Affinage

PIK3CG

Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit gamma isoform · UniProt P48736

Length
1102 aa
Mass
126.5 kDa
Annotated
2026-06-10
16 papers in source corpus 9 papers cited in narrative 9 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PIK3CG encodes the catalytic subunit p110γ of PI3Kγ, and across the available corpus it functions as a signaling node that couples upstream transcriptional and metabolic inputs to cell migration, inflammation, and tumor progression (PMID:25808869, PMID:38602596). Its expression is regulated at multiple levels: it is a direct transcriptional target of Mfng-facilitated Notch/RBPJκ signaling in claudin-low breast cancer (PMID:25808869), and is epigenetically silenced by promoter CpG hypermethylation in colon cancer, where demethylation restores expression and reactivates the PI3K-Akt/PKB axis (PMID:12473596). In cancer cells, PIK3CG drives migration, epithelial-mesenchymal transition, and metastasis, acting in lung cancer through enhanced MMP expression and neutrophil/cathepsin G recruitment (PMID:38602596) and in metastatic prostate cancer through EMT reversal upon PI3Kγ inhibition (PMID:32805234). PIK3CG also operates upstream of the NLRP3 inflammasome to promote GSDMD-mediated pyroptosis in septic myocardial injury (PMID:37676465) and to mediate central post-stroke pain in the thalamus (PMID:40551174), and it sustains glutamine catabolism through an mTORC1–S6K2–p53–GLS2 axis whose loss restricts TCA cycle entry and elevates mitochondrial ROS (PMID:41539001).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2002 Medium

    Established a mechanism controlling PIK3CG abundance: rather than being constitutively expressed, p110γ is subject to epigenetic silencing, linking its loss to attenuated PI3K-Akt signaling in cancer.

    Evidence Methylation-sensitive PCR and 5-aza-2'-deoxycytidine demethylation rescue with RT-PCR/Western readout in colon cancer cell lines

    PMID:12473596

    Open questions at the time
    • Does not define which upstream signals direct promoter methylation
    • Functional consequence of restored p110γ not assayed beyond expression and pathway association
  2. 2015 Medium

    Identified a transcriptional input to PIK3CG, showing it is a direct target of Mfng-facilitated Notch/RBPJκ signaling and required for migration and tumorsphere formation, framing it as an effector downstream of Notch.

    Evidence Mfng silencing/conditional knockout in claudin-low breast cancer cell lines and mouse mammary model with reporter-based transcriptional target identification and pharmacologic PI3Kγ inhibition

    PMID:25808869

    Open questions at the time
    • Direct RBPJκ occupancy mapping of the PIK3CG promoter not detailed
    • Catalytic activity contribution versus scaffold not separated
  3. 2020 Medium

    Connected PIK3CG to EMT-driven metastasis, demonstrating its enrichment in poorly differentiated AR-negative tumors and that PI3Kγ inhibition reverses EMT and blocks metastasis.

    Evidence Trp53-KO/Kras-activated genetically engineered mouse prostate cancer model with pharmacologic PI3Kγ inhibition and in vitro/in vivo growth and metastasis readouts

    PMID:32805234

    Open questions at the time
    • Relies on pharmacologic inhibition without genetic deletion
    • Molecular effectors linking p110γ to EMT not resolved
  4. 2023 Medium

    Placed PIK3CG upstream of the NLRP3 inflammasome, establishing it as a driver of GSDMD-mediated pyroptosis in septic myocardial injury.

    Evidence siRNA knockdown and overexpression in HL-1 cardiomyocytes with CLP mouse model, pharmacologic inhibition (AS-604850), and Western blot for inflammasome components

    PMID:37676465

    Open questions at the time
    • Mechanism linking p110γ activity to NLRP3 activation not defined
    • Direct versus indirect regulation of inflammasome priming unresolved
  5. 2023 Low

    Linked PIK3CG to tumor cell growth in multiple myeloma via the c-Myc pathway, extending its pro-proliferative role to a hematologic malignancy.

    Evidence Pharmacologic inhibition (AS-605240) in MM cell lines with Western blot for c-Myc and apoptosis markers and proliferation/migration assays

    PMID:38163179

    Open questions at the time
    • Pharmacologic inhibitor only, no genetic knockdown to confirm on-target effect
    • c-Myc regulation inferred indirectly
  6. 2024 Medium

    Defined a non-cell-autonomous metastatic mechanism, showing PIK3CG drives migration through MMP upregulation and neutrophil/cathepsin G recruitment in lung cancer.

    Evidence Knockdown and overexpression in A549/H1299, pharmacologic inhibition, tail-vein LLC metastasis model, and Transwell neutrophil co-culture

    PMID:38602596

    Open questions at the time
    • Direct enzymatic link between p110γ and MMP transcription not established
    • Mechanism of neutrophil recruitment downstream of PIK3CG unresolved
  7. 2024 Low

    Implicated PIK3CG in autophagy regulation in neuronal injury, opposing AMPK/mTOR-driven autophagy and influencing neuronal survival.

    Evidence siRNA knockdown in SH-SY5Y cells under OGD/R with AMPK activator co-treatment and Western blot for Beclin1/LC3 II

    PMID:39603405

    Open questions at the time
    • Pathway inferred from pharmacologic AMPK activation rather than direct mechanistic reconstitution
    • Single cell line, single lab
  8. 2025 Medium

    Generalized the PIK3CG–NLRP3 axis to the CNS, using epistasis to confirm NLRP3 acts downstream of PIK3CG in mediating central post-stroke pain.

    Evidence PIK3CG overexpression/knockdown in a CPSP mouse model with simultaneous NLRP3 overexpression epistasis, RNA sequencing, and molecular docking

    PMID:40551174

    Open questions at the time
    • Biochemical intermediates between p110γ and NLRP3 not identified
    • Docking of Danshenol B not validated by direct binding assay
  9. 2026 Medium

    Resolved a metabolic role, showing PIK3CG sustains glutamine catabolism through an mTORC1–S6K2–p53–GLS2 axis, with GLS2 loss restricting TCA entry and elevating mitochondrial ROS.

    Evidence PIK3CG knockdown in vitro and in vivo with GLS2 overexpression rescue, mTORC1 pathway analysis, and mitochondrial ROS/pyroptosis assays

    PMID:41539001

    Open questions at the time
    • How p110γ activates mTORC1 in this context not defined
    • Single lab; specificity of S6K2(Glu163)-p53(Arg273) interaction not independently confirmed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How p110γ catalytic lipid kinase output is mechanistically partitioned between its migration/metastasis, inflammasome, autophagy, and metabolic functions remains unresolved across the corpus.
  • No structural or biochemical study in the corpus links specific p110γ catalytic outputs to each downstream branch
  • Upstream GPCR/receptor activation events not directly characterized in the captured findings

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 1
Pathway
R-HSA-162582 Signal Transduction 2 R-HSA-1643685 Disease 2 R-HSA-168256 Immune System 2 R-HSA-1430728 Metabolism 1

Evidence

Reading pass · 9 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2015 Manic Fringe (Mfng) promotes claudin-low breast cancer through RBPJκ-dependent Notch signaling that directly induces PIK3CG transcription; PIK3CG was identified as a direct transcriptional target of Mfng-facilitated Notch signaling, and pharmacologic inhibition of PI3Kγ blocked migration and tumorsphere formation in CLBC cell lines. Mfng silencing/deletion in CLBC cell lines and mouse mammary tumor model, pharmacologic PI3Kγ inhibition, reporter/transcriptional target identification Cancer research Medium 25808869
2023 PIK3CG activates the NLRP3 inflammasome, thereby promoting GSDMD-mediated pyroptosis in septic myocardial injury; PIK3CG siRNA suppressed NLRP3, GSDMD, IL-1β, Caspase-1, and IL-18, while PIK3CG overexpression worsened these changes, and the PIK3CG inhibitor AS-604850 reversed CLP-induced pyroptosis. siRNA knockdown and overexpression in HL-1 cardiomyocytes, CLP mouse model, pharmacologic inhibition (AS-604850), transcriptome analysis, Western blot Inflammation Medium 37676465
2025 PIK3CG acts upstream of NLRP3 in the thalamus to mediate central post-stroke pain; PIK3CG overexpression increased NLRP3 and negated analgesic effects, while PIK3CG knockdown alleviated pain and reduced NLRP3. Simultaneous NLRP3 overexpression attenuated the analgesic effects of PIK3CG knockdown, confirming NLRP3 is downstream of PIK3CG in this pathway. Molecular docking showed Danshenol B binds PIK3CG (−9.127 kcal/mol). PIK3CG overexpression and knockdown in CPSP mouse model, epistasis via simultaneous NLRP3 overexpression, RNA sequencing, molecular docking Journal of translational medicine Medium 40551174
2026 PIK3CG deficiency suppresses mTORC1, leading to enhanced phosphorylation of S6K2, which disrupts the nuclear S6K2 (Glu163)–p53 (Arg273) interaction and inhibits GLS2 transcription; this blocks glutamine catabolism, restricts TCA cycle entry, and causes mitochondrial ROS accumulation with suppressed pyroptosis. GLS2 overexpression rescued all phenotypes induced by PIK3CG knockdown. PIK3CG knockdown in vitro and in vivo, GLS2 overexpression rescue, mTORC1 pathway analysis, mitochondrial ROS and membrane potential assays, pyroptosis assays International immunopharmacology Medium 41539001
2024 PIK3CG overexpression in lung cancer cells promotes migration and metastasis through enhanced MMP expression and neutrophil recruitment/activation; knockdown or pharmacologic inhibition (Eganelisib, CAY10505) reduced cell migration and MMP levels, while overexpression increased them. Co-culture with neutrophils and cathepsin G promoted lung cancer cell migration downstream of PIK3CG. PIK3CG knockdown and overexpression in A549 and H1299 cell lines, pharmacologic inhibition, tail-vein LLC mouse metastasis model, Transwell co-culture with neutrophils Biochemical genetics Medium 38602596
2024 PIK3CG knockdown in OGD/R-injured neuronal cells inhibits autophagy by opposing AMPK/mTOR pathway activation (suppressing AMPK phosphorylation increase and restoring mTOR phosphorylation), reducing Beclin1 and LC3 II levels, decreasing apoptosis, and protecting cell proliferation. siRNA knockdown in SH-SY5Y cells under OGD/R, AMPK activator (metformin) co-treatment, CCK8 proliferation assay, flow cytometry apoptosis, Western blot for autophagy markers Neuroscience Low 39603405
2023 PIK3CG regulates multiple myeloma cell growth via the c-Myc pathway; pharmacologic inhibition of PIK3CG (AS-605240) suppressed c-Myc expression, reduced proliferation and migration, promoted apoptosis, decreased Bcl-2/Bax ratio, and reduced vimentin expression. Pharmacologic inhibition with AS-605240 in MM cell lines, Western blot for c-Myc and apoptosis markers, proliferation and migration assays Heliyon Low 38163179
2002 PIK3CG promoter CpG hypermethylation silences PIK3CG expression in colon cancer cells; treatment with the demethylating agent 5-aza-2'-deoxycytidine restored PIK3CG expression in DLD-1 and LoVo cells. PIK3CG encodes the catalytic subunit p110γ of PI3K, and its loss is associated with suppression of the PI3K-Akt/PKB signaling axis. Methylation-sensitive PCR (HpaII/MspI digestion), 5-aza-2'-deoxycytidine demethylation treatment, RT-PCR, Western blot, immunohistochemistry Clinical cancer research Medium 12473596
2020 In a Trp53-deletion/Kras-activation mouse model of metastatic prostate cancer, Pik3cg is highly expressed in poorly differentiated, AR-negative tumors; pharmacologic inhibition of Pi3kγ blocked tumor cell growth in vitro, reversed epithelial-mesenchymal transition, and abated tumor metastasis in vivo. Genetically engineered mouse model (Trp53 KO + Kras activation), pharmacologic PI3Kγ inhibition, in vitro growth assays, in vivo metastasis assessment, immunohistochemistry The American journal of pathology Medium 32805234

Source papers

Stage 0 corpus · 16 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2002 Down-regulation of PIK3CG, a catalytic subunit of phosphatidylinositol 3-OH kinase, by CpG hypermethylation in human colorectal carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research 61 12473596
2015 Manic fringe promotes a claudin-low breast cancer phenotype through notch-mediated PIK3CG induction. Cancer research 60 25808869
2002 Genomic structure of the PIK3CG gene on chromosome band 7q22 and evaluation as a candidate myeloid tumor suppressor. Blood 29 11756194
2020 PIK3CG Is a Potential Therapeutic Target in Androgen Receptor-Indifferent Metastatic Prostate Cancer. The American journal of pathology 18 32805234
2020 Targeting PIK3CG in Combination with Paclitaxel as a Potential Therapeutic Regimen in Claudin-Low Breast Cancer. Cancer management and research 14 32368142
2017 Association of PIK3CG gene polymorphisms with attention-deficit/hyperactivity disorder: A case-control study. Progress in neuro-psychopharmacology & biological psychiatry 11 29097255
2023 PIK3CG Regulates NLRP3/GSDMD-Mediated Pyroptosis in Septic Myocardial Injury. Inflammation 9 37676465
2017 Notch signaling via regulation of RB and p-AKT but not PIK3CG contributes to MIA PaCa-2 cell growth and migration to affect pancreatic carcinogenesis. Oncology letters 8 29434912
2023 Angong niuhuang wan attenuates LPS-induced acute lung injury by inhibiting PIK3CG/p65/MMP9 signaling in mice based on proteomics. Heliyon 5 37810062
2024 Overexpression of PIK3CG in Cancer Cells Promotes Lung Cancer Cell Migration and Metastasis Through Enhanced MMPs Expression and Neutrophil Recruitment and Activation. Biochemical genetics 3 38602596
2024 Protective effects of PIK3CG knockdown against OGD/R-induced neuronal damage via inhibition of autophagy through the AMPK/mTOR pathway. Neuroscience 3 39603405
2025 Danshenol B alleviates central post-stroke pain by regulating the PIK3CG/NLRP3 signaling pathway. Journal of translational medicine 2 40551174
2022 Synonymous mutation rs1129293 is associated with PIK3CG expression and PI3Kγ activation in patients with chronic Chagas cardiomyopathy. Immunobiology 2 35870262
2023 Therapeutic potential of anti-PIK3CG treatment for multiple myeloma via inhibiting c-Myc pathway. Heliyon 1 38163179
2026 PIK3CG deficiency promotes metabolic reprogramming in pancreatic Cancer by suppressing GLS2-driven glutamine metabolism. International immunopharmacology 0 41539001
2026 Role of hsa-miR-122-5p in chronic thromboembolic pulmonary hypertension and chronic thromboembolic disease: Targeting PIK3CG in the PI3K/Akt signaling pathway. Medicine 0 41560055

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