P110δ Explained

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.^[1]

Activated PI3K delta syndrome

Inherited mutations in the PIK3CD gene which increase p110δ catalytic activity cause a primary immunodeficiency syndrome called APDS or PASLI. ^{[2] [3]}

Pharmacology

US pharmaceutical company ICOS produced a selective inhibitor of p110δ called IC87114.^[4] This inhibitor selectively impairs B cell, mast cell and neutrophil functions and is therefore a potential immune-modulator.^[5]

The p110δ inhibitor idelalisib was developed by Gilead Sciences.^[6] 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.^[7]

In July 2014 idelalisib was approved by the FDA as a treatment for CLL patients.^[8]

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.^[9]

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.^[10]

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.^[11]

Interactions

PIK3CD interacts with PIK3R1, and PIK3R2.

See also

• Phosphoinositide 3-kinase inhibitor

Further reading

• Lee C, Liu QH, Tomkowicz B, Yi Y, Freedman BD, Collman RG . Macrophage activation through CCR5- and CXCR4-mediated gp120-elicited signaling pathways . Journal of Leukocyte Biology . 74 . 5 . 676–82 . November 2003 . 12960231 . 10.1189/jlb.0503206 . 11362623 .
• Rommel C, Camps M, Ji H . PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond? . Nature Reviews. Immunology . 7 . 3 . 191–201 . March 2007 . 17290298 . 10.1038/nri2036 . 43376714 .
• Milani D, Mazzoni M, Borgatti P, Zauli G, Cantley L, Capitani S . Extracellular human immunodeficiency virus type-1 Tat protein activates phosphatidylinositol 3-kinase in PC12 neuronal cells . The Journal of Biological Chemistry . 271 . 38 . 22961–4 . September 1996 . 8798481 . 10.1074/jbc.271.38.22961 . free .
• Hillier LD, Lennon G, Becker M, Bonaldo MF, Chiapelli B, Chissoe S, Dietrich N, DuBuque T, Favello A, Gish W, Hawkins M, Hultman M, Kucaba T, Lacy M, Le M, Le N, Mardis E, Moore B, Morris M, Parsons J, Prange C, Rifkin L, Rohlfing T, Schellenberg K, Bento Soares M, Tan F, Thierry-Meg J, Trevaskis E, Underwood K, Wohldman P, Waterston R, Wilson R, Marra M . Generation and analysis of 280,000 human expressed sequence tags . Genome Research . 6 . 9 . 807–28 . September 1996 . 8889549 . 10.1101/gr.6.9.807 . free .
• Chantry D, Vojtek A, Kashishian A, Holtzman DA, Wood C, Gray PW, Cooper JA, Hoekstra MF . p110delta, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes . The Journal of Biological Chemistry . 272 . 31 . 19236–41 . August 1997 . 9235916 . 10.1074/jbc.272.31.19236 . free .
• Mazerolles F, Barbat C, Fischer A . Down-regulation of LFA-1-mediated T cell adhesion induced by the HIV envelope glycoprotein gp160 requires phosphatidylinositol-3-kinase activity . European Journal of Immunology . 27 . 9 . 2457–65 . September 1997 . 9341793 . 10.1002/eji.1830270946 . 33397908 .
• Borgatti P, Zauli G, Colamussi ML, Gibellini D, Previati M, Cantley LL, Capitani S . Extracellular HIV-1 Tat protein activates phosphatidylinositol 3- and Akt/PKB kinases in CD4+ T lymphoblastoid Jurkat cells . European Journal of Immunology . 27 . 11 . 2805–11 . November 1997 . 9394803 . 10.1002/eji.1830271110 . 6303471 .
• Borgatti P, Zauli G, Cantley LC, Capitani S . Extracellular HIV-1 Tat protein induces a rapid and selective activation of protein kinase C (PKC)-alpha, and -epsilon and -zeta isoforms in PC12 cells . Biochemical and Biophysical Research Communications . 242 . 2 . 332–7 . January 1998 . 9446795 . 10.1006/bbrc.1997.7877 .
• Milani D, Mazzoni M, Zauli G, Mischiati C, Gibellini D, Giacca M, Capitani S . HIV-1 Tat induces tyrosine phosphorylation of p125FAK and its association with phosphoinositide 3-kinase in PC12 cells . AIDS . 12 . 11 . 1275–84 . July 1998 . 9708406 . 10.1097/00002030-199811000-00008 . 25758704 . free .
• Jauliac S, Mazerolles F, Jabado N, Pallier A, Bernard F, Peake J, Fischer A, Hivroz C . Ligands of CD4 inhibit the association of phospholipase Cgamma1 with phosphoinositide 3 kinase in T cells: regulation of this association by the phosphoinositide 3 kinase activity . European Journal of Immunology . 28 . 10 . 3183–91 . October 1998 . 9808187 . 10.1002/(SICI)1521-4141(199810)28:10<3183::AID-IMMU3183>3.0.CO;2-A . free .
• Vanhaesebroeck B, Higashi K, Raven C, Welham M, Anderson S, Brennan P, Ward SG, Waterfield MD . Autophosphorylation of p110delta phosphoinositide 3-kinase: a new paradigm for the regulation of lipid kinases in vitro and in vivo . The EMBO Journal . 18 . 5 . 1292–302 . March 1999 . 10064595 . 1171219 . 10.1093/emboj/18.5.1292 .
• Park IW, Wang JF, Groopman JE . HIV-1 Tat promotes monocyte chemoattractant protein-1 secretion followed by transmigration of monocytes . Blood . 97 . 2 . 352–8 . January 2001 . 11154208 . 10.1182/blood.V97.2.352 . free .
• Zauli G, Milani D, Mirandola P, Mazzoni M, Secchiero P, Miscia S, Capitani S . HIV-1 Tat protein down-regulates CREB transcription factor expression in PC12 neuronal cells through a phosphatidylinositol 3-kinase/AKT/cyclic nucleoside phosphodiesterase pathway . FASEB Journal . 15 . 2 . 483–91 . February 2001 . 11156964 . 10.1096/fj.00-0354com . free . 26315564 .
• Deregibus MC, Cantaluppi V, Doublier S, Brizzi MF, Deambrosis I, Albini A, Camussi G . HIV-1-Tat protein activates phosphatidylinositol 3-kinase/ AKT-dependent survival pathways in Kaposi's sarcoma cells . The Journal of Biological Chemistry . 277 . 28 . 25195–202 . July 2002 . 11994280 . 10.1074/jbc.M200921200 . free .
• Cook JA, August A, Henderson AJ . Recruitment of phosphatidylinositol 3-kinase to CD28 inhibits HIV transcription by a Tat-dependent mechanism . Journal of Immunology . 169 . 1 . 254–60 . July 2002 . 12077252 . 10.4049/jimmunol.169.1.254 . free .
• François F, Klotman ME . Phosphatidylinositol 3-kinase regulates human immunodeficiency virus type 1 replication following viral entry in primary CD4+ T lymphocytes and macrophages . Journal of Virology . 77 . 4 . 2539–49 . February 2003 . 12551992 . 141101 . 10.1128/JVI.77.4.2539-2549.2003 .

Notes and References

1. Aksoy E, Taboubi S, Torres D, Delbauve S, Hachani A, Whitehead MA, Pearce WP, Berenjeno IM, Nock G, Filloux A, Beyaert R, Flamand V, Vanhaesebroeck B . 6 . The p110δ isoform of the kinase PI(3)K controls the subcellular compartmentalization of TLR4 signaling and protects from endotoxic shock . Nature Immunology . 13 . 11 . 1045–1054 . November 2012 . 23023391 . 4018573 . 10.1038/ni.2426 .
2. Angulo I, Vadas O, Garçon F, Banham-Hall E, Plagnol V, Leahy TR, Baxendale H, Coulter T, Curtis J, Wu C, Blake-Palmer K, Perisic O, Smyth D, Maes M, Fiddler C, Juss J, Cilliers D, Markelj G, Chandra A, Farmer G, Kielkowska A, Clark J, Kracker S, Debré M, Picard C, Pellier I, Jabado N, Morris JA, Barcenas-Morales G, Fischer A, Stephens L, Hawkins P, Barrett JC, Abinun M, Clatworthy M, Durandy A, Doffinger R, Chilvers ER, Cant AJ, Kumararatne D, Okkenhaug K, Williams RL, Condliffe A, Nejentsev S . 6 . Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage . Science . 342 . 6160 . 866–71 . November 2013 . 24136356 . 10.1126/science.1243292 . 3930011 . 2013Sci...342..866A .
3. Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, Avery DT, Moens L, Cannons JL, Biancalana M, Stoddard J, Ouyang W, Frucht DM, Rao VK, Atkinson TP, Agharahimi A, Hussey AA, Folio LR, Olivier KN, Fleisher TA, Pittaluga S, Holland SM, Cohen JI, Oliveira JB, Tangye SG, Schwartzberg PL, Lenardo MJ, Uzel G . 6 . Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency . Nature Immunology . 15 . 1 . 88–97 . January 2014 . 24165795 . 10.1038/ni.2771 . 4209962 .
4. Sadhu C, Masinovsky B, Dick K, Sowell CG, Staunton DE . Essential role of phosphoinositide 3-kinase delta in neutrophil directional movement . Journal of Immunology . 170 . 5 . 2647–54 . March 2003 . 12594293 . 10.4049/jimmunol.170.5.2647 . free .
5. Lee KS, Lee HK, Hayflick JS, Lee YC, Puri KD . Inhibition of phosphoinositide 3-kinase delta attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model . FASEB Journal . 20 . 3 . 455–65 . March 2006 . 16507763 . 10.1096/fj.05-5045com . free . 8013052 .
6. Meadows SA, Vega F, Kashishian A, Johnson D, Diehl V, Miller LL, Younes A, Lannutti BJ . PI3Kδ inhibitor, GS-1101 (CAL-101), attenuates pathway signaling, induces apoptosis, and overcomes signals from the microenvironment in cellular models of Hodgkin lymphoma . Blood . 119 . 8 . 1897–900 . February 2012 . 22210877 . 10.1182/blood-2011-10-386763 . free .
7. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, Barrientos JC, Zelenetz AD, Kipps TJ, Flinn I, Ghia P, Eradat H, Ervin T, Lamanna N, Coiffier B, Pettitt AR, Ma S, Stilgenbauer S, Cramer P, Aiello M, Johnson DM, Miller LL, Li D, Jahn TM, Dansey RD, Hallek M, O'Brien SM . 6 . Idelalisib and rituximab in relapsed chronic lymphocytic leukemia . The New England Journal of Medicine . 370 . 11 . 997–1007 . March 2014 . 24450857 . 4161365 . 10.1056/NEJMoa1315226 .
8. https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm406387.htm FDA approves Zydelig for three types of blood cancers
9. Web site: FDA approves new treatment for adults with relapsed follicular lymphoma . September 14, 2017 . US Food and Drug Administration.
10. Web site: Full prescribing information: COPIKTRA (duvelisib). U.S. Food and Drug Administration. 23 October 2018.
11. Web site: Leukemia drug found to stimulate immunity against many cancer types KurzweilAI. www.kurzweilai.net. 2016-01-01. June 17, 2014.