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PIK3CG

Official Full Name
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma
Organism
Homo sapiens
GeneID
5294
Background
Phosphoinositide 3-kinases (PI3Ks) phosphorylate inositol lipids and are involved in the immune response. The protein encoded by this gene is a class I catalytic subunit of PI3K. Like other class I catalytic subunits (p110-alpha p110-beta, and p110-delta), the encoded protein binds a p85 regulatory subunit to form PI3K. This gene is located in a commonly deleted segment of chromosome 7 previously identified in myeloid leukemias. Several transcript variants encoding the same protein have been found for this gene. [provided by RefSeq, Jun 2015]
Synonyms
PI3K; PIK3; IMD97; PI3CG; PI3Kgamma; p110gamma; p120-PI3K;
Bio Chemical Class
Kinase
Protein Sequence
MELENYKQPVVLREDNCRRRRRMKPRSAAASLSSMELIPIEFVLPTSQRKCKSPETALLHVAGHGNVEQMKAQVWLRALETSVAADFYHRLGPHHFLLLYQKKGQWYEIYDKYQVVQTLDCLRYWKATHRSPGQIHLVQRHPPSEESQAFQRQLTALIGYDVTDVSNVHDDELEFTRRGLVTPRMAEVASRDPKLYAMHPWVTSKPLPEYLWKKIANNCIFIVIHRSTTSQTIKVSPDDTPGAILQSFFTKMAKKKSLMDIPESQSEQDFVLRVCGRDEYLVGETPIKNFQWVRHCLKNGEEIHVVLDTPPDPALDEVRKEEWPLVDDCTGVTGYHEQLTIHGKDHESVFTVSLWDCDRKFRVKIRGIDIPVLPRNTDLTVFVEANIQHGQQVLCQRRTSPKPFTEEVLWNVWLEFSIKIKDLPKGALLNLQIYCGKAPALSSKASAESPSSESKGKVQLLYYVNLLLIDHRFLLRRGEYVLHMWQISGKGEDQGSFNADKLTSATNPDKENSMSISILLDNYCHPIALPKHQPTPDPEGDRVRAEMPNQLRKQLEAIIATDPLNPLTAEDKELLWHFRYESLKHPKAYPKLFSSVKWGQQEIVAKTYQLLARREVWDQSALDVGLTMQLLDCNFSDENVRAIAVQKLESLEDDDVLHYLLQLVQAVKFEPYHDSALARFLLKRGLRNKRIGHFLFWFLRSEIAQSRHYQQRFAVILEAYLRGCGTAMLHDFTQQVQVIEMLQKVTLDIKSLSAEKYDVSSQVISQLKQKLENLQNSQLPESFRVPYDPGLKAGALAIEKCKVMASKKKPLWLEFKCADPTALSNETIGIIFKHGDDLRQDMLILQILRIMESIWETESLDLCLLPYGCISTGDKIGMIEIVKDATTIAKIQQSTVGNTGAFKDEVLNHWLKEKSPTEEKFQAAVERFVYSCAGYCVATFVLGIGDRHNDNIMITETGNLFHIDFGHILGNYKSFLGINKERVPFVLTPDFLFVMGTSGKKTSPHFQKFQDICVKAYLALRHHTNLLIILFSMMLMTGMPQLTSKEDIEYIRDALTVGKNEEDAKKYFLDQIEVCRDKGWTVQFNWFLHLVLGIKQGEKHSA
Open
Disease
Adrenal cancer, Asthma, Bacterial infection, B-cell lymphoma, BCR-ABL1-negative chronic myeloid leukaemia, Bladder cancer, Brain cancer, Breast cancer, Cardiovascular disease, Central nervous system disease, Colorectal cancer, Diffuse large B-cell lymphoma, Endometrial cancer, Follicular lymphoma, Head and neck cancer, Innate/adaptive immunodeficiency, Liver cancer, Lymphoma, Malignant haematopoietic neoplasm, Mature B-cell leukaemia, Melanoma, Metastatic lymph node neoplasm, Myelodysplastic syndrome, Myocardial infarction, Pain, Peritoneal cancer, Pleural mesothelioma, Postoperative inflammation, Prostate cancer, Rheumatoid arthritis, Solid tumour/cancer, Type 2 diabetes mellitus
Approved Drug
2 +
Clinical Trial Drug
35 +
Discontinued Drug
5 +

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Detailed Information

The PIK3CG gene is located on human chromosome 7q22.3 and contains 21 exons, encoding an mRNA of 3,234 bp that translates into the PI3Kγ catalytic subunit p110γ, composed of 1,102 amino acids. The protein has a molecular weight of approximately 126 kDa and features the canonical PI3K domains: adaptor-binding domain (ABD), Ras-binding domain (RBD), C2 domain, helical domain, and kinase catalytic domain. Unlike class IA PI3Ks, PI3Kγ (class IB) is activated independently of p85 adaptor proteins, forming heterodimers with regulatory subunits p101 (encoded by PIK3R5) or p84 (encoded by PIK3R6) to respond to G protein-coupled receptor (GPCR) signaling. Biochemical studies indicate that p110γ lipid kinase activity is strictly dependent on its regulatory subunit; without p101, p110γ can bind Gβγ but its catalytic efficiency is less than 1%. Notably, p110γ also exhibits serine/threonine protein kinase activity, catalyzing autophosphorylation at Ser1101, which is important for receptor internalization.

Figure 1. Overview of the PI3K family, highlighting the structural domains, subfamily classification, and distinct cellular functions of class I, II, and III enzymes.Figure 1. Overview of the PI3K family, highlighting the structural domains, subfamily classification, and distinct cellular functions of class I, II, and III enzymes. (Mognol GP, et al., 2025)

PIK3CG expression is largely restricted to hematopoietic cells (neutrophils, monocytes, mast cells) and cardiovascular tissues (cardiomyocytes, endothelial cells). Inflammatory stimuli can upregulate its expression 3–5-fold, mediated by transcription factors such as SPI1 (PU.1) and NF-κB. Structural studies show that the ABD domain of p110γ binds p101 via hydrophobic interactions, and the C2 domain’s basic residues (Lys771-Lys781) mediate electrostatic binding to membrane phospholipids. Unlike PIK3CA/B/D, PIK3CG is activated directly by Gβγ subunits released from GPCRs, making it a rapid responder in inflammatory signaling. Evolutionary analysis shows that PIK3CG is highly conserved in mammals (92% human-mouse homology) but absent in lower vertebrates, highlighting its role in advanced immune responses.

Biological Functions and Signaling Networks

PI3Kγ plays a central role in innate immunity and inflammation, coordinating leukocyte migration, mediator release, and remodeling of the immune microenvironment. During leukocyte chemotaxis, p110γ generates PIP3, guiding PH-domain-containing proteins (e.g., AKT, PDPK1) to the leading edge, regulating actin polymerization and integrin affinity, crucial for neutrophil transendothelial migration. PIK3CG knockout mice show a 60–80% reduction in neutrophil migration efficiency and impaired bacterial clearance. In adaptive immunity, p110γ mediates dendritic cell (DC) migration and T cell co-stimulation; inhibitor treatment reduces DC homing to lymph nodes by 50% and suppresses Th1/Th17 differentiation.

A distinctive feature of PI3Kγ is noncanonical signaling. In acute leukemia, the p110γ/p101 complex phosphorylates PAK1 (rather than AKT), regulating mitochondrial function. PAK1 recruitment to the outer mitochondrial membrane leads to phosphorylation of complex I subunit NDUFV2 (Ser177), enhancing electron transport chain activity and oxidative phosphorylation (OXPHOS), which is particularly active in leukemia stem cells, providing metabolic advantages. In the cardiovascular system, p110γ exerts dual roles: its protein kinase activity phosphorylates GRK2 (Ser670) to promote β-adrenergic receptor internalization, negatively regulating myocardial contractility, while also anchoring PKA and PDE3B to reduce cAMP levels (~40%) in cardiomyocytes and inhibit calcium transients. Overexpression can induce cardiac hypertrophy, whereas cardiac-specific knockout enhances contractile function.

Disease Mechanisms and Therapeutic Implications

PIK3CG dysfunction is implicated in hematologic malignancies and immune modulation. Genome-wide studies show that acute leukemias (AML, ALL, and BPDCN) exhibit selective dependency on PIK3CG, mediated by innate immune signals and regulated by PIK3R5 expression. TLR agonists can upregulate PIK3R5 2–3-fold, forming the p110γ/p101 complex and enhancing mitochondrial OXPHOS via the PAK1-NDUFV2 axis. Clinically, high PIK3R5 expression correlates with poorer prognosis and increased sensitivity to PI3Kγ inhibition.

In solid tumors, PI3Kγ contributes to immune suppression by promoting M2-like polarization of tumor-associated macrophages (TAMs) through CSF1R-GPCR signaling, increasing IL-10 and TGF-β secretion, and reducing IL-12 production. PI3Kγ inhibitors reverse TAM polarization, enhance CD8+ T cell infiltration, and inhibit tumor growth and metastasis in preclinical models. In chronic lymphocytic leukemia (CLL), PI3Kγ supports stromal-mediated survival signals, which can be overcome by combining PI3Kγ inhibitors with BTK blockers.

Figure 2. PI3Kγ signaling drives myeloid cell recruitment during inflammation by generating PIP3 and assembling membrane signaling complexes that activate integrins.Figure 2. PI3Kγ signaling drives myeloid cell recruitment during inflammation by generating PIP3 and assembling membrane signaling complexes that activate integrins. (Mognol GP, et al., 2025)

Targeted Therapy and Clinical Translation

Therapeutic strategies targeting PIK3CG include:

  1. Small-molecule inhibitors: Eganelisib (IPI-549), a selective PI3Kγ inhibitor (IC50 = 16 nM), prolongs survival in PIK3R5-high leukemia models without impairing baseline neutrophil function.
  2. Combination therapy: Eganelisib combined with cytarabine shows synergistic effects in AML, ALL, and BPDCN models, improving survival by 80–120%.
  3. Immune modulation: In solid tumors, PI3Kγ inhibitors enhance PD-1 inhibitor efficacy, with clinical trials demonstrating improved objective response rates and tolerability.

Challenges remain due to potential cardiovascular toxicity, long-term immune effects, and heterogeneity in PIK3R5 expression, emphasizing the need for patient stratification, novel allosteric inhibitors, PROTAC-based degradation, and biomarker-guided therapy.

Research Challenges and Future Directions

Key challenges include the spatial-temporal specificity of PI3Kγ signaling and complex feedback regulation. Future work should focus on high-resolution structures of the p110γ/p101 complex to guide selective inhibitor design, dissecting GPCR-PI3Kγ dynamics in the tumor immune microenvironment, and developing tissue-targeted delivery systems. Chemical biology tools (e.g., optogenetic modulators) and epigenetic editing via CRISPR/dCas9 may allow precise PI3Kγ modulation. Ongoing clinical studies, including Eganelisib-based combination therapies, highlight its emerging role in hematologic malignancies, inflammatory diseases, and cardiovascular research.

Reference

  1. Mognol GP, Ghebremedhin A, Varner JA. Targeting PI3Kγ in cancer. Trends Cancer. 2025 May;11(5):462-474.

  2. Xu H, Russell SN, Steiner K, et al. Targeting PI3K-gamma in myeloid-driven tumour immune suppression: a systematic review and meta-analysis of the preclinical literature. Cancer Immunol Immunother. 2024 Aug 6;73(10):204.

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