Alt. symbols: p110D

Approved name: phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta
Alt. names: phosphoinositide-3-kinase, catalytic, delta polypeptide, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta | phosphatidylinositol 3-kinase, catalytic, delta polypeptide, phosphoinositide-3-kinase C

Location: 1p36.22: 9629889 - 9729114 (+)
Gene type: protein_coding, 23 transcripts.

Scores: LoFtool: 0.183000 | pLI: 0.99998429 | LOEUF: 0.196

HGNC: 8977

NCBI: 5293, RefSeq: NG_023434.1

Ensembl: ENSG00000171608.18

LRG_191 | Status: public

OMIM: 602839

Expression | ProteinAtlas

PIK3CD encodes the delta catalytic subunit of the class I phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K), which is also known as phosphoinositide 3-kinase delta (PI3K-delta) or p110-delta protein. Class I PI3Ks are heterodimers composed of a catalytic subunit (p110-alpha, p110-beta, p110-gamma, or p110-delta) and a regulatory subunit (p85-alpha, p85-beta, p55-gamma, p150, p101, or p87). The most highly expressed regulatory subunit is p85-alpha (PIK3R1 gene), and the catalytic subunit p110-delta (PIK3CD) is specially enriched in leukocytes and other immune cells. Generally, PI3Ks phosphorylate PftdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). PIP3 is essential for the recruitment of PH domain-containing proteins to the plasma membrane, thus activating signalling cascades involved in cell growth, survival, proliferation, differentiation, motility and morphology. Like the other PI3 kinases, the PI3K-delta isoform phosphorylates other proteins such as signalling molecules that transmit chemical signals within lymphocytes and other immune cells. In T cells, p110-delta is required for proliferation, signalling and cytokine production of naive, effector and memory T-cells. The cell receptor (TCR) and co-stimulatory membrane receptors (CD28 and ICOS) are thought to recruit and activate p110-delta to transmit the TCR-mediated signalling. Activation by TCR leads to antigen-dependent memory T-cell migration and retention to antigenic tissues. It also participates in T-cell development, and contributes to T-helper cell expansion and differentiation. In B cells, p110-delta is required for B-cell receptor (BCR) signalling, which is essential for B-cell development, proliferation, migration, and function. In this manner, p110-delta mediates B-cell proliferation in response to anti-IgM, anti-CD40 and IL4 stimulation; and it promotes cytokine production in response to TLR4 and TLR9. p110-delta is also needed for antibody class switch mediated by TLR9, for antigen presentation function of B-cells and for B-cell chemotaxis in response to CXCL13 and sphingosine 1-phosphate (S1P). In natural killer (NK) cells, p110-delta, together with p110-gamma, participates in NK cell receptor activation, NK development, maturation, cytokine production and migration towards the sites of inflammation. In neutrophils, p110-delta, in conjunction with p110-gamma, controls the release of reactive oxygen species, and participates in neutrophil chemotaxis and extravasation. In mast cells, p110-delta controls the release of the granules responsible for allergic reactions and is involved in mast-cell development. In dendritic cells (DC), p110-delta controls lipopolysaccharide induced Toll-like-receptor-4 mediated innate immune responses.

Heterozygous gain-of-function (GOF) mutations in PIK3CD have been shown to cause autosomal dominant activated PI3K-delta type I syndrome (APDS1), also known as Immunodeficiency 14 [MIM:615513], in over 60 affected individuals from over 30 families to date (Jou et al., 2006; Angulo et al., 2013; Crank et al., 2014; Lucas et al., 2014; Hartman et al., 2015; Nademi et al., 2017; Takeda et al., 2017). Most affected individuals with activated APDS1 present with recurrent sinopulmonary infections, inc luding pneumonias, and other viral infections like EBV, CMV, HSV and VZV in early childhood. The majority of them develop bronchiectasis. Laboratory studies show defects in both B- and T-cell populations and increased serum IgM, with an inability to control infection by EBV and CMV. Patient CD8+ T cells are skewed toward differentiation and senescence. Many patients develop lymphadenopathy, splenomegaly, hepatomegaly, autoimmune disease, mucosal lymphoid aggregates, and/or enteropathy (Coulter et al., 2017). The first and most predominantly reported mutation in PIK3CD is the p.E1021K, with at least 50 patients identified. Additional pathogenic missense mutations are the p.E525K p.C416R, and p.N334K. A PI3K-delta enzyme containing the altered p110? subunit is abnormally activated. Overactive signalling causes T cells to mature and die too quickly, and blocks maturation of B cells at an early stage; which cannot respond to pathogens and likely self-destruct. Overactivation of PI3K-delta signalling can also stimulate abnormal proliferation of lymphocytes, and lymphadenopathy. Activated PI3K-delta syndrome also increases the risk of developing B-cell lymphomas. [Load More]