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

2011-02-01   Emily Burns , Bart Vanhaesebroeck 

Centre of Cell Signalling, Barts Cancer Institute, Queen Mary University of London, London, EC1M 6BQ, UK


Atlas Image
Location of PIK3CD on human chromosome 1.


Atlas Image
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.


The PIK3CD gene spans a genomic region of 24 coding exons and over 77.17 kb.


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).


Atlas Image
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.


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).


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).


p110 delta localises to the cytosol and is recruited to the periplasmic region upon stimulation of upstream activators.


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 Akts 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).


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



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

Implicated in

Entity name
Haematological malignancy
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 its 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).
CLL, T-ALL, B-ALL, DLBCL, AML, and multiple myeloma.
Entity name
Allergic disease (Ali et al., 2004; Lee et al., 2006; Medina-Tato et al., 2007; Park et al., 2008)
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).
Asthma, allergic rhinitis.
Entity name
Chronic inflammatory conditions
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.
Rheumatoid arthritis, inflammatory bowel disease (IBD).


Pubmed IDLast YearTitleAuthors
154969272004Essential role for the p110delta phosphoinositide 3-kinase in the allergic response.Ali K et al
167029482006A 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 et al
122352092002A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation.Clayton E et al
111626742001Structural organization of the mouse phosphatidylinositol 3-kinase p110d gene.Clayton E et al
193623722009Role of phosphoinositide 3-kinase p110 delta in TLR4- and TLR9-mediated B cell cytokine production and differentiation.Dil N et al
174059172007Gene expression profiling of LPS-stimulated murine macrophages and role of the NF-kappaB and PI3K/mTOR signaling pathways.Dos Santos S et al
178466642007Control of axonal growth and regeneration of sensory neurons by the p110delta PI 3-kinase.Eickholt BJ et al
168474622006The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism.Engelman JA et al
166252102006Critical role for the p110alpha phosphoinositide-3-OH kinase in growth and metabolic regulation.Foukas LC et al
90058521997Direct regulation of the Akt proto-oncogene product by phosphatidylinositol-3,4-bisphosphate.Franke TF et al
208649142010New agents in early clinical trials for CLL therapy.Furman RR et al
174707922007Class IA phosphoinositide 3-kinases are obligate p85-p110 heterodimers.Geering B et al
205227082010Phosphatidylinositol 3-kinase-δ inhibitor CAL-101 shows promising preclinical activity in chronic lymphocytic leukemia by antagonizing intrinsic and extrinsic cellular survival signals.Herman SE et al
205051582010PI3K/p110{delta} is a novel therapeutic target in multiple myeloma.Ikeda H et al
176268382007Inactivation of PI3Kgamma and PI3Kdelta distorts T-cell development and causes multiple organ inflammation.Ji H et al
124467772002Essential, nonredundant role for the phosphoinositide 3-kinase p110delta in signaling by the B-cell receptor complex.Jou ST et al
193577692009Regulation of p110delta PI 3-kinase gene expression.Kok K et al
209596062011CAL-101, a p110delta selective phosphatidylinositol-3-kinase inhibitor for the treatment of B-cell malignancies, inhibits PI3K signaling and cellular viability.Lannutti BJ et al
165077632006Inhibition of phosphoinositide 3-kinase delta attenuates allergic airway inflammation and hyperresponsiveness in murine asthma model.Lee KS et al
208377692010Phosphoinositide 3-kinase δ regulates membrane fission of Golgi carriers for selective cytokine secretion.Low PC et al
176148782007Phosphoinositide 3-kinase signalling in lung disease: leucocytes and beyond.Medina-Tato DA et al
127507232003Constitutive phosphorylation of Akt/PKB protein in acute myeloid leukemia: its significance as a prognostic variable.Min YH et al
126690222003PI3K in lymphocyte development, differentiation and activation.Okkenhaug K et al
190333892008Distinct roles of class IA PI3K isoforms in primary and immortalised macrophages.Papakonstanti EA et al
188118762008Phosphoinositide 3-kinase delta inhibitor as a novel therapeutic agent in asthma.Park SJ et al
147519232004Mechanisms and implications of phosphoinositide 3-kinase delta in promoting neutrophil trafficking into inflamed tissue.Puri KD et al
172902982007PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond?Rommel C et al
126709212003Regulation of breast cancer cell chemotaxis by the phosphoinositide 3-kinase p110delta.Sawyer C et al
94554861997Identification and chromosome assignment of a human gene encoding a novel phosphatidylinositol-3 kinase.Seki N et al
206372032010Altered macrophage function contributes to colitis in mice defective in the phosphoinositide-3 kinase subunit p110δ.Uno JK et al
105799261999Signaling by distinct classes of phosphoinositide 3-kinases.Vanhaesebroeck B et al
94884531998Regulation of the p85/p110 phosphatidylinositol 3'-kinase: stabilization and inhibition of the p110alpha catalytic subunit by the p85 regulatory subunit.Yu J et al

Other Information

Locus ID:

NCBI: 5293
MIM: 602839
HGNC: 8977
Ensembl: ENSG00000171608


dbSNP: 5293
ClinVar: 5293
TCGA: ENSG00000171608


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Inositol phosphate metabolismKEGGko00562
ErbB signaling pathwayKEGGko04012
Phosphatidylinositol signaling systemKEGGko04070
Autophagy - animalKEGGko04140
mTOR signaling pathwayKEGGko04150
Axon guidanceKEGGko04360
VEGF signaling pathwayKEGGko04370
Focal adhesionKEGGko04510
Toll-like receptor signaling pathwayKEGGko04620
Jak-STAT signaling pathwayKEGGko04630
Natural killer cell mediated cytotoxicityKEGGko04650
T cell receptor signaling pathwayKEGGko04660
B cell receptor signaling pathwayKEGGko04662
Fc epsilon RI signaling pathwayKEGGko04664
Leukocyte transendothelial migrationKEGGko04670
Regulation of actin cytoskeletonKEGGko04810
Insulin signaling pathwayKEGGko04910
Progesterone-mediated oocyte maturationKEGGko04914
Type II diabetes mellitusKEGGko04930
Colorectal cancerKEGGko05210
Renal cell carcinomaKEGGko05211
Pancreatic cancerKEGGko05212
Endometrial cancerKEGGko05213
Prostate cancerKEGGko05215
Chronic myeloid leukemiaKEGGko05220
Acute myeloid leukemiaKEGGko05221
Small cell lung cancerKEGGko05222
Non-small cell lung cancerKEGGko05223
Inositol phosphate metabolismKEGGhsa00562
ErbB signaling pathwayKEGGhsa04012
Phosphatidylinositol signaling systemKEGGhsa04070
Autophagy - animalKEGGhsa04140
mTOR signaling pathwayKEGGhsa04150
Axon guidanceKEGGhsa04360
VEGF signaling pathwayKEGGhsa04370
Focal adhesionKEGGhsa04510
Toll-like receptor signaling pathwayKEGGhsa04620
Jak-STAT signaling pathwayKEGGhsa04630
Natural killer cell mediated cytotoxicityKEGGhsa04650
T cell receptor signaling pathwayKEGGhsa04660
B cell receptor signaling pathwayKEGGhsa04662
Fc epsilon RI signaling pathwayKEGGhsa04664
Leukocyte transendothelial migrationKEGGhsa04670
Regulation of actin cytoskeletonKEGGhsa04810
Insulin signaling pathwayKEGGhsa04910
Type II diabetes mellitusKEGGhsa04930
Pathways in cancerKEGGhsa05200
Colorectal cancerKEGGhsa05210
Renal cell carcinomaKEGGhsa05211
Pancreatic cancerKEGGhsa05212
Endometrial cancerKEGGhsa05213
Prostate cancerKEGGhsa05215
Chronic myeloid leukemiaKEGGhsa05220
Acute myeloid leukemiaKEGGhsa05221
Small cell lung cancerKEGGhsa05222
Non-small cell lung cancerKEGGhsa05223
Chemokine signaling pathwayKEGGko04062
Chemokine signaling pathwayKEGGhsa04062
Neurotrophin signaling pathwayKEGGko04722
Neurotrophin signaling pathwayKEGGhsa04722
Fc gamma R-mediated phagocytosisKEGGko04666
Fc gamma R-mediated phagocytosisKEGGhsa04666
Progesterone-mediated oocyte maturationKEGGhsa04914
Aldosterone-regulated sodium reabsorptionKEGGko04960
Aldosterone-regulated sodium reabsorptionKEGGhsa04960
Chagas disease (American trypanosomiasis)KEGGko05142
Chagas disease (American trypanosomiasis)KEGGhsa05142
Bacterial invasion of epithelial cellsKEGGko05100
Bacterial invasion of epithelial cellsKEGGhsa05100
Carbohydrate digestion and absorptionKEGGko04973
Carbohydrate digestion and absorptionKEGGhsa04973
Hepatitis CKEGGko05160
Hepatitis CKEGGhsa05160
Osteoclast differentiationKEGGko04380
Osteoclast differentiationKEGGhsa04380
Influenza AKEGGko05164
Influenza AKEGGhsa05164
Cholinergic synapseKEGGhsa04725
HTLV-I infectionKEGGko05166
HTLV-I infectionKEGGhsa05166
Epstein-Barr virus infectionKEGGhsa05169
Epstein-Barr virus infectionKEGGko05169
Viral carcinogenesisKEGGhsa05203
Viral carcinogenesisKEGGko05203
PI3K-Akt signaling pathwayKEGGhsa04151
PI3K-Akt signaling pathwayKEGGko04151
Hepatitis BKEGGhsa05161
HIF-1 signaling pathwayKEGGhsa04066
Proteoglycans in cancerKEGGhsa05205
Proteoglycans in cancerKEGGko05205
Estrogen signaling pathwayKEGGhsa04915
Estrogen signaling pathwayKEGGko04915
TNF signaling pathwayKEGGhsa04668
TNF signaling pathwayKEGGko04668
Prolactin signaling pathwayKEGGhsa04917
Prolactin signaling pathwayKEGGko04917
Non-alcoholic fatty liver disease (NAFLD)KEGGhsa04932
Non-alcoholic fatty liver disease (NAFLD)KEGGko04932
Ras signaling pathwayKEGGhsa04014
Rap1 signaling pathwayKEGGhsa04015
Rap1 signaling pathwayKEGGko04015
FoxO signaling pathwayKEGGhsa04068
Thyroid hormone signaling pathwayKEGGhsa04919
Inflammatory mediator regulation of TRP channelsKEGGhsa04750
Inflammatory mediator regulation of TRP channelsKEGGko04750
Platelet activationKEGGhsa04611
AMPK signaling pathwayKEGGhsa04152
AMPK signaling pathwayKEGGko04152
cAMP signaling pathwayKEGGhsa04024
cAMP signaling pathwayKEGGko04024
Signaling pathways regulating pluripotency of stem cellsKEGGhsa04550
Signaling pathways regulating pluripotency of stem cellsKEGGko04550
Central carbon metabolism in cancerKEGGhsa05230
Choline metabolism in cancerKEGGhsa05231
Central carbon metabolism in cancerKEGGko05230
Choline metabolism in cancerKEGGko05231
PI3K-Akt signalingKEGGhsa_M00676
PI3K-Akt signalingKEGGM00676
Sphingolipid signaling pathwayKEGGhsa04071
Sphingolipid signaling pathwayKEGGko04071
Regulation of lipolysis in adipocytesKEGGhsa04923
Diseases of signal transductionREACTOMER-HSA-5663202
PI3K/AKT Signaling in CancerREACTOMER-HSA-2219528
Constitutive Signaling by Aberrant PI3K in CancerREACTOMER-HSA-2219530
Immune SystemREACTOMER-HSA-168256
Adaptive Immune SystemREACTOMER-HSA-1280218
Signaling by the B Cell Receptor (BCR)REACTOMER-HSA-983705
Antigen activates B Cell Receptor (BCR) leading to generation of second messengersREACTOMER-HSA-983695
Downstream signaling events of B Cell Receptor (BCR)REACTOMER-HSA-1168372
PIP3 activates AKT signalingREACTOMER-HSA-1257604
Negative regulation of the PI3K/AKT networkREACTOMER-HSA-199418
Innate Immune SystemREACTOMER-HSA-168249
DAP12 interactionsREACTOMER-HSA-2172127
DAP12 signalingREACTOMER-HSA-2424491
Fc epsilon receptor (FCERI) signalingREACTOMER-HSA-2454202
Role of LAT2/NTAL/LAB on calcium mobilizationREACTOMER-HSA-2730905
Cytokine Signaling in Immune systemREACTOMER-HSA-1280215
Signaling by InterleukinsREACTOMER-HSA-449147
Interleukin-2 signalingREACTOMER-HSA-451927
Interleukin receptor SHC signalingREACTOMER-HSA-912526
Interleukin-3, 5 and GM-CSF signalingREACTOMER-HSA-512988
Regulation of signaling by CBLREACTOMER-HSA-912631
Platelet activation, signaling and aggregationREACTOMER-HSA-76002
GPVI-mediated activation cascadeREACTOMER-HSA-114604
Signal TransductionREACTOMER-HSA-162582
Signaling by EGFRREACTOMER-HSA-177929
GAB1 signalosomeREACTOMER-HSA-180292
Signalling by NGFREACTOMER-HSA-166520
NGF signalling via TRKA from the plasma membraneREACTOMER-HSA-187037
PI3K/AKT activationREACTOMER-HSA-198203
Signaling by PDGFREACTOMER-HSA-186797
Downstream signal transductionREACTOMER-HSA-186763
Signaling by SCF-KITREACTOMER-HSA-1433557
Signaling by GPCRREACTOMER-HSA-372790
GPCR downstream signalingREACTOMER-HSA-388396
G-protein beta:gamma signallingREACTOMER-HSA-397795
G beta:gamma signalling through PI3KgammaREACTOMER-HSA-392451
Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
Phospholipid metabolismREACTOMER-HSA-1483257
PI MetabolismREACTOMER-HSA-1483255
Synthesis of PIPs at the plasma membraneREACTOMER-HSA-1660499
Developmental BiologyREACTOMER-HSA-1266738
Axon guidanceREACTOMER-HSA-422475
Insulin resistanceKEGGhsa04931
Phospholipase D signaling pathwayKEGGko04072
Phospholipase D signaling pathwayKEGGhsa04072
AGE-RAGE signaling pathway in diabetic complicationsKEGGko04933
AGE-RAGE signaling pathway in diabetic complicationsKEGGhsa04933
Longevity regulating pathwayKEGGhsa04211
Longevity regulating pathway - multiple speciesKEGGko04213
Longevity regulating pathway - multiple speciesKEGGhsa04213
PI5P, PP2A and IER3 Regulate PI3K/AKT SignalingREACTOMER-HSA-6811558
EGFR tyrosine kinase inhibitor resistanceKEGGko01521
Platinum drug resistanceKEGGko01524
Endocrine resistanceKEGGko01522
Platinum drug resistanceKEGGhsa01524
EGFR tyrosine kinase inhibitor resistanceKEGGhsa01521
Endocrine resistanceKEGGhsa01522
RET signalingREACTOMER-HSA-8853659
Breast cancerKEGGko05224
Breast cancerKEGGhsa05224
Fluid shear stress and atherosclerosisKEGGko05418
Fluid shear stress and atherosclerosisKEGGhsa05418

Protein levels (Protein atlas)

Not detected


Entity IDNameTypeEvidenceAssociationPKPDPMIDs


Pubmed IDYearTitleCitations
241657952014Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency.164
241363562013Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage.155
172902982007PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond?131
164321802006Oncogenic transformation induced by the p110beta, -gamma, and -delta isoforms of class I phosphoinositide 3-kinase.106
125942932003Essential role of phosphoinositide 3-kinase delta in neutrophil directional movement.98
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
158789792005Sequential activation of class IB and class IA PI3K is important for the primed respiratory burst of human but not murine neutrophils.83
200810912010PI3K p110delta regulates T-cell cytokine production during primary and secondary immune responses in mice and humans.81
170156962006The p110delta isoform of phosphoinositide 3-kinase controls clonal expansion and differentiation of Th cells.77
158406952005Essential role for the p110delta isoform in phosphoinositide 3-kinase activation and cell proliferation in acute myeloid leukemia.72


Emily Burns ; Bart Vanhaesebroeck

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

Atlas Genet Cytogenet Oncol Haematol. 2011-02-01

Online version: http://atlasgeneticsoncology.org/gene/46261/pik3cd