Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform also known as phosphoinositide 3-kinase (PI3K) delta isoform or p110ô is an enzyme that in humans is encoded by the PIK3CD gene.
p110ô regulates immune function. In contrast to the other class IA PI3Ks p110ñ and p110ò, p110ô is principally expressed in leukocytes (white blood cells). Genetic and pharmacological inactivation of p110ô has revealed that this enzyme is important for the function of T cells, B cell, mast cells and neutrophils. Hence, p110ô is a promising target for drugs that aim to prevent or treat inflammation, autoimmunity and transplant rejection.
Phosphoinositide 3-kinases (PI3Ks) phosphorylate the 3-prime OH position of the inositol ring of inositol lipids. The class I PI3Ks display a broad phosphoinositide lipid substrate specificity and include p110ñ, p110ò and p110ó. p110ñ and p110ò interact with SH2/SH3-domain-containing p85 adaptor proteins and with GTP-bound Ras.
Like the other class IA PI3Ks, p110ô is a catalytic subunit, whose activity and subcellular localisation are controlled by an associated p85ñ, p55ñ, p50ñ or p85ò regulatory subunit. The p55ó regulatory subunit is not thought to be expressed at significant levels in immune cells. There is no evidence for selective association between p110ñ, p110ò or p110ô for any particular regulatory subunit. The class IA regulatory subunits (collectively referred to here as p85) bind to proteins that have been phosphorylated on tyrosines. Tyrosine kinases often operate near the plasma membrane and hence control the recruitment of p110ô to the plasma membrane where its substrate PtdIns(4,5)P2 is found. The conversion of PtdIns(4,5)P2 to PtdIns(3,4,5)P3 triggers signal transduction cascades controlled by PKB (also known as Akt), Tec family kinases and other proteins that contain PH domains. In immune cells, antigen receptors, cytokine receptors and costimulatory and accessory receptors stimulate tyrosine kinase activity and hence all have the potential to initiate PI3K signalling.
For reasons that are not well understood, p110ô appears to be activated in preference to p110ñ and p110ò in a number of immune cells. The following is a brief summary of the role of p110ô in selected leukocyte subsets.
In T cells, the antigen receptor (TCR) and costimulatory receptors (CD28 and ICOS) are thought to be main receptors responsible for recruiting and activating p110ô. Genetic inactivation of p110ô in mice causes T cells to be less responsive to antigen as determined by their reduced ability to proliferate and secrete interleukin 2. T cell specific deletion of p110ô has revealed its role in antibody responses. This may in part result from incomplete assembly of other signalling proteins at the immune synapse. The TCR cannot stimulate the phosphorylation of Akt in that absence of p110ô activity.
p110ô is a regulator of B cell proliferation and function. p110ô-deficient mice have deficient antibody responses. They also lack to B cell subsets: B1 cells (found in body cavities such as the peritoneum) and marginal zone B cells, found in the periphery of spleen follicles).
p110ô controls mast cell release of the granules responsible for allergic reactions. Thus inhibition of p110ô reduces allergic responses.
In conjunction with p110ó, p110ô controls the release of reactive oxygen species in neutrophils.
p110ô controls lipopolysaccharide induced Toll-like-receptor-4 mediated innate immune responses in dendritic cells and mice carrying an inactive p110ô is susceptible to lipopolysaccharide mediated endotoxin shock.
Inherited mutations in the PIK3CD gene which increase p110ô catalytic activity cause a primary immunodeficiency syndrome called APDS or PASLI.
US pharmaceutical company ICOS produced a selective inhibitor of p110ô called IC87114. This inhibitor selectively impairs B cell, mast cell and neutrophil functions and is therefore a potential immune-modulator.
The p110ô inhibitor idelalisib was developed by Gilead Sciences. Idelalisib in combination with rituximab showed favourable progression free survival in a phase III clinical trial for chronic lymphocytic leukemia (CLL) compared with patients that received rituximab and placebo.
In July 2014 idelalisib was approved by the FDA as a treatment for CLL patients.
In September 2017 copanlisib, inhibiting predominantly p110ñ and p110ô, got FDA approval for the treatment of adult patients with relapsed follicular lymphoma (FL) who have received at least two prior systemic therapies.
In September 2018 duvelisib was approved by the FDA as a treatment for relapsed or refractory CLL, and relapsed follicular lymphoma (FL) patients, who have received at least two prior therapies.
A 2015 study found that p110ô inhibitors had a side-effect of boosting mouse immune responses against multiple cancers, including both solid and hematological types. Breast cancer mice survival times nearly doubled and spread significantly less, with far fewer and smaller tumors. Post-surgical survival also improved. Subject immune systems could also develop an effective memory response, extending protection.
PIK3CD interacts with PIK3R1, and PIK3R2.