P110δ

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.[5][6][7]

PIK3CD
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPIK3CD, APDS, IMD14, P110DELTA, PI3K, p110D, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta, IMD14B, ROCHIS, IMD14A
External IDsOMIM: 602839 MGI: 1098211 HomoloGene: 3686 GeneCards: PIK3CD
Orthologs
SpeciesHumanMouse
Entrez

5293

18707

Ensembl

ENSG00000171608

ENSMUSG00000039936

UniProt

O00329

O35904

RefSeq (mRNA)

NM_005026
NM_001350234
NM_001350235

RefSeq (protein)

NP_005017
NP_001337163
NP_001337164
NP_005017.3

Location (UCSC)Chr 1: 9.65 – 9.73 MbChr 4: 149.73 – 149.79 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[8]

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.[7]

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.[9][10]

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.[11] 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.[12]

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).[12][13]

Mast cells

p110δ controls mast cell release of the granules responsible for allergic reactions. Thus inhibition of p110δ reduces allergic responses.[14]

Neutrophils

In conjunction with p110γ, p110δ controls the release of reactive oxygen species in neutrophils.[15]

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.[16]

Activated PI3K delta syndrome

Inherited mutations in the PIK3CD gene which increase p110δ catalytic activity cause a primary immunodeficiency syndrome called APDS or PASLI. [17][18]

Pharmacology

US pharmaceutical company ICOS produced a selective inhibitor of p110δ called IC87114.[19] This inhibitor selectively impairs B cell, mast cell and neutrophil functions and is therefore a potential immune-modulator.[20]

The p110δ inhibitor idelalisib was developed by Gilead Sciences.[21] 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.[22]

In July 2014 idelalisib was approved by the FDA as a treatment for CLL patients.[23]

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.[24]

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.[25]

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.[26] p110δ inactivation in regulatory T cells unleashes CD8+ cytotoxic T cells.[27]

Interactions

PIK3CD interacts with PIK3R1,[5] and PIK3R2.[5]

See also

References
  1. GRCh38: Ensembl release 89: ENSG00000171608 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000039936 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Vanhaesebroeck B, Welham MJ, Kotani K, Stein R, Warne PH, Zvelebil MJ, et al. (April 1997). "P110delta, a novel phosphoinositide 3-kinase in leukocytes". Proceedings of the National Academy of Sciences of the United States of America. 94 (9): 4330–5. Bibcode:1997PNAS...94.4330V. doi:10.1073/pnas.94.9.4330. PMC 20722. PMID 9113989.
  6. Seki N, Nimura Y, Ohira M, Saito T, Ichimiya S, Nomura N, et al. (October 1997). "Identification and chromosome assignment of a human gene encoding a novel phosphatidylinositol-3 kinase". DNA Research. 4 (5): 355–8. doi:10.1093/dnares/4.5.355. PMID 9455486.
  7. "Entrez Gene: PIK3CD phosphoinositide-3-kinase, catalytic, delta polypeptide".
  8. Harris SJ, Foster JG, Ward SG (November 2009). "PI3K isoforms as drug targets in inflammatory diseases: lessons from pharmacological and genetic strategies". Current Opinion in Investigational Drugs. 10 (11): 1151–62. PMID 19876783.
  9. Okkenhaug K, Vanhaesebroeck B (April 2003). "PI3K in lymphocyte development, differentiation and activation". Nature Reviews. Immunology. 3 (4): 317–30. doi:10.1038/nri1056. PMID 12669022. S2CID 20806981.
  10. Deane JA, Fruman DA (2004). "Phosphoinositide 3-kinase: diverse roles in immune cell activation". Annual Review of Immunology. 22: 563–98. doi:10.1146/annurev.immunol.22.012703.104721. PMID 15032589.
  11. Rolf J, Bell SE, Kovesdi D, Janas ML, Soond DR, Webb LM, et al. (October 2010). "Phosphoinositide 3-kinase activity in T cells regulates the magnitude of the germinal center reaction". Journal of Immunology. 185 (7): 4042–52. doi:10.4049/jimmunol.1001730. PMID 20826752.
  12. Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, et al. (August 2002). "Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice". Science. 297 (5583): 1031–4. doi:10.1126/science.1073560. PMID 12130661. S2CID 2104018.
  13. Clayton E, Bardi G, Bell SE, Chantry D, Downes CP, Gray A, et al. (September 2002). "A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation". The Journal of Experimental Medicine. 196 (6): 753–63. doi:10.1084/jem.20020805. PMC 2194055. PMID 12235209.
  14. Ali K, Bilancio A, Thomas M, Pearce W, Gilfillan AM, Tkaczyk C, et al. (October 2004). "Essential role for the p110delta phosphoinositide 3-kinase in the allergic response". Nature. 431 (7011): 1007–11. Bibcode:2004Natur.431.1007A. doi:10.1038/nature02991. PMID 15496927.
  15. Condliffe AM, Davidson K, Anderson KE, Ellson CD, Crabbe T, Okkenhaug K, et al. (August 2005). "Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils". Blood. 106 (4): 1432–40. doi:10.1182/blood-2005-03-0944. PMID 15878979.
  16. Aksoy E, Taboubi S, Torres D, Delbauve S, Hachani A, Whitehead MA, et al. (November 2012). "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. doi:10.1038/ni.2426. PMC 4018573. PMID 23023391.
  17. Angulo I, Vadas O, Garçon F, Banham-Hall E, Plagnol V, Leahy TR, et al. (November 2013). "Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage". Science. 342 (6160): 866–71. Bibcode:2013Sci...342..866A. doi:10.1126/science.1243292. PMC 3930011. PMID 24136356.
  18. Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, et al. (January 2014). "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. doi:10.1038/ni.2771. PMC 4209962. PMID 24165795.
  19. Sadhu C, Masinovsky B, Dick K, Sowell CG, Staunton DE (March 2003). "Essential role of phosphoinositide 3-kinase delta in neutrophil directional movement". Journal of Immunology. 170 (5): 2647–54. doi:10.4049/jimmunol.170.5.2647. PMID 12594293.
  20. Lee KS, Lee HK, Hayflick JS, Lee YC, Puri KD (March 2006). "Inhibition of phosphoinositide 3-kinase delta attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model". FASEB Journal. 20 (3): 455–65. doi:10.1096/fj.05-5045com. PMID 16507763. S2CID 8013052.
  21. Meadows SA, Vega F, Kashishian A, Johnson D, Diehl V, Miller LL, Younes A, Lannutti BJ (February 2012). "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. doi:10.1182/blood-2011-10-386763. PMID 22210877.
  22. Furman RR, Sharman JP, Coutre SE, Cheson BD, Pagel JM, Hillmen P, et al. (March 2014). "Idelalisib and rituximab in relapsed chronic lymphocytic leukemia". The New England Journal of Medicine. 370 (11): 997–1007. doi:10.1056/NEJMoa1315226. PMC 4161365. PMID 24450857.
  23. FDA approves Zydelig for three types of blood cancers
  24. "FDA approves new treatment for adults with relapsed follicular lymphoma". US Food and Drug Administration. September 14, 2017.
  25. "Full prescribing information: COPIKTRA (duvelisib)" (PDF). U.S. Food and Drug Administration. Retrieved 23 October 2018.
  26. "Leukemia drug found to stimulate immunity against many cancer types | KurzweilAI". www.kurzweilai.net. June 17, 2014. Retrieved 2016-01-01.
  27. Ali K, Soond DR, Pineiro R, Hagemann T, Pearce W, Lim EL, et al. (June 2014). "Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer". Nature. 510 (7505): 407–411. Bibcode:2014Natur.510..407A. doi:10.1038/nature13444. PMC 4501086. PMID 24919154.

Further reading
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