P110δ

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform also known as is_associated_with::phosphoinositide 3-kinase (PI3K) delta isoform or p110δ is an is_associated_with::enzyme that in humans is encoded by the PIK3CD is_associated_with::gene.

p110δ regulates immune function. In contrast to the other class IA PI3Ks is_associated_with::p110α and p110β, p110δ is principally expressed in is_associated_with::leukocytes (white blood cells). Genetic and pharmacological inactivation of p110δ has revealed that this enzyme is important for the function of is_associated_with::T cells, is_associated_with::B cell, is_associated_with::mast cells and is_associated_with::neutrophils. Hence, p110δ is considered to be a promising target for drugs that aim to prevent or treat inflammation and 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 p110α, p110β, and is_associated_with::p110γ. p110α and p110β interact with SH2/SH3-domain-containing p85 adaptor proteins and with GTP-bound Ras.

Biochemistry
Like the other class IA PI3Ks, p110δ is a catalytic subunit, whose activity and subcellular localisation are controlled by an associated is_associated_with::p85α, p55α, p50α or is_associated_with::p85β regulatory subunit. The p55γ regulatory subunit is not thought to be expressed at significant levels in immune cells. There is no evidence for selective association between p110α, p110β or p110δ for any particular regulatory subunit. The class IA regulatory subunits (collectively referred to here as p85) bind to proteins which have been phosphorylated on is_associated_with::tyrosines. is_associated_with::Tyrosine kinases often operate near the plasma membrane and hence control the recruitment of p110δ to the plasma membrane where it substrate PtdIns(4,5)P2 is found. The conversion of is_associated_with::PtdIns(4,5)P2 to is_associated_with::PtdIns(3,4,5)P3 triggers signal transduction cascades controlled by PKB (also known as is_associated_with::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.

Functions
For reasons that are not well understood, p110δ appears to be activated in preference to p110α and p110β in a number of immune cells. The following is a brief summary of the role of p110δ in selected leukocyte subsets.

T cells
In is_associated_with::T cells, the antigen receptor (TCR) and costimulatory receptors (is_associated_with::CD28 and ICOS) are thought to be main receptors responsible for recruiting and activating p110δ. Genetic inactivation of p110δ in mice causes is_associated_with::T cells to be less responsive to antigen as determined by their reduced ability to proliferate and secrete is_associated_with::interleukin 2. T cell specific deletion of p110δ 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 is_associated_with::Akt in that absence of p110δ activity.

B cells
p110δ is a key regulator of is_associated_with::B cell proliferation and function. p110δ deficient mice have deficient is_associated_with::antibody responses. They also lack to B cell subsets: B1 cells (found in body cavities such as the is_associated_with::peritoneum) and marginal zone B cells, found in the periphery of spleen follicles).

Mast cells
p110δ controls is_associated_with::mast cell release of the granules responsible for allergic reactions. Thus inhibition of p110δ reduces allergic responses.

Neutrophils
In conjunction with p110γ, p110δ controls the release of is_associated_with::reactive oxygen species in is_associated_with::neutrophils.

Activated PI3K delta Syndrome
Inherited mutations in the PIK3CD gene which increase p110δ catalytic activity cause a primary immunodeficiency syndrome called APDS or PASLI. .

Pharmacology
The US pharmaceutical company is_associated_with::ICOS produced a selective inhibitor of p110δ called is_associated_with::IC87114. This inhibitor has been shown to selectively impair B cell, mast cell and neutrophil functions and is therefore a potential immune-modulator.

The p110δ inhibitor is_associated_with::idelalisib (formerly known as is_associated_with::CAL-101) has been developed by is_associated_with::Gilead Sciences. Idelalisib in combination with is_associated_with::rituximab showed favourable progression free survival in a phase III clinical trial for is_associated_with::chronic lymphocytic leukemia (CLL) compared with patients that received is_associated_with::rituximab and is_associated_with::placebo.

July 2014: is_associated_with::Idelalisib (marketed as is_associated_with::Zydelig) was approved by US FDA as a treatment for patients with CLL.

Interactions
PIK3CD has been shown to interact with is_associated_with::PIK3R1, and is_associated_with::PIK3R2.