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PIK3CD (phosphoinositide-3-kinase, catalytic, delta polypeptide)

Written2011-02Emily Burns, Bart Vanhaesebroeck
Centre of Cell Signalling, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK

(Note : for Links provided by Atlas : click)


Other aliasP110DELTA
LocusID (NCBI) 5293
Atlas_Id 46261
Location 1p36.22  [Link to chromosome band 1p36]
Location_base_pair Starts at and ends at bp from pter
Local_order Telomere-SPSB1-SLC25A33-TMEM201-PIK3CD-C1orf200-CR604408-KIAAO00911-centromere.
  Location of PIK3CD on human chromosome 1.
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
PIK3CD (1p36.22) / CDS2 (20p12.3)PIK3CD (1p36.22) / PIK3CD (1p36.22)PIK3CD (1p36.22) / TNFRSF8 (1p36.22)
RERE (1p36.23) / PIK3CD (1p36.22)SLC35E4 (22q12.2) / PIK3CD (1p36.22)ZNF814 (19q13.43) / PIK3CD (1p36.22)


  The illustration represents the exon structure of the most prevalent transcript in leukocytes, which contains two untranslated exons upstream of the start site (-2a and -1) and 24 coding exons.
Description The PIK3CD gene spans a genomic region of 24 coding exons and over 77.17 kb.
Transcription The dominant transcript contains two upstream untranslated exons, -2a and -1, as well as an additional first untranslated exon (-2b) identified in the human PIK3CD gene (Kok et al., 2009).


  p110delta protein domains. p110delta interacts with its associated p85 regulatory subunit via the adaptor binding domain (ABD). The C Lobe and N Lobe together form the catalytic domain.
Description The PI3K enzymes are a family of activation dependent lipid kinases, which have been divided into three classes (Vanhaesebroeck et al., 1999a). PIK3CD encodes p110delta which belongs to the class I PI3Ks alongside p110alpha, p110beta and p110gamma.

The PI3K enzymes are heterodimeric molecules which consist of a catalytic p110 subunit, and a constitutively bound p85 regulatory unit of which there are five isoforms encoded by three genes (PIK3R1, PIK3R2 and PIK3R3) (Vanhaesebroeck and Waterfield, 1999; Geering et al., 2007).
The regulatory subunit has a dual function of recruiting the p110 catalytic subunit to an activated upstream tyrosine kinase receptor, and inhibiting catalytic activity in the absence of this stimulatory interaction (Yu et al., 1998). Unlike p110alpha, p110delta does not phoshorylate its associated p85 regulatory subunit and instead auto-phosphorylates (Vanhaesebroeck et al., 1997; Vanhaesebroeck et al., 1999a).

Expression p110delta has a restricted expression pattern; it is highly expressed in leukocytes (Seki et al., 1997; Vanhaesebroeck et al., 1997) and to a lesser extent expressed in neurons (Eickholt et al., 2007). In addition p110delta expression has also been observed in a number of cancerous tissues including breast cancer and melanoma cells (Sawyer et al., 2003).

A transcription factor binding cluster located immediately upstream of the untranslated exon -2a in the human gene, has been identified and found to have enhanced promotor activity in leukocytes. This promoter region may therefore facilitate the enhanced expression of p110delta in leukocytes (Kok et al., 2009).

Localisation p110 delta localises to the cytosol and is recruited to the periplasmic region upon stimulation of upstream activators.
Function Cell signalling and lipid kinase activity. PI3K signalling has been found to play a crucial role in the regulation of numerous cellular processes including proliferation, metabolism (Foukas et al., 2006; Engelman et al., 2006), and migration (Papakonstanti et al., 2007).
Active p110delta initiates signalling cascades by phosphorylating phosphoinositide (PI) lipids such as PIP2 producing pools of PIP3 in the periplasmic region (Vanhaesebroeck et al., 1997). A wide range of effector proteins recognise and interact with the PI species produced, and the resulting alteration in location and activities of these effectors initiates a number of signalling cascades. The classical effector of PI3K signalling is the serine/threonin kinase AKT (aka protein kinase B), which contains a pleckstrin homology (PH) domain that interacts with PIP3 (Franke et al., 1997). The affinity of Akt for PIP3 facilitates activation of Akt's protein kinase activity, resulting in activity-modifying phosphorylation of a range of downstream Akt targets.

Roles of p110delta in immune function. The role of p110delta in vivo has been studied in a p110delta null mouse (Clayton et al., 2002; Jou et al., 2002) and in a p110delta kinase-dead mouse known as p110deltaD910A/D910A (Okkenhaug et al., 2002). Phenotypic analysis of the p110deltaD910A/D910A mouse revealed an important role for p110delta in immunity; the mice have notable defects in their T and B cell responses, as well as several other immunological abnormalities (Okkenhaug et al., 2002). In vitro and ex vivo studies suggest that p110delta is the predominant PI3K class IA isoform regulating the phenotype and responses of many leukocyte cell types (Vanhaesebroeck et al., 1999b; Puri et al., 2004; Papakonstanti et al., 2008). In mast cells derived from the p110delta kinase-dead mice, ninety percent of the total PI3K lipid kinase activity was dependent on p110delta (Ali et al., 2004). p110delta has been found to be a key player in the induction of amongst other things, proliferation, chemotaxis, and cytokine/chemokine release in response to both physiological stimuli and pathological stimuli, in many leukocytes (Okkenhaug and Vanhaesebroeck, 2003; Dos Santos et al., 2007; Papakonstanti et al., 2008; Dil et al., 2009; Low et al., 2010).

Homology p110delta is most homologous to p110beta (Clayton et al., 2001).


Note No prevalent p110delta mutations have been observed in primary samples or cell lines.

Implicated in

Entity Haematological malignancy
Note Constitutive phosphorylation of Akt (indicating constitutive activity) has been observed in many haematological malignancies, and appears to be responsible for or contributing to growth factor-independent proliferation (Min et al., 2003, Ikeda et al., 2010). p110delta appears to be upstream of the constitutively active Akt in these transformed cells; p110delta-selective inhibitors significantly reduce the abberent Akt activation and also results in a reduction in proliferation (Billottet et al., 2006; Ikeda et al., 2010; Herman et al., 2010; Lannutti et al., 2011).
Despite the dominance of p110delta in the regulation of proliferation in leukocytes and the abberant activity of it's major downstream target Akt, no mutations or amplifications of p110delta have been observed in these or other haematological malignancies.
A series of clinical trials are now underway to assess the effects of selective inhibition of p110delta on refractory haematological malignancies, and preliminary results are promising (Furman, 2010).
Disease CLL, T-ALL, B-ALL, DLBCL, AML, and multiple myeloma.
Entity Allergic disease (Ali et al., 2004; Lee et al., 2006; Medina-Tato et al., 2007; Park et al., 2008)
Note Mast cells derived from p110deltaD910A/D910A mice have a degranulation defect, as do wild-type mast cells treated with a p110delta-selective inhibitor. Specifically cells lacking active p110delta showed a 45-55% reduction in degranulation induced by an antigen-IgE complex, compared to the degranulation observed in WT mast cells (Ali et al., 2004). Furthermore inactivation of p110delta has been shown to attenuate anaphylactic responses in mice (Ali et al., 2004). p110delta-selective inhibitors have been shown to attenuate OVA-induced influx into lungs of total leukocytes, eosinophils, neutrophils, and lymphocytes, as well as reducing the production of a number of pro-inflammatory mediators (Lee et al., 2006).
Disease Asthma, allergic rhinitis.
Entity Chronic inflammatory conditions
Note p110delta has been identified as a major regulator of inflammatory responses in a wide range of leukocytes (including macrophages, neutrophils, mast cells as well as the adaptive immune cells). It it is considered an excellent potential therapeutic target for reducing inflammation both in the acute allergic context but also in the context of chronic inflammatory disorders (Ji et al., 2007; Rommel et al., 2007). The importance of p110delta in the regulation of inflammatory responses is highlighted by the development of spontaneous chronic colonic inflammation in the p110deltaD910A/D910A mice, which has been attributed to a failure to repress inflammatory responses to commensal bacteria in the gut (Uno et al., 2010). Thus p110delta-selective drugs are currently under investigation as a treatment for rheumatoid arthritis, asthma and other inflammatory conditions.
Disease Rheumatoid arthritis, inflammatory bowel disease (IBD).


Essential role for the p110delta phosphoinositide 3-kinase in the allergic response.
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.
Nature. 2004 Oct 21;431(7011):1007-11.
PMID 15496927
A selective inhibitor of the p110delta isoform of PI 3-kinase inhibits AML cell proliferation and survival and increases the cytotoxic effects of VP16.
Billottet C, Grandage VL, Gale RE, Quattropani A, Rommel C, Vanhaesebroeck B, Khwaja A.
Oncogene. 2006 Oct 26;25(50):6648-59. Epub 2006 May 15.
PMID 16702948
A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation.
Clayton E, Bardi G, Bell SE, Chantry D, Downes CP, Gray A, Humphries LA, Rawlings D, Reynolds H, Vigorito E, Turner M.
J Exp Med. 2002 Sep 16;196(6):753-63.
PMID 12235209
Structural organization of the mouse phosphatidylinositol 3-kinase p110d gene.
Clayton E, McAdam S, Coadwell J, Chantry D, Turner M.
Biochem Biophys Res Commun. 2001 Feb 9;280(5):1328-32.
PMID 11162674
Role of phosphoinositide 3-kinase p110 delta in TLR4- and TLR9-mediated B cell cytokine production and differentiation.
Dil N, Marshall AJ.
Mol Immunol. 2009 Jun;46(10):1970-8. Epub 2009 Apr 10.
PMID 19362372
Gene expression profiling of LPS-stimulated murine macrophages and role of the NF-kappaB and PI3K/mTOR signaling pathways.
Dos Santos S, Delattre AI, De Longueville F, Bult H, Raes M.
Ann N Y Acad Sci. 2007 Jan;1096:70-7.
PMID 17405917
Control of axonal growth and regeneration of sensory neurons by the p110delta PI 3-kinase.
Eickholt BJ, Ahmed AI, Davies M, Papakonstanti EA, Pearce W, Starkey ML, Bilancio A, Need AC, Smith AJ, Hall SM, Hamers FP, Giese KP, Bradbury EJ, Vanhaesebroeck B.
PLoS One. 2007 Sep 11;2(9):e869.
PMID 17846664
The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism.
Engelman JA, Luo J, Cantley LC.
Nat Rev Genet. 2006 Aug;7(8):606-19. (REVIEW)
PMID 16847462
Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation.
Foukas LC, Claret M, Pearce W, Okkenhaug K, Meek S, Peskett E, Sancho S, Smith AJ, Withers DJ, Vanhaesebroeck B.
Nature. 2006 May 18;441(7091):366-70. Epub 2006 Apr 12.
PMID 16625210
Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate.
Franke TF, Kaplan DR, Cantley LC, Toker A.
Science. 1997 Jan 31;275(5300):665-8.
PMID 9005852
New agents in early clinical trials for CLL therapy.
Furman RR.
Clin Adv Hematol Oncol. 2010 Jul;8(7):475-6.
PMID 20864914
Class IA phosphoinositide 3-kinases are obligate p85-p110 heterodimers.
Geering B, Cutillas PR, Nock G, Gharbi SI, Vanhaesebroeck B.
Proc Natl Acad Sci U S A. 2007 May 8;104(19):7809-14. Epub 2007 Apr 30.
PMID 17470792
Phosphatidylinositol 3-kinase-? inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals.
Herman SE, Gordon AL, Wagner AJ, Heerema NA, Zhao W, Flynn JM, Jones J, Andritsos L, Puri KD, Lannutti BJ, Giese NA, Zhang X, Wei L, Byrd JC, Johnson AJ.
Blood. 2010 Sep 23;116(12):2078-88. Epub 2010 Jun 3.
PMID 20522708
PI3K/p110{delta} is a novel therapeutic target in multiple myeloma.
Ikeda H, Hideshima T, Fulciniti M, Perrone G, Miura N, Yasui H, Okawa Y, Kiziltepe T, Santo L, Vallet S, Cristea D, Calabrese E, Gorgun G, Raje NS, Richardson P, Munshi NC, Lannutti BJ, Puri KD, Giese NA, Anderson KC.
Blood. 2010 Sep 2;116(9):1460-8. Epub 2010 May 26.
PMID 20505158
Inactivation of PI3Kgamma and PI3Kdelta distorts T-cell development and causes multiple organ inflammation.
Ji H, Rintelen F, Waltzinger C, Bertschy Meier D, Bilancio A, Pearce W, Hirsch E, Wymann MP, Ruckle T, Camps M, Vanhaesebroeck B, Okkenhaug K, Rommel C.
Blood. 2007 Oct 15;110(8):2940-7. Epub 2007 Jul 12.
PMID 17626838
Essential, nonredundant role for the phosphoinositide 3-kinase p110delta in signaling by the B-cell receptor complex.
Jou ST, Carpino N, Takahashi Y, Piekorz R, Chao JR, Carpino N, Wang D, Ihle JN.
Mol Cell Biol. 2002 Dec;22(24):8580-91.
PMID 12446777
Regulation of p110delta PI 3-kinase gene expression.
Kok K, Nock GE, Verrall EA, Mitchell MP, Hommes DW, Peppelenbosch MP, Vanhaesebroeck B.
PLoS One. 2009;4(4):e5145. Epub 2009 Apr 9.
PMID 19357769
CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability.
Lannutti BJ, Meadows SA, Herman SE, Kashishian A, Steiner B, Johnson AJ, Byrd JC, Tyner JW, Loriaux MM, Deininger M, Druker BJ, Puri KD, Ulrich RG, Giese NA.
Blood. 2011 Jan 13;117(2):591-4. Epub 2010 Oct 19.
PMID 20959606
Inhibition of phosphoinositide 3-kinase delta attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model.
Lee KS, Lee HK, Hayflick JS, Lee YC, Puri KD.
FASEB J. 2006 Mar;20(3):455-65.
PMID 16507763
Phosphoinositide 3-kinase ? regulates membrane fission of Golgi carriers for selective cytokine secretion.
Low PC, Misaki R, Schroder K, Stanley AC, Sweet MJ, Teasdale RD, Vanhaesebroeck B, Meunier FA, Taguchi T, Stow JL.
J Cell Biol. 2010 Sep 20;190(6):1053-65. Epub 2010 Sep 13.
PMID 20837769
Phosphoinositide 3-kinase signalling in lung disease: leucocytes and beyond.
Medina-Tato DA, Ward SG, Watson ML.
Immunology. 2007 Aug;121(4):448-61. (REVIEW)
PMID 17614878
Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable.
Min YH, Eom JI, Cheong JW, Maeng HO, Kim JY, Jeung HK, Lee ST, Lee MH, Hahn JS, Ko YW.
Leukemia. 2003 May;17(5):995-7.
PMID 12750723
PI3K in lymphocyte development, differentiation and activation.
Okkenhaug K, Vanhaesebroeck B.
Nat Rev Immunol. 2003 Apr;3(4):317-30. (REVIEW)
PMID 12669022
Distinct roles of class IA PI3K isoforms in primary and immortalised macrophages.
Papakonstanti EA, Zwaenepoel O, Bilancio A, Burns E, Nock GE, Houseman B, Shokat K, Ridley AJ, Vanhaesebroeck B.
J Cell Sci. 2008 Dec 15;121(Pt 24):4124-33. Epub 2008 Nov 25.
PMID 19033389
Phosphoinositide 3-kinase delta inhibitor as a novel therapeutic agent in asthma.
Park SJ, Min KH, Lee YC.
Respirology. 2008 Nov;13(6):764-71. (REVIEW)
PMID 18811876
Mechanisms and implications of phosphoinositide 3-kinase delta in promoting neutrophil trafficking into inflamed tissue.
Puri KD, Doggett TA, Douangpanya J, Hou Y, Tino WT, Wilson T, Graf T, Clayton E, Turner M, Hayflick JS, Diacovo TG.
Blood. 2004 May 1;103(9):3448-56. Epub 2004 Jan 29.
PMID 14751923
PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond?
Rommel C, Camps M, Ji H.
Nat Rev Immunol. 2007 Mar;7(3):191-201. Epub 2007 Feb 9. (REVIEW)
PMID 17290298
Regulation of breast cancer cell chemotaxis by the phosphoinositide 3-kinase p110delta.
Sawyer C, Sturge J, Bennett DC, O'Hare MJ, Allen WE, Bain J, Jones GE, Vanhaesebroeck B.
Cancer Res. 2003 Apr 1;63(7):1667-75.
PMID 12670921
Identification and chromosome assignment of a human gene encoding a novel phosphatidylinositol-3 kinase.
Seki N, Nimura Y, Ohira M, Saito T, Ichimiya S, Nomura N, Nakagawara A.
DNA Res. 1997 Oct 31;4(5):355-8.
PMID 9455486
Altered macrophage function contributes to colitis in mice defective in the phosphoinositide-3 kinase subunit p110delta.
Uno JK, Rao KN, Matsuoka K, Sheikh SZ, Kobayashi T, Li F, Steinbach EC, Sepulveda AR, Vanhaesebroeck B, Sartor RB, Plevy SE.
Gastroenterology. 2010 Nov;139(5):1642-53, 1653.e1-6. Epub 2010 Jul 14.
PMID 20637203
Signaling by distinct classes of phosphoinositide 3-kinases.
Vanhaesebroeck B, Waterfield MD.
Exp Cell Res. 1999 Nov 25;253(1):239-54. (REVIEW)
PMID 10579926
Regulation of the p85/p110 phosphatidylinositol 3'-kinase: stabilization and inhibition of the p110alpha catalytic subunit by the p85 regulatory subunit.
Yu J, Zhang Y, McIlroy J, Rordorf-Nikolic T, Orr GA, Backer JM.
Mol Cell Biol. 1998 Mar;18(3):1379-87.
PMID 9488453


This paper should be referenced as such :
Burns, E ; Vanhaesebroeck, B
PIK3CD (phosphoinositide-3-kinase, catalytic, delta polypeptide)
Atlas Genet Cytogenet Oncol Haematol. 2011;15(9):731-734.
Free journal version : [ pdf ]   [ DOI ]
On line version :

Other Solid tumors implicated (Data extracted from papers in the Atlas) [ 2 ]
  del(1)(p36p36) RERE/PIK3CD
inv(1)(p35p36) MARCKSL1/PIK3CD

External links

Genomic and cartography
Gene and transcription
RefSeq transcript (Entrez)
RefSeq genomic (Entrez)
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
BioGPS (Tissue expression)5293
Protein : pattern, domain, 3D structure
Domain families : Pfam (Sanger)
Domain families : Pfam (NCBI)
Protein Interaction databases
Ontologies - Pathways
Clinical trials, drugs, therapy
canSAR (ICR) (select the gene name)
REVIEW articlesautomatic search in PubMed
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