P110δ

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Phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit delta
Identifiers
Symbols PIK3CD ; APDS; IMD14; P110DELTA; PI3K; p110D
External IDs OMIM602839 MGI1098211 HomoloGene3686 ChEMBL: 3130 GeneCards: PIK3CD Gene
EC number 2.7.1.153
RNA expression pattern
PBB GE PIK3CD 203879 at tn.png
PBB GE PIK3CD 211230 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 5293 18707
Ensembl ENSG00000171608 ENSMUSG00000039936
UniProt O00329 O35904
RefSeq (mRNA) NM_005026 NM_001029837
RefSeq (protein) NP_005017 NP_001025008
Location (UCSC) Chr 1:
9.71 – 9.79 Mb
Chr 4:
149.65 – 149.7 Mb
PubMed search [1] [2]

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 considered to be a promising target for drugs that aim to prevent or treat inflammation and 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[edit]

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 p85) bind to proteins which 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 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.[5][6]

Functions[edit]

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[edit]

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[edit]

p110δ is a key 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[edit]

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

Neutrophils[edit]

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

Pharmacology[edit]

The US pharmaceutical company ICOS has produced a selective inhibitor of p110δ called IC87114.[12] This inhibitor has been shown to selectively impair B cell, mast cell and neutrophil functions and is therefore a potential immune-modulator.[13]

Another p110δ inhibitor is GS-1101 (formerly known as CAL-101 or CAL101) which is being developed by Gilead Sciences.[14] GS-1101 has reported good results from phase I clinical trials.[15] As of May 2012, GS-1101 was being tested in clinical trials for safety and efficacy in treatment of chronic lymphocytic leukemia (as an add-on agent) and indolent non-Hodgkin lymphoma.[16]

As of July 2014, GS-1101, now known as Zydelig (idelalisib) has now been approved as a treatment for patients with blood cancers. [17]

Interactions[edit]

PIK3CD has been shown to interact with PIK3R1,[1] PIK3CG[1] and PIK3R2.[1]

See also[edit]

References[edit]

  1. ^ a b c d Vanhaesebroeck B, Welham MJ, Kotani K, Stein R, Warne PH, Zvelebil MJ, Higashi K, Volinia S, Downward J, Waterfield MD (May 1997). "P110delta, a novel phosphoinositide 3-kinase in leukocytes". Proc Natl Acad Sci U S A 94 (9): 4330–5. doi:10.1073/pnas.94.9.4330. PMC 20722. PMID 9113989. 
  2. ^ Seki N, Nimura Y, Ohira M, Saito T, Ichimiya S, Nomura N, Nakagawara A (Feb 1998). "Identification and chromosome assignment of a human gene encoding a novel phosphatidylinositol-3 kinase". DNA Res 4 (5): 355–8. doi:10.1093/dnares/4.5.355. PMID 9455486. 
  3. ^ a b "Entrez Gene: PIK3CD phosphoinositide-3-kinase, catalytic, delta polypeptide". 
  4. ^ Harris SJ, Foster JG, Ward SG (November 2009). "PI3K isoforms as drug targets in inflammatory diseases: lessons from pharmacological and genetic strategies". Curr Opin Investig Drugs 10 (11): 1151–62. PMID 19876783. 
  5. ^ Okkenhaug K, Vanhaesebroeck B (April 2003). "PI3K in lymphocyte development, differentiation and activation". Nat. Rev. Immunol. 3 (4): 317–30. doi:10.1038/nri1056. PMID 12669022. 
  6. ^ Deane JA, Fruman DA (2004). "Phosphoinositide 3-kinase: diverse roles in immune cell activation". Annu. Rev. Immunol. 22: 563–98. doi:10.1146/annurev.immunol.22.012703.104721. PMID 15032589. 
  7. ^ Rolf J, Bell SE, Kovesdi D, Janas ML, Soond DR, Webb LM, Santinelli S, Saunders T, Hebeis B, Killeen N, Okkenhaug K, Turner M. (October 2010). "Phosphoinositide 3-kinase activity in T cells regulates the magnitude of the germinal center reaction". J Immunol 185 (7): 4042–52. doi:10.4049/jimmunol.1001730. PMID 20826752. 
  8. ^ a b Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, Pearce W, Meek SE, Salpekar A, Waterfield MD, Smith AJ, Vanhaesebroeck B (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. 
  9. ^ Clayton, E, Bardi, G, Bell, SE, Chantry, D, Downes, CP, Gray, A, Humphries, LA, Rawlings, D, Reynolds, H, Vigorito, E and Turner (September 2002). "A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation". J Exp Med 196 (6): 753–63. doi:10.1084/jem.20020805. PMID 12235209. 
  10. ^ Ali K, Bilancio A, Thomas M, Pearce W, Gilfillan AM, Tkaczyk C, Kuehn N, Gray A, Giddings J, Peskett E, Fox R, Bruce I, Walker C, Sawyer C, Okkenhaug K, Finan P, Vanhaesebroeck B (October 2004). "Essential role for the p110delta phosphoinositide 3-kinase in the allergic response". Nature 431 (7011): 1007–11. doi:10.1038/nature02991. PMID 15496927. 
  11. ^ Condliffe AM, Davidson K, Anderson KE, Ellson CD, Crabbe T, Okkenhaug K, Vanhaesebroeck B, Turner M, Webb L, Wymann MP, Hirsch E, Ruckle T, Camps M, Rommel C, Jackson SP, Chilvers ER, Stephens LR, Hawkins PT (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. 
  12. ^ Sadhu C, Masinovsky B, Dick K, Sowell CG, Staunton DE (March 2003). "Essential role of phosphoinositide 3-kinase delta in neutrophil directional movement". J. Immunol. 170 (5): 2647–54. doi:10.4049/jimmunol.170.5.2647. PMID 12594293. 
  13. ^ 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 J. 20 (3): 455–65. doi:10.1096/fj.05-5045com. PMID 16507763. 
  14. ^ 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. 
  15. ^ "Calistoga Pharmaceuticals presents CAL-101 PI3K inhibitor data at European Hematology Association Congress". News-Medical.Net. 2010-06-14. 
  16. ^ "Gilead Begins GS-1101 Trial". Drug Discovery & Development. 2012-05-03. Retrieved 2012-06-03. 
  17. ^ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm406387.htm

Further reading[edit]