Biology:P110δ

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1][2][3]

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.[4]

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.[3]

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.[5][6]

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.[7] 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.[8]

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).[8][9]

Mast cells

p110δ controls mast cell release of the granules responsible for allergic reactions. Thus inhibition of p110δ reduces allergic responses.[10]

Neutrophils

In conjunction with p110γ, p110δ controls the release of reactive oxygen species in neutrophils.[11]

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.[12]

Activated PI3K delta syndrome

Inherited mutations in the PIK3CD gene which increase p110δ catalytic activity cause a primary immunodeficiency syndrome called APDS or PASLI. [13][14]

Pharmacology

US pharmaceutical company ICOS produced a selective inhibitor of p110δ called IC87114.[15] This inhibitor selectively impairs B cell, mast cell and neutrophil functions and is therefore a potential immune-modulator.[16]

The p110δ inhibitor idelalisib was developed by Gilead Sciences.[17] 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.[18]

In July 2014 idelalisib was approved by the FDA as a treatment for CLL patients.[19]

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.[20]

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.[21]

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.[22] p110δ inactivation in regulatory T cells unleashes CD8+ cytotoxic T cells.[23]

Interactions

PIK3CD interacts with PIK3R1,[1] and PIK3R2.[1]

See also

References

  1. ↑ 1.0 1.1 1.2 "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. April 1997. doi:10.1073/pnas.94.9.4330. PMID 9113989. Bibcode: 1997PNAS...94.4330V. 
  2. ↑ "Identification and chromosome assignment of a human gene encoding a novel phosphatidylinositol-3 kinase". DNA Research 4 (5): 355–8. October 1997. doi:10.1093/dnares/4.5.355. PMID 9455486. 
  3. ↑ 3.0 3.1 "Entrez Gene: PIK3CD phosphoinositide-3-kinase, catalytic, delta polypeptide". https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=5293. 
  4. ↑ "PI3K isoforms as drug targets in inflammatory diseases: lessons from pharmacological and genetic strategies". Current Opinion in Investigational Drugs 10 (11): 1151–62. November 2009. PMID 19876783. 
  5. ↑ "PI3K in lymphocyte development, differentiation and activation". Nature Reviews. Immunology 3 (4): 317–30. April 2003. doi:10.1038/nri1056. PMID 12669022. 
  6. ↑ "Phosphoinositide 3-kinase: diverse roles in immune cell activation". Annual Review of Immunology 22: 563–98. 2004. doi:10.1146/annurev.immunol.22.012703.104721. PMID 15032589. 
  7. ↑ "Phosphoinositide 3-kinase activity in T cells regulates the magnitude of the germinal center reaction". Journal of Immunology 185 (7): 4042–52. October 2010. doi:10.4049/jimmunol.1001730. PMID 20826752. 
  8. ↑ 8.0 8.1 "Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice". Science 297 (5583): 1031–4. August 2002. doi:10.1126/science.1073560. PMID 12130661. 
  9. ↑ "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. September 2002. doi:10.1084/jem.20020805. PMID 12235209. 
  10. ↑ "Essential role for the p110delta phosphoinositide 3-kinase in the allergic response". Nature 431 (7011): 1007–11. October 2004. doi:10.1038/nature02991. PMID 15496927. Bibcode: 2004Natur.431.1007A. 
  11. ↑ "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. August 2005. doi:10.1182/blood-2005-03-0944. PMID 15878979. 
  12. ↑ "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. doi:10.1038/ni.2426. PMID 23023391. 
  13. ↑ "Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage". Science 342 (6160): 866–71. November 2013. doi:10.1126/science.1243292. PMID 24136356. Bibcode: 2013Sci...342..866A. 
  14. ↑ "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. doi:10.1038/ni.2771. PMID 24165795. 
  15. ↑ "Essential role of phosphoinositide 3-kinase delta in neutrophil directional movement". Journal of Immunology 170 (5): 2647–54. March 2003. doi:10.4049/jimmunol.170.5.2647. PMID 12594293. 
  16. ↑ "Inhibition of phosphoinositide 3-kinase delta attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model". FASEB Journal 20 (3): 455–65. March 2006. doi:10.1096/fj.05-5045com. PMID 16507763. 
  17. ↑ "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. doi:10.1182/blood-2011-10-386763. PMID 22210877. 
  18. ↑ "Idelalisib and rituximab in relapsed chronic lymphocytic leukemia". The New England Journal of Medicine 370 (11): 997–1007. March 2014. doi:10.1056/NEJMoa1315226. PMID 24450857. 
  19. ↑ FDA approves Zydelig for three types of blood cancers
  20. ↑ "FDA approves new treatment for adults with relapsed follicular lymphoma". US Food and Drug Administration. September 14, 2017. https://www.fda.gov/newsevents/newsroom/pressannouncements/ucm576129.htm. 
  21. ↑ "Full prescribing information: COPIKTRA (duvelisib)". https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/211155s000lbl.pdf. 
  22. ↑ "Leukemia drug found to stimulate immunity against many cancer types | KurzweilAI". June 17, 2014. http://www.kurzweilai.net/leukemia-drug-found-to-stimulate-immunity-against-many-cancer-types. 
  23. ↑ "Inactivation of PI(3)K p110δ breaks regulatory T-cell-mediated immune tolerance to cancer". Nature 510 (7505): 407–411. June 2014. doi:10.1038/nature13444. PMID 24919154. Bibcode: 2014Natur.510..407A. 

Further reading



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