PIK3CD Gene

The PIK3CD gene (PIK3CD stands for "phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta") is a protein-coding gene located on chromosome 1p36.22.

PI 3-kinases (phosphoinositide 3-kinases, PI 3-Ks) are a family of lipid kinases capable of phosphorylating the 3'OH of the inositol ring of phosphoinositides. They are responsible for coordinating a variety of cellular functions, including proliferation and survival. Phosphoinositide 3-kinase (PI3K), encoded by the PIK3CD gene, phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides (Chantry D et al. (1997).

PI3K uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to form phosphatidylinositol 3,4,5-trisphosphate (PIP3) (Meier TI et al. 2004). 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. PIK3CD kinase plays a role in B cell development, proliferation, migration and function. It sit required for B cell receptor (BCR) signaling. Mediates the 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 switching mediated by TLR9. Participates in antigen presentation function of B cells. Involved in chemotaxis of B cells in response to CXCL13 and sphingosine-1-phosphate (S1P). Furthermore, PIK3CD is required for proliferation, signaling, and cytokine production of naive, effector, and memory T cells and for T cell receptor (TCR) signaling. Mediates TCR signaling events at the immune synapse. Activation by the TCR leads to antigen-dependent migration and retention of memory T cells in antigenic tissues. PIK3CD, together with PIK3CG, is involved in T cell development. Contributes to the expansion and differentiation of T helper cells. This kinase is involved in the activation of NK cell receptors. Plays a role in NK cell maturation and cytokine production. Is involved with PIK3CG in neutrophil chemotaxis and extravasation, as well as in mast cell development and the mast cell-mediated allergic response. This kinase is required for allergen IgE-induced degranulation and cytokine release.

Diseases associated with PIK3CD include immunodeficiency 14A, autosomal dominant and immunodeficiency 14B, autosomal recessive, both primary immunodeficiency syndromes characterized by the presence of recurrent sinopulmonary and other infections in early childhood (Lucas CL et al 2014).

1. Angulo I et al. (2013) Phosphoinositide 3-kinase-delta gene mutation predisposes to respiratory infection and airway damage. Science 342: 866-871.
2. Chantry D et al. (1997) p110delta, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes. J Biol Chem 272:19236-192341.
3. Crank MC et al (2014) Mutations in PIK3CD can cause hyper IgM syndrome associated with increased cancer susceptibility. J. Clin. Immun. 34: 272-276.
4. Jou S-T et al (2006) Identification of variations in the human phosphoinositide 3-kinase p110-delta gene in children with primary B-cell immunodeficiency of unknown aetiology. Int J Immunogenet 33: 361-369.
5. Lucas CL et al. (2014) Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110-delta result in T cell senescence and human immunodeficiency. Nature Immun 15: 88-97.
6. Meier TI et al. (2004) Cloning, expression, purification, and characterization of the human Class Ia phosphoinositide 3-kinase isoforms. Protein Expr Purif 35:218-224)
7. Okkenhaug K et al (2002) Impaired B and T cell antigen receptor signaling in p110-delta PI 3-kinase mutant mice. Science 297: 1031-1034.