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PIK3CD

Official Full Name
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta
Organism
Homo sapiens
GeneID
5293
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 PI3K found primarily in leukocytes. Like other class I PI3Ks (p110-alpha p110-beta, and p110-gamma), the encoded protein binds p85 adapter proteins and GTP-bound RAS. However, unlike the other class I PI3Ks, this protein phosphorylates itself, not p85 protein.[provided by RefSeq, Jul 2010]
Synonyms
APDS; PI3K; IMD14; p110D; IMD14A; IMD14B; ROCHIS; P110DELTA;
Bio Chemical Class
Kinase
Protein Sequence
MPPGVDCPMEFWTKEENQSVVVDFLLPTGVYLNFPVSRNANLSTIKQLLWHRAQYEPLFHMLSGPEAYVFTCINQTAEQQELEDEQRRLCDVQPFLPVLRLVAREGDRVKKLINSQISLLIGKGLHEFDSLCDPEVNDFRAKMCQFCEEAAARRQQLGWEAWLQYSFPLQLEPSAQTWGPGTLRLPNRALLVNVKFEGSEESFTFQVSTKDVPLALMACALRKKATVFRQPLVEQPEDYTLQVNGRHEYLYGSYPLCQFQYICSCLHSGLTPHLTMVHSSSILAMRDEQSNPAPQVQKPRAKPPPIPAKKPSSVSLWSLEQPFRIELIQGSKVNADERMKLVVQAGLFHGNEMLCKTVSSSEVSVCSEPVWKQRLEFDINICDLPRMARLCFALYAVIEKAKKARSTKKKSKKADCPIAWANLMLFDYKDQLKTGERCLYMWPSVPDEKGELLNPTGTVRSNPNTDSAAALLICLPEVAPHPVYYPALEKILELGRHSECVHVTEEEQLQLREILERRGSGELYEHEKDLVWKLRHEVQEHFPEALARLLLVTKWNKHEDVAQMLYLLCSWPELPVLSALELLDFSFPDCHVGSFAIKSLRKLTDDELFQYLLQLVQVLKYESYLDCELTKFLLDRALANRKIGHFLFWHLRSEMHVPSVALRFGLILEAYCRGSTHHMKVLMKQGEALSKLKALNDFVKLSSQKTPKPQTKELMHLCMRQEAYLEALSHLQSPLDPSTLLAEVCVEQCTFMDSKMKPLWIMYSNEEAGSGGSVGIIFKNGDDLRQDMLTLQMIQLMDVLWKQEGLDLRMTPYGCLPTGDRTGLIEVVLRSDTIANIQLNKSNMAATAAFNKDALLNWLKSKNPGEALDRAIEEFTLSCAGYCVATYVLGIGDRHSDNIMIRESGQLFHIDFGHFLGNFKTKFGINRERVPFILTYDFVHVIQQGKTNNSEKFERFRGYCERAYTILRRHGLLFLHLFALMRAAGLPELSCSKDIQYLKDSLALGKTEEEALKHFRVKFNEALRESWKTKVNWLAHNVSKDNRQ
Open
Disease
Asthma, B-cell lymphoma, Breast cancer, Colorectal cancer, Diffuse large B-cell lymphoma, Follicular lymphoma, Lymphoma, Malignant haematopoietic neoplasm, Mature B-cell leukaemia, Mature B-cell lymphoma, Mycosis fungoides, Rheumatoid arthritis, Sjogren syndrome, Solid tumour/cancer, Stomach cancer
Approved Drug
5 +
Clinical Trial Drug
16 +
Discontinued Drug
1 +

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Detailed Information

The PIK3CD gene, located at 1p36.2, contains 24 exons and encodes a 4,319 bp mRNA that translates into the p110δ catalytic subunit of class IA PI3K, consisting of 1,044 amino acids with a molecular weight of ~119 kDa. p110δ includes conserved PI3K domains: the adapter-binding domain (ABD), Ras-binding domain (RBD), C2 domain, helical domain, and kinase catalytic domain.

Unlike other PI3K family members, PIK3CD expression is highly leukocyte-specific, predominantly in T cells, B cells, NK cells, mast cells, and neutrophils, making p110δ a central regulator of immune signaling, particularly during adaptive immune responses. Two splicing isoforms exist: isoform 1 is full-length and functional, while isoform 2, lacking part of the ABD, is kinase-inactive but may enhance ERK signaling via RAS stabilization.

During immune cell development and activation, PIK3CD expression is dynamically regulated. Expression increases 2–3 fold during B cell differentiation into memory B cells and can be upregulated 4-fold within six hours of TCR activation. Transcriptional control involves factors such as SPI1/PU.1, promoter binding, and epigenetic modifications. Innate immune signals, including TLR4/TLR9 activation, further enhance PIK3CD expression, creating positive feedback to amplify inflammation. Despite 68% sequence homology with PIK3CB, p110δ functions in immune cells are non-redundant—knockout mice show impaired B and T cell function, whereas PIK3CB deletion minimally affects immune homeostasis.

Biological Function and Signaling

p110δ is the leukocyte-dominant class IA PI3K catalytic subunit and a key regulator of immune synapse formation, lymphocyte activation, and inflammatory responses.

In B cells, p110δ mediates BCR-induced PI3K/AKT signaling, supporting germinal center formation, class-switch recombination, and plasma cell differentiation. Upon antigen engagement, p110δ is recruited to the immune synapse, generates PIP3, and recruits PH-domain-containing proteins (e.g., BTK, AKT) to assemble signaling complexes. Loss of p110δ impairs B cell proliferation in response to IgM, CD40L, and IL-4, reducing antibody production by 50–70%.

In T cells, p110δ participates in early TCR signaling, thymocyte positive selection, initial T cell activation, and effector migration to inflammatory sites. It promotes Th1/Th17 differentiation via the AKT-mTOR axis while suppressing Treg function and coordinates chemokine-directed migration by integrating CCR7, S1PR1, and CD62L signals.

Figure 1. Mechanism of PI3K ActivationFigure 1. Mechanism of PI3K Activation

In innate immune cells, p110δ fine-tunes function: in NK cells, it cooperates with p110γ for cytotoxicity and cytokine production; in neutrophils, it regulates Fcγ receptor-mediated respiratory burst and chemotaxis; in mast cells, it is critical for IgE-FcεRI-mediated degranulation and release of histamine and leukotrienes. Its function strictly depends on lipid kinase activity, with kinase-dead mutants (e.g., D910A) losing signaling capability.

Disease Associations and Pathology

PIK3CD dysfunction is implicated in primary immunodeficiencies and hematologic malignancies.

Primary Immunodeficiency: Gain-of-function mutations cause Activated PI3Kδ Syndrome (APDS1), an autosomal dominant disease. The E1021K mutation in the kinase domain is predominant, leading to constitutive p110δ activation. Clinically, patients present in early childhood with recurrent respiratory infections, chronic diarrhea, EBV/CMV viremia, and lymphadenopathy. Immunophenotypes include elevated IgM, reduced IgG, decreased naïve CD4⁺ T cells, increased terminal effector CD8⁺ T cells, and B cell abnormalities. Untreated patients risk lymphoma development (~10%).

Hematologic Malignancies: PIK3CD is often overexpressed in DLBCL, particularly the ABC subtype, and promotes tumor cell survival through BCR-like signaling. In acute leukemias, p110δ partners with PIK3R5 to form non-canonical signaling modules that enhance mitochondrial oxidative phosphorylation, conferring a proliferative advantage.

Targeted Therapy and Clinical Translation

Therapeutic strategies against PIK3CD include:

  1. Small Molecule Inhibitors: Idelalisib selectively inhibits p110δ (IC50=2.5 nM) with 20–300× selectivity over other PI3Ks. In APDS1, it reduces lymphadenopathy, improves lung function, and decreases infection frequency. mTOR inhibitors like rapamycin mitigate hepatosplenomegaly but require monitoring for myelosuppression.
  2. Immune Modulation: Regular IVIG partially compensates for antibody deficiencies; rituximab can manage autoimmune cytopenias.
  3. Combination Therapy: In acute leukemia, p110δ inhibitors (e.g., Eganelisib) synergize with cytarabine, enhancing survival in preclinical models, particularly in PIK3R5-high tumors.

Challenges include drug resistance, immune-related adverse events, and long-term toxicity. Gene therapy approaches using CRISPR-Cas9 or stem cell transplantation remain exploratory.

Emerging Challenges and Future Directions

Key challenges involve functional complexity and pathological heterogeneity: moderate p110δ activity is essential for host defense, whereas hyperactivation causes immune pathology. Even identical mutations (e.g., E1021K) show variable clinical outcomes, influenced by modifier genes and environment.

Future research priorities:

  1. Humanized mouse models to study GOF mutation dynamics and lymphoma progression.
  2. Development of allosteric inhibitors that selectively block aberrant p110δ interactions while preserving basal signaling.
  3. Biomarker-guided stratification for therapy, e.g., using PIK3R5 expression or circulating tumor DNA to monitor resistance.

Advances in single-cell sequencing and proteomics will clarify the spatiotemporal regulation of p110δ signaling, including immune synapse activation and subtype-specific dependency. Next-generation selective inhibitors (e.g., Leniolisib) and nanobody-based PROTACs achieving >90% target degradation offer new avenues to overcome resistance. Integrating immunology, structural biology, and clinical medicine may enable precision therapy targeting PIK3CD to reshape treatment for immunodeficiency and hematologic malignancies.

Reference

  1. Blanco J, Cameirao C, López MC, et al. Phosphatidylinositol-3-kinase-Akt pathway in negative-stranded RNA virus infection: a minireview. Arch Virol. 2020 Oct;165(10):2165-2176.

  2. Fan L, Xiao H, Ren J, et al. Newcastle disease virus induces clathrin-mediated endocytosis to establish infection through the activation of PI3K/AKT signaling pathway by VEGFR2. J Virol. 2024 Oct 22;98(10):e0132224.

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