questions at the time
    • Molecular link between AKT/mTOR and AID transcription not mapped
    • Plasmablast differentiation block mechanism not detailed
  6. 2018 High

    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

    PMID:29800648

    Open questions at the time
    • Mechanism linking PI3Kδ hyperactivity to senescence/exhaustion program not resolved
    • Reversibility not tested here
  7. 2018 High

    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

    PMID:30194267

    Open questions at the time
    • Stage-specific signaling thresholds not defined
    • Effector mechanism downstream of pS6 not identified at this stage
  8. 2019 High

    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

    PMID:30738173

    Open questions at the time
    • Molecular driver of impaired B-helper function not identified
    • Antigen-specific GC dynamics not fully resolved
  9. 2019 Medium

    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

    PMID:31537641

    Open questions at the time
    • Single patient with compound mutation limits generalizability
    • Mechanism of pathway imbalance not reconstituted
  10. 2019 Medium

    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

    PMID:30618098

    Open questions at the time
    • Cause of PIK3CD overexpression in CRC not established here
    • Single tumor type
  11. 2021 Medium

    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

    PMID:33964933

    Open questions at the time
    • Causality in patient tissue not demonstrated in vivo
    • Single mutation
  12. 2022 Medium

    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

    PMID:35851857

    Open questions at the time
    • Direct molecular link to PAK3/PLEK2 not established
    • Axonogenesis pathway involvement only suggested by RNAseq
  13. 2023 Medium

    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

    PMID:36939972 PMID:38811189

    Open questions at the time
    • Relative contribution of each regulatory layer not compared
    • Single disease models
  14. 2023 Medium

    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

    PMID:36831678

    Open questions at the time
    • Prevalence of PIK3CD-S across tumors not established
    • In vivo validation limited
  15. 2023 Medium

    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

    PMID:36515172 PMID:38152700

    Open questions at the time
    • Long-term durability and off-target effects not fully assessed
    • Single labs/models
  16. 2024 Medium

    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

    PMID:38421448 PMID:38545256 PMID:39401868

    Open questions at the time
    • Isoform selectivity mechanism of upstream pathways not fully explained
    • Cross-talk among regulators not integrated
  17. 2025 Medium

    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)

    PMID:40694900 PMID:bio_10.1101_2024.08.04.606503

    Open questions at the time
    • Link between p110δ activity and polyamine gene regulation not mechanistically established
    • Preprint epistasis findings not peer-reviewed
  18. 2026 High

    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

    PMID:41495526 PMID:42228175

    Open questions at the time
    • Mechanism linking p110δ activity to ADAM10 surface levels not defined
    • Generalizability of CAR-specific mutation effects across constructs not exhaustively mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • The mechanism connecting PI3Kδ hyperactivity to specific downstream transcriptional and metabolic programs (AID suppression, exhaustion, polyamine and ADAM10 regulation) remains incompletely resolved.
  • 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

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140657 ATP-dependent activity 3 GO:0016740 transferase activity 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-1643685 Disease 4 R-HSA-168256 Immune System 4 R-HSA-74160 Gene expression (Transcription) 4 R-HSA-162582 Signal Transduction 3 R-HSA-8953854 Metabolism of RNA 2
Partners
ADAM10PIK3R1
Complex memberships
class IA PI3K (p110δ/p85α)

Evidence

Reading pass · 25 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2017 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. HDX-MS, biochemical kinase assays, active-site/domain mutagenesis analysis Proceedings of the National Academy of Sciences of the United States of America High 28167755
2018 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. CRISPR/Cas9 knock-in mouse model, ex vivo B cell functional assays, AID expression analysis, pharmacological inhibition with leniolisib The Journal of experimental medicine High 30018075
2018 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. Ex vivo phenotypic and functional analysis of patient T and NK cells, novel GOF mouse model, cytotoxicity assays The Journal of allergy and clinical immunology High 29800648
2019 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. Ex vivo and in vitro patient T cell analysis, Pik3cd GOF mouse model, mixed bone marrow chimeras, in vivo immunization experiments The Journal of allergy and clinical immunology High 30738173
2019 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. Functional signaling assays in patient T cells, calcium flux, RAS-MAPK activation assays The Journal of experimental medicine Medium 31537641
2012 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. Promoter cloning, transcription start site mapping, TNFα stimulation assays, biochemical and bioinformatic characterization The Biochemical journal High 22375552
2019 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. siRNA knockdown, idelalisib inhibition, overexpression, AKT inhibitor rescue, β-catenin knockdown rescue, in vitro and xenograft in vivo assays Cancer science Medium 30618098
2021 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. In vitro functional studies in HUVECs, mTOR pathway activation assays, cell proliferation and migration assays Orphanet journal of rare diseases Medium 33964933
2017 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. ChIP assay, promoter reporter assays, CK2 inhibitor treatment, shRNA knockdown, miR-26b overexpression with luciferase reporter Leukemia Medium 28280276
2021 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. ChIP assay, CK2 inhibitor treatment, promoter binding assays in primary T-ALL International journal of molecular sciences Medium 33467550
2022 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. CRISPR/Cas9 knockout, migration/invasion assays, RT2 profiler PCR array, RNAseq, xenograft tumorigenesis assay Laboratory investigation; a journal of technical methods and pathology Medium 35851857
2024 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. FAM76B knockout in U937 cells, mRNA stability assays, western blot, in vivo IBD model Cellular and molecular life sciences : CMLS Medium 38421448
2023 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. Co-immunoprecipitation, dual-luciferase reporter assay, ChIP assay, siRNA knockdown, overexpression rescue experiments Biochemical genetics Medium 36939972
2024 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. RNA immunoprecipitation (RIP), RNA pull-down, mRNA stability assay (actinomycin D), siRNA knockdown, overexpression rescue Endocrine journal Medium 38811189
2023 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. Molecular docking, ATP-competitive assay, PI3 kinase assay, RT-PCR, Western blot, SRPIN340 treatment, cell viability assays Cancers Medium 36831678
2023 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. Dual rAAV1 CRISPR/Cas9 delivery with endothelial-specific promoter, indel quantification, Western blot, OIR mouse model, retinal angiogenesis assessment Human gene therapy Medium 36515172
2023 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. TALEN-mediated gene editing, phospho-AKT measurement, cytotoxicity assays, single-cell RNA sequencing Molecular therapy. Methods & clinical development Medium 38152700
2024 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. ChIP assay, luciferase reporter assay, lentiviral PIK3CD silencing, Akt activator rescue, flow cytometry Nephrology (Carlton, Vic.) Medium 39401868
2025 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. Overexpression in murine T cell line, PIP3 accumulation assay, AKT phosphorylation assay, transcriptomic analysis, intracellular polyamine measurement, spermidine rescue, in silico structural modeling Biochemical and biophysical research communications Medium 40694900
2026 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. CAR-adapted base-editing screen, in vitro T cell functional assays (proliferation, metabolic fitness, effector function), in vivo therapeutic efficacy models Nature cancer High 41495526
2025 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. Mouse model of APDS1, bone marrow transfer, cell-type-specific depletion/reconstitution experiments, in vivo T cell phenotyping bioRxivpreprint Medium bio_10.1101_2024.08.04.606503
2001 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. Genomic library cloning, sequencing, and structural organization analysis Biochemical and biophysical research communications Medium 11162674
2018 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. Inducible mouse model with B cell-specific Cre lines (Mb1-Cre, CD21-Cre, AID-Cre), flow cytometry, immunization experiments, ELISA for Ig isotypes The Journal of experimental medicine High 30194267
2024 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. siRNA knockdown, overexpression, pharmacological PIK3CD inhibition, in vivo xenograft, STAT5 pathway inhibition, qRT-PCR, IHC Journal of cell communication and signaling Medium 38545256
2026 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. Mouse model of activated PI3Kδ syndrome, ADAM10 inhibitor treatment, single-cell RNA sequencing (scRNA-seq), flow cytometry Inflammation research Medium 42228175

Source papers

Stage 0 corpus · 68 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2014 Mutations in PIK3CD can cause hyper IgM syndrome (HIGM) associated with increased cancer susceptibility. Journal of clinical immunology 144 24610295
2014 MicroRNA-30b functions as a tumour suppressor in human colorectal cancer by targeting KRAS, PIK3CD and BCL2. The Journal of pathology 128 24293274
2017 Conformational disruption of PI3Kδ regulation by immunodeficiency mutations in PIK3CD and PIK3R1. Proceedings of the National Academy of Sciences of the United States of America 98 28167755
2018 Germline-activating mutations in PIK3CD compromise B cell development and function. The Journal of experimental medicine 87 30018075
2013 miR-30a suppresses cell migration and invasion through downregulation of PIK3CD in colorectal carcinoma. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 83 23486085
2019 Concomitant PIK3CD and TNFRSF9 deficiencies cause chronic active Epstein-Barr virus infection of T cells. The Journal of experimental medicine 80 31537641
2018 Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity. The Journal of allergy and clinical immunology 76 29800648
2016 Abnormal B-cell maturation in the bone marrow of patients with germline mutations in PIK3CD. The Journal of allergy and clinical immunology 65 27697496
2019 PIK3CD induces cell growth and invasion by activating AKT/GSK-3β/β-catenin signaling in colorectal cancer. Cancer science 64 30618098
2019 Activating mutations in PIK3CD disrupt the differentiation and function of human and murine CD4+ T cells. The Journal of allergy and clinical immunology 58 30738173
2014 Gain of Function Mutations of PIK3CD as a Cause of Primary Sclerosing Cholangitis. Journal of clinical immunology 56 25352054
2017 Regulation of PI3K signaling in T-cell acute lymphoblastic leukemia: a novel PTEN/Ikaros/miR-26b mechanism reveals a critical targetable role for PIK3CD. Leukemia 55 28280276
2012 Isoform-selective induction of human p110δ PI3K expression by TNFα: identification of a new and inducible PIK3CD promoter. The Biochemical journal 46 22375552
2018 Activated PIK3CD drives innate B cell expansion yet limits B cell-intrinsic immune responses. The Journal of experimental medicine 43 30194267
2020 The long non-coding RNA PIK3CD-AS2 promotes lung adenocarcinoma progression via YBX1-mediated suppression of p53 pathway. Oncogenesis 41 32165621
2017 MiR-125b inhibits anaplastic thyroid cancer cell migration and invasion by targeting PIK3CD. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 41 28122310
2019 Immune Dysregulation and Disease Pathogenesis due to Activating Mutations in PIK3CD-the Goldilocks' Effect. Journal of clinical immunology 35 30911953
2020 CiRS-7 functions as a ceRNA of RAF-1/PIK3CD to promote metastatic progression of oral squamous cell carcinoma via MAPK/AKT signaling pathways. Experimental cell research 29 32956704
2018 Hepatic miR-125b inhibits insulin signaling pathway by targeting PIK3CD. Journal of cellular physiology 29 29319168
2021 LncRNA HOTAIRM1, miR-433-5p and PIK3CD function as a ceRNA network to exacerbate the development of PCOS. Journal of ovarian research 24 33485372
2022 A 5'-tiRNA fragment that inhibits proliferation and migration of laryngeal squamous cell carcinoma by targeting PIK3CD. Genomics 22 35644410
2019 Overexpression of lncRNA PIK3CD-AS1 promotes expression of LATS1 by competitive binding with microRNA-566 to inhibit the growth, invasion and metastasis of hepatocellular carcinoma cells. Cancer cell international 20 31624469
2018 Identification of a novel de novo gain-of-function mutation of PIK3CD in a patient with activated phosphoinositide 3-kinase δ syndrome. Clinical immunology (Orlando, Fla.) 20 30138677
2024 FAM76B regulates PI3K/Akt/NF-κB-mediated M1 macrophage polarization by influencing the stability of PIK3CD mRNA. Cellular and molecular life sciences : CMLS 19 38421448
2022 Cellular Mechanisms Underlying B Cell Abnormalities in Patients With Gain-of-Function Mutations in the PIK3CD Gene. Frontiers in immunology 18 35799777
2019 A mutation in PIK3CD gene causing pediatric systemic lupus erythematosus: A case report. Medicine 18 31045771
2018 Associations of high-altitude polycythemia with polymorphisms in PIK3CD and COL4A3 in Tibetan populations. Human genomics 17 30053909
2020 E1021K Homozygous Mutation in PIK3CD Leads to Activated PI3K-Delta Syndrome 1. Journal of clinical immunology 16 31953711
2022 Oncogenic potential of PIK3CD in glioblastoma is exerted through cytoskeletal proteins PAK3 and PLEK2. Laboratory investigation; a journal of technical methods and pathology 15 35851857
2021 Case Report: Activating PIK3CD Mutation in Patients Presenting With Granulomatosis With Polyangiitis. Frontiers in immunology 15 33995405
2023 Tracheal epithelial cell-exosome-derived MiR-21-5p inhibits alveolar macrophage pyroptosis to resist pulmonary bacterial infection through PIK3CD-autophagy pathway. Life sciences 12 38092143
2021 A somatic mutation in PIK3CD unravels a novel candidate gene for lymphatic malformation. Orphanet journal of rare diseases 12 33964933
2019 Transcription of PIK3CD in human brain and schizophrenia: regulation by proinflammatory cytokines. Human molecular genetics 12 31211828
2021 Case Report: Intestinal Nodular Lymphoid Hyperplasia as First Manifestation of Activated PI3Kδ Syndrome Due to a Novel PIK3CD Variant. Frontiers in pediatrics 11 34692603
2024 Activated phosphoinositide 3-kinase δ syndrome caused by PIK3CD mutations: expanding the phenotype. Pediatric rheumatology online journal 10 38287413
2021 Transcriptional Regulation of PIK3CD and PIKFYVE in T-Cell Acute Lymphoblastic Leukemia by IKAROS and Protein Kinase CK2. International journal of molecular sciences 10 33467550
2023 Molecular Insight into Drug Resistance Mechanism Conferred by Aberrant PIK3CD Splice Variant in African American Prostate Cancer. Cancers 9 36831678
2023 USP14 Regulates ATF2/PIK3CD Axis to Promote Microvascular Endothelial Cell Proliferation, Migration, and Angiogenesis in Diabetic Retinopathy. Biochemical genetics 7 36939972
2025 Polyethylene terephthalate microplastics promote pulmonary fibrosis via AKT1, PIK3CD, and PIM1: A network toxicology and multi-omics analysis. Ecotoxicology and environmental safety 6 40876188
2023 Genome Editing of Pik3cd Impedes Abnormal Retinal Angiogenesis. Human gene therapy 6 36515172
2018 Auto-immune disorders in a child with PIK3CD variant and 22q13 deletion. European journal of medical genetics 6 29673649
2016 PIK3CD promoted proliferation in diffuse large B cell lymphoma through upregulation of c-myc. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 6 27448819
2016 A novel PIK3CD C896T mutation detected in bilateral sudden sensorineural hearing loss using next generation sequencing: An indication of primary immunodeficiency. Journal of otology 6 29937814
2001 Structural organization of the mouse phosphatidylinositol 3-kinase p110d gene. Biochemical and biophysical research communications 5 11162674
2024 The H5N1-NS1 protein affects the host cell cycle and apoptosis through interaction with the host lncRNA PIK3CD-AS2. Virus genes 4 39424707
2023 Immunodeficiency due to a novel variant in PIK3CD: a case report. Pediatric rheumatology online journal 4 37475052
2023 Rescuing the cytolytic function of APDS1 patient T cells via TALEN-mediated PIK3CD gene correction. Molecular therapy. Methods & clinical development 4 38152700
2022 Association between single-nucleotide polymorphism in PIK3CD gene and litter size in Small Tail Han sheep. Animal biotechnology 4 36332162
2020 [Mechanism of MiR-224 Affecting DLBCL Cell Proliferation and Invasion by Targeted Inhibition of PIK3CD]. Zhongguo shi yan xue ye xue za zhi 4 33067957
2017 [Clinical and immunological analysis of patients with activated phosphoinositide 3-kinase δ syndrome resulting from PIK3CD mutation]. Zhonghua er ke za zhi = Chinese journal of pediatrics 4 28072954
2023 Triclosan induces earlier puberty onset in female mice via interfering with L-type calcium channels and activating Pik3cd. Ecotoxicology and environmental safety 3 38043413
2022 Initial sirolimus dosage recommendations for pediatric patients with PIK3CD mutation-related immunodeficiency disease. Frontiers in pharmacology 3 36188573
2016 [Clinical and genetic analysis for activated PI3K-δ syndrome by PIK3CD gene mutation]. Zhonghua er ke za zhi = Chinese journal of pediatrics 3 27596086
2026 CAR-adapted PIK3CD base editing enhances T cell anti-tumor potency. Nature cancer 2 41495526
2024 JAK3/STAT5 signaling-triggered upregulation of PIK3CD contributes to gastric carcinoma development. Journal of cell communication and signaling 2 38545256
2024 circZNF532 promotes endothelial-to-mesenchymal transition in diabetic retinopathy by recruiting TAF15 to stabilize PIK3CD. Endocrine journal 2 38811189
2024 Case report: Deep sequencing and long-read genome sequencing refine prior genetic analyses in families with apparent gonadal mosaicism in PIK3CD-related activated PI3K delta syndrome. Frontiers in immunology 2 39253077
2022 miR-193-5p negatively regulates PIK3CD to promote crop fibrocyte proliferation in pigeon (Columba livia). Poultry science 2 36565634
2025 Recurrent Panuveitis as a Manifestation of a Novel PIK3CD Gene Mutation: A Diagnostic and Management Challenge. Ocular immunology and inflammation 1 39932361
2025 Homozygous Loss of Function PIK3CD Mutation in Multiple Siblings Leading To B Cell Dysregulation and Autoimmunity. Journal of clinical immunology 1 41026257
2024 POU2F2 activates the Akt/mTOR signalling pathway and enhances B lymphocyte function during diabetic kidney disease by promoting PIK3CD transcription. Nephrology (Carlton, Vic.) 1 39401868
2026 E1021K mutation in PIK3CD gene: clinical heterogeneity and therapeutic implications in three pediatric APDS cases. Open life sciences 0 41815640
2026 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 pathway. Allergy, asthma, and clinical immunology : official journal of the Canadian Society of Allergy and Clinical Immunology 0 41845460
2026 Activated PIK3CD drives marginal zone B cell development from early transitional progenitors by enhancing ADAM10 expression. Inflammation research : official journal of the European Histamine Research Society ... [et al.] 0 42228175
2025 A gain-of-function PIK3CD variant, R512W, impairs T cell function through polyamine-dependent metabolic dysregulation. Biochemical and biophysical research communications 0 40694900
2025 Senescent B cells regulate CD38 expression via FOXO1 in pneumonia resulting from PIK3CD (R437C) mutations. Life medicine 0 41626283
2024 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. Stem cell research 0 38507881
2024 A Case of Dysgerminoma in a Pediatric Patient With a PIK3CD Mutation. Urology 0 39168413

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