biology

P110δ

P110δ is a biology topic covered in the lgStudy science library. This page brings together a partial reference excerpt, illustrations, worked examples, real-world applications and a short study plan, so you can understand P110δ rather than just read about it. In short: Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform also known as phosphoinositide 3-kinase (PI3K) delta isoform 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).

Key takeaways

P110δ belongs to biology; place it in that map before memorising details.
Learn the definition first, then one example that makes the definition concrete.
Connect P110δ to a quantity you can measure, compute or draw — that is where exam questions come from.
Reproduce the core statement of P110δ from memory before moving on to harder problems.

Reference excerpt

Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform also known as phosphoinositide 3-kinase (PI3K) delta isoform 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 enzyme is important for the function of T cells, B cell, mast cells and neutrophils. Hence, p110δ 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 p110α, p110β and 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 p85α, p55α, p50α or 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 that have been phosphorylated on tyrosines. Tyrosine kinases often operate near the plasma membrane and hence control the recruitment of p110δ 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.

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 cells, 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. 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 Akt in that absence of p110δ activity.

B cells p110δ is a regulator of B cell 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).

Mast cells p110δ controls 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 reactive oxygen species in neutrophils.

Dendritic cells p110δ controls lipopolysaccharide induced Toll-like-receptor-4 mediated innate immune responses in dendritic cells and mice carrying an inactive p110δ is susceptible to lipopolysaccharide mediated endotoxin shock.

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 US pharmaceutical company ICOS produced a selective inhibitor of p110δ called IC87114. This inhibitor selectively impairs B cell, mast cell and neutrophil functions and is therefore a potential immune-modulator. The p110δ 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 p110α and p110δ, 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 p110δ 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.

Interactions PIK3CD interacts with PIK3R1, and PIK3R2.

See also Phosphoinositide 3-kinase inhibitor

References

Illustrations

Worked examples

Example 1 — a first encounter with P110δ

Start with the simplest possible case. Write down what P110δ claims or describes in one sentence, then invent the smallest concrete situation in which that sentence is true. In biology, the smallest case is usually a single object, a single equation or a single measurement. Check that every symbol or term in your sentence has a meaning in that case.

Example 2 — changing one variable

Take the situation from Example 1 and change exactly one quantity: double it, halve it, or set it to zero. Predict what should happen to P110δ before you calculate. Comparing your prediction with the result is the fastest way to find out whether you understand the idea or only the words.

Example 3 — an exam-style question

Typical questions about P110δ ask you to (a) state it precisely, (b) apply it to given data, and (c) explain a limitation. Practise writing all three answers in under five minutes; the third part is what separates a full-mark answer from an average one.

Applications of P110δ

In research: P110δ appears in biology research whenever the underlying quantities have to be modelled precisely. Papers usually cite it as a starting assumption and then explore where it breaks down.
In technology and industry: Engineering practice reuses P110δ in design rules, simulations and safety margins. Knowing the idea lets you read a specification sheet and understand why the numbers look the way they do.
In the classroom: P110δ is common in secondary-school and first-year university syllabi. It links to neighbouring topics EC 2.7.1, Genes on human chromosome 1, Immune system, so understanding it makes those chapters shorter.
In everyday life: Look for P110δ outside the textbook — in sport, cooking, traffic, electronics or the sky above you. An example you found yourself is remembered far longer than one you were given.

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How to study P110δ in 20 minutes

Read the reference excerpt below once, without taking notes.
Close the page and write down what P110δ means in your own words.
Compare your version with the excerpt and mark what you missed.
Work through the three examples above with pen and paper.
Explain P110δ out loud to somebody else — or to Teacher Smith in the lgStudy chat.

Frequently asked questions

What is P110δ in simple terms?

Why does P110δ matter?

Because it connects several biology ideas at once: it gives you a definition you can apply, a quantity you can calculate, and a way to check whether a result is plausible.

How should I study P110δ?

Read the excerpt, restate it from memory, then work through the examples and applications listed on this page. The five-step study plan above takes about twenty minutes.

What does this page cover?

It gives you a compact reference excerpt plus original lgStudy explanations, examples, applications and study material on P110δ.