P110δ
Encyclopedia
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform also known as phosphoinositide 3-kinase
(PI3K) or p110δ is an enzyme
that in humans is encoded by the PIK3CD gene
.
p110δ regulates immune function. In contrast to the other class IA PI3Ks p110α and p110β
, p110δ is principally expressed in leukocytes (white blood cells). Genetic and pharmacological inactivation of p110δ has revealed that this enzymes is important for the function of T cells, B cell
, mast cells and neutrophils. Hence, p110δ is consider 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 p110γ. p110α and p110β interact with SH2
/SH3
-domain-containing p85 adaptor proteins and with GTP-bound Ras.
) bind to proteins which have been phosphorylated on tyrosine
s. Tyrosine kinase
s 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 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.
s, the antigen receptor (TCR) and costimulatory receptors (CD28
and ICOS
) are thought to be main receptors responsible for recruiting and activating p110δ. Genetic inactivation of p110δ in mice causes T cells to be less responsive to antigen as determined by their reduced ability to proliferate and secrete interleukin 2
. This may in part results from incomplete assembly of other signalling proteins at the immune synapse. The TCR cannot stimulate the phosphorylation of Akt
in that absence of p110δ activity.
proliferation and function. p110δ 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).
release of the granules responsible for allergic
reactions. Thus inhibition of p110δ reduces allergic responses.
in neutrophils.
has produced a selective inhibitor of p110δ called IC87114. This inhibitor has been shown to selectively impair B cell, mast cell and neutrophil functions and is therefore a potential immune-modulator.
Another p110δ inhibitor is CAL101 which has reported good results from phase I clinical trials.
with PIK3R1
, PIK3CG
and PIK3R2
.
Phosphoinositide 3-kinase
Phosphatidylinositol 3-kinases are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In response to lipopolysaccharide, PI3K phosphorylates p65, inducing...
(PI3K) or p110δ is an enzyme
Enzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
that in humans is encoded by the PIK3CD gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
p110δ regulates immune function. In contrast to the other class IA PI3Ks p110α and p110β
PIK3CB
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta isoform is an enzyme that in humans is encoded by the PIK3CB gene.-Further reading:...
, p110δ is principally expressed in leukocytes (white blood cells). Genetic and pharmacological inactivation of p110δ has revealed that this enzymes is important for the function of T cells, B cell
B cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
, mast cells and neutrophils. Hence, p110δ is consider 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 p110γ. p110α and p110β interact with SH2
SH2 domain
The SH2 domain is a structurally conserved protein domain contained within the Src oncoprotein and in many other intracellular signal-transducing proteins...
/SH3
SH3 domain
The SRC Homology 3 Domain is a small protein domain of about 60 amino acids residues first identified as a conserved sequence in the viral adaptor protein v-Crk and the non-catalytic parts of enzymes such as phospholipase and several cytoplasmic tyrosine kinases such as Abl and Src...
-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 p85α, p55α, p50α or p85β regulatory subunit. The p55γ regulatory subunit is not thought to be expressed at significant levels in immune cells. These 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 p85P85
P85 or p85 may refer to:* Ruger P85, a 1985 pistol model* Yamaha P-85, an entry-level digital piano* McDonnell P-85, an expermental parasite fighter of the USAF in the 1950s.and also :* a Latvian State first class road...
) bind to proteins which have been phosphorylated on tyrosine
Tyrosine
Tyrosine or 4-hydroxyphenylalanine, is one of the 22 amino acids that are used by cells to synthesize proteins. Its codons are UAC and UAU. It is a non-essential amino acid with a polar side group...
s. Tyrosine kinase
Tyrosine kinase
A tyrosine kinase is an enzyme that can transfer a phosphate group from ATP to a protein in a cell. It functions as an "on" or "off" switch in many cellular functions....
s 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 PtdIns(4,5)P2 to PtdIns(3,4,5)P3 triggers signal transduction cascades controlled by PKB
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
(also known as Akt
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
), Tec
TEC (gene)
Tyrosine-protein kinase Tec is an enzyme that in humans is encoded by the TEC gene.-Interactions:TEC has been shown to interact with GNA12, Janus kinase 2, CD117, Suppressor of cytokine signaling 1, ARHGEF12 and DOK1.-Further reading:...
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 T cellT cell
T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes, and play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and natural killer cells , by the presence of a T cell receptor on the cell surface. They are...
s, the antigen receptor (TCR) and costimulatory receptors (CD28
CD28
CD28 is one of the molecules expressed on T cells that provide co-stimulatory signals, which are required for T cell activation. CD28 is the receptor for CD80 and CD86 . When activated by Toll-like receptor ligands, the CD80 expression is upregulated in antigen presenting cells...
and ICOS
CD278
Inducible T-cell costimulator is a protein that in humans is encoded by the ICOS gene.CD278 or ICOS is a CD28-superfamily costimulatory molecule that is expressed on activated T cells...
) are thought to be main receptors responsible for recruiting and activating p110δ. Genetic inactivation of p110δ in mice causes T cells to be less responsive to antigen as determined by their reduced ability to proliferate and secrete interleukin 2
Interleukin 2
Interleukin-2 is an interleukin, a type of cytokine immune system signaling molecule, which is a leukocytotrophic hormone that is instrumental in the body's natural response to microbial infection and in discriminating between foreign and self...
. This may in part results from incomplete assembly of other signalling proteins at the immune synapse. The TCR cannot stimulate the phosphorylation of Akt
AKT
Akt, also known as Protein Kinase B , is a serine/threonine protein kinase that plays a key role in multiple cellular processes such as glucose metabolism, cell proliferation, apoptosis, transcription and cell migration.-Family members:...
in that absence of p110δ activity.
B cells
p110δ is a key regulator of B cellB cell
B cells are lymphocytes that play a large role in the humoral immune response . The principal functions of B cells are to make antibodies against antigens, perform the role of antigen-presenting cells and eventually develop into memory B cells after activation by antigen interaction...
proliferation and function. p110δ deficient mice have deficient antibody
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
responses. They also lack to B cell subsets: B1 cells (found in body cavities such as the peritoneum
Peritoneum
The peritoneum is the serous membrane that forms the lining of the abdominal cavity or the coelom — it covers most of the intra-abdominal organs — in amniotes and some invertebrates...
) and marginal zone B cells, found in the periphery of spleen follicles).
Mast cells
p110δ controls mast cellMast cell
A mast cell is a resident cell of several types of tissues and contains many granules rich in histamine and heparin...
release of the granules responsible for allergic
Allergy
An Allergy is a hypersensitivity disorder of the immune system. Allergic reactions occur when a person's immune system reacts to normally harmless substances in the environment. A substance that causes a reaction is called an allergen. These reactions are acquired, predictable, and rapid...
reactions. Thus inhibition of p110δ reduces allergic responses.
Neutrophils
In conjunction with p110γ, p110δ controls the release of reactive oxygen speciesReactive oxygen species
Reactive oxygen species are chemically reactive molecules containing oxygen. Examples include oxygen ions and peroxides. Reactive oxygen species are highly reactive due to the presence of unpaired valence shell electrons....
in neutrophils.
Pharmacology
The US pharmaceutical company ICOSICOS
Icos Corporation was the largest biotechnology company in the U.S. state of Washington before it was sold to Eli Lilly and Company in 2007. Co-founded in 1989 by George B. Rathmann, a pioneer in the industry and Chief Executive Officer and co-founder of Amgen, Icos focused on the development of...
has produced a selective inhibitor of p110δ called IC87114. This inhibitor has been shown to selectively impair B cell, mast cell and neutrophil functions and is therefore a potential immune-modulator.
Another p110δ inhibitor is CAL101 which has reported good results from phase I clinical trials.
Interactions
PIK3CD has been shown to interactProtein-protein interaction
Protein–protein interactions occur when two or more proteins bind together, often to carry out their biological function. Many of the most important molecular processes in the cell such as DNA replication are carried out by large molecular machines that are built from a large number of protein...
with PIK3R1
PIK3R1
Phosphatidylinositol 3-kinase regulatory subunit alpha is an enzyme that in humans is encoded by the PIK3R1 gene.-Interactions:PIK3R1 has been shown to interact with EPH receptor A2, KHDRBS1, Lymphocyte cytosolic protein 2, Janus kinase 2, GAB2, CD117, BCAR1, CD28, SHB, EZR, PIK3CD, GAB1, HRAS,...
, PIK3CG
PIK3CG
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit gamma isoform is an enzyme that in humans is encoded by the PIK3CG gene.-Interactions:PIK3CG has been shown to interact with PIK3CD, KRAS, PIK3R5 and BCR gene.-Further reading:...
and PIK3R2
PIK3R2
Phosphatidylinositol 3-kinase regulatory subunit beta is an enzyme that in humans is encoded by the PIK3R2 gene.-Interactions:PIK3R2 has been shown to interact with FYN, HER2/neu, Epidermal growth factor, Cbl gene, PIK3CD, CRKL and Macrophage colony-stimulating factor.-Further reading:...
.