O00329 (PK3CD_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform
Short name=PI3-kinase subunit delta
Short name=PI3K-delta
Short name=PI3Kdelta
Short name=PtdIns-3-kinase subunit delta
EC=2.7.1.153

Alternative name(s):
Phosphatidylinositol-4,5-bisphosphate 3-kinase 110 kDa catalytic subunit delta
Short name=PtdIns-3-kinase subunit p110-delta
Short name=p110delta

Gene names

Name:

PIK3CD

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	1044 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Phosphoinositide-3-kinase (PI3K) that phosphorylates PftdIns(4,5)P2 (Phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol-3,4,5-triphosphate (PIP3). PIP3 plays a key role by recruiting PH domain-containing proteins to the membrane, including AKT1 and PDPK1, activating signaling cascades involved in cell growth, survival, proliferation, motility and morphology. Mediates immune responses. Plays a role in B-cell development, proliferation, migration, and function. Required for B-cell receptor (BCR) signaling. Mediates B-cell proliferation response to anti-IgM, anti-CD40 and IL4 stimulation. Promotes cytokine production in response to TLR4 and TLR9. Required for antibody class switch mediated by TLR9. Involved in the antigen presentation function of B-cells. Involved in B-cell chemotaxis in response to CXCL13 and sphingosine 1-phosphate (S1P). Required for proliferation, signaling and cytokine production of naive, effector and memory T-cells. Required for T-cell receptor (TCR) signaling. Mediates TCR signaling events at the immune synapse. Activation by TCR leads to antigen-dependent memory T-cell migration and retention to antigenic tissues. Together with PIK3CG participates in T-cell development. Contributes to T helper cell expansion and differentiation. Required for T-cell migration mediated by homing receptors SELL/CD62L, CCR7 and S1PR1 and antigen dependent recruitment of T-cells. Together with PIK3CG is involved in natural killer (NK) cell development and migration towards the sites of inflammation. Participates in NK cell receptor activation. Have a role in NK cell maturation and cytokine production. Together with PIK3CG is involved in neutrophil chemotaxis and extravasation. Together with PIK3CG participates in neutrophil respiratory burst. Have important roles in mast-cell development and mast cell mediated allergic response. Involved in stem cell factor (SCF)-mediated proliferation, adhesion and migration. Required for allergen-IgE-induced degranulation and cytokine release. The lipid kinase activity is required for its biological function. Ref.10
Catalytic activity	ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate = ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate.
Enzyme regulation	Activated by growth factors and cytokine receptors through a tyrosine-kinase-dependent mechanism. Activated by RAS. IC87114 inhibits lipid kinase activity and is selective in cells at doses up to 5-10 µM. IC87114 blocks T-cell receptor signaling in naive and memory T-cells and reduces cytokine production by memory T-cells. Ref.10
Pathway	Phospholipid metabolism; phosphatidylinositol phosphate biosynthesis.
Subunit structure	Heterodimer of a catalytic subunit PIK3CD and a p85 regulatory subunit (PIK3R1, PIK3R2 or PIK3R3). Interacts with ERAS By similarity.
Tissue specificity	Expressed predominantly in leukocytes.
Post-translational modification	Autophosphorylation on Ser-1039 results in the almost complete inactivation of the lipid kinase activity.
Miscellaneous	IC87114 inhibitor reduces passive cutaneous anaphylaxis, attenuates allergic airway inflammation and hyperresponsiveness and allergen induced rhinitis response. Inhibitors may have therapeutic potential for the treatment of immune system-mediated diseases such as auto-immune diseases, inflamation and allergy (Ref.12; Ref.11).
Sequence similarities	Belongs to the PI3/PI4-kinase family. Contains 1 C2 PI3K-type domain. Contains 1 PI3K-ABD domain. Contains 1 PI3K-RBD domain. Contains 1 PI3K/PI4K domain. Contains 1 PIK helical domain.

Ontologies

Keywords
Biological process	Adaptive immunity Chemotaxis Differentiation Immunity Inflammatory response Innate immunity
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Transferase
PTM	Phosphoprotein
Technical term	Complete proteome Direct protein sequencing Reference proteome
Gene Ontology (GO)
Biological process	cell differentiation Inferred from electronic annotation. Source: UniProtKB-KW chemotaxis Inferred from electronic annotation. Source: UniProtKB-KW inflammatory response Inferred from electronic annotation. Source: UniProtKB-KW innate immune response Inferred from electronic annotation. Source: UniProtKB-KW phosphatidylinositol-mediated signaling Inferred from electronic annotation. Source: InterPro protein phosphorylation Non-traceable author statement Ref.1. Source: UniProtKB
Cellular component	phosphatidylinositol 3-kinase complex Non-traceable author statement Ref.1Ref.3. Source: UniProtKB plasma membrane Traceable author statement. Source: Reactome
Molecular function	1-phosphatidylinositol-3-kinase activity Non-traceable author statement Ref.3. Source: UniProtKB ATP binding Inferred from electronic annotation. Source: UniProtKB-KW phosphatidylinositol-4,5-bisphosphate 3-kinase activity Inferred from electronic annotation. Source: EC
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 1044	1044	Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta isoform		PRO_0000088790
Regions
	Domain	16 – 105	90	PI3K-ABD
	Domain	187 – 278	92	PI3K-RBD
	Domain	319 – 476	158	C2 PI3K-type
	Domain	497 – 674	178	PIK helical
	Domain	774 – 1041	268	PI3K/PI4K
Amino acid modifications
	Modified residue	484	1	Phosphotyrosine Ref.9
	Modified residue	520	1	Phosphoserine Ref.9
	Modified residue	524	1	Phosphotyrosine Ref.8 Ref.9
	Modified residue	1039	1	Phosphoserine; by autocatalysis Ref.7 Ref.9
Experimental info
	Mutagenesis	894	1	R → P: Abolishes lipid and protein kinase activities. Ref.7
	Mutagenesis	1039	1	S → A: Abolishes autophosphorylation, no effect on lipid kinase activity. Ref.7
	Mutagenesis	1039	1	S → D or E: Abolishes autophosphorylation, reduced lipid kinase activity. Ref.7
	Sequence conflict	253	1	S → N in AAC25677. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	O00329 [UniParc]. Last modified June 7, 2005. Version 2. Checksum: A38B5D1A1081A3D0	FASTA	1,044	119,479
	10 20 30 40 50 60 MPPGVDCPME FWTKEENQSV VVDFLLPTGV YLNFPVSRNA NLSTIKQLLW HRAQYEPLFH 70 80 90 100 110 120 MLSGPEAYVF TCINQTAEQQ ELEDEQRRLC DVQPFLPVLR LVAREGDRVK KLINSQISLL 130 140 150 160 170 180 IGKGLHEFDS LCDPEVNDFR AKMCQFCEEA AARRQQLGWE AWLQYSFPLQ LEPSAQTWGP 190 200 210 220 230 240 GTLRLPNRAL LVNVKFEGSE ESFTFQVSTK DVPLALMACA LRKKATVFRQ PLVEQPEDYT 250 260 270 280 290 300 LQVNGRHEYL YGSYPLCQFQ YICSCLHSGL TPHLTMVHSS SILAMRDEQS NPAPQVQKPR 310 320 330 340 350 360 AKPPPIPAKK PSSVSLWSLE QPFRIELIQG SKVNADERMK LVVQAGLFHG NEMLCKTVSS 370 380 390 400 410 420 SEVSVCSEPV WKQRLEFDIN ICDLPRMARL CFALYAVIEK AKKARSTKKK SKKADCPIAW 430 440 450 460 470 480 ANLMLFDYKD QLKTGERCLY MWPSVPDEKG ELLNPTGTVR SNPNTDSAAA LLICLPEVAP 490 500 510 520 530 540 HPVYYPALEK ILELGRHSEC VHVTEEEQLQ LREILERRGS GELYEHEKDL VWKLRHEVQE 550 560 570 580 590 600 HFPEALARLL LVTKWNKHED VAQMLYLLCS WPELPVLSAL ELLDFSFPDC HVGSFAIKSL 610 620 630 640 650 660 RKLTDDELFQ YLLQLVQVLK YESYLDCELT KFLLDRALAN RKIGHFLFWH LRSEMHVPSV 670 680 690 700 710 720 ALRFGLILEA YCRGSTHHMK VLMKQGEALS KLKALNDFVK LSSQKTPKPQ TKELMHLCMR 730 740 750 760 770 780 QEAYLEALSH LQSPLDPSTL LAEVCVEQCT FMDSKMKPLW IMYSNEEAGS GGSVGIIFKN 790 800 810 820 830 840 GDDLRQDMLT LQMIQLMDVL WKQEGLDLRM TPYGCLPTGD RTGLIEVVLR SDTIANIQLN 850 860 870 880 890 900 KSNMAATAAF NKDALLNWLK SKNPGEALDR AIEEFTLSCA GYCVATYVLG IGDRHSDNIM 910 920 930 940 950 960 IRESGQLFHI DFGHFLGNFK TKFGINRERV PFILTYDFVH VIQQGKTNNS EKFERFRGYC 970 980 990 1000 1010 1020 ERAYTILRRH GLLFLHLFAL MRAAGLPELS CSKDIQYLKD SLALGKTEEE ALKHFRVKFN 1030 1040 EALRESWKTK VNWLAHNVSK DNRQ

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"P110delta, a novel phosphoinositide 3-kinase in leukocytes." Vanhaesebroeck B.A.M., Welham M.J., Kotani K., Stein R., Warne P.H., Zvelebil M.J., Higashi K., Volinia S., Downward J., Waterfield M.D. Proc. Natl. Acad. Sci. U.S.A. 94:4330-4335(1997) [PubMed: 9113989] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	Vanhaesebroeck B.A.M. Submitted (OCT-2003) to the EMBL/GenBank/DDBJ databases Cited for: SEQUENCE REVISION TO 675.
[3]	"p110delta, a novel phosphatidylinositol 3-kinase catalytic subunit that associates with p85 and is expressed predominantly in leukocytes." Chantry D., Vojtek A., Kashishian A., Holtzman D.A., Wood C., Gray P.W., Cooper J.A., Hoekstra M.F. J. Biol. Chem. 272:19236-19241(1997) [PubMed: 9235916] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[4]	"Variations in the human phosphoinositide-3-kinase p110 gene in children with primary B-cell immunodeficiency of unknown etiology." Jou S.-T., Chien Y.-H., Yang Y.-H., Shyur S.-D., Chou C.-C., Chiang B.-L. Submitted (OCT-2005) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[5]	"The DNA sequence and biological annotation of human chromosome 1." Gregory S.G., Barlow K.F., McLay K.E., Kaul R., Swarbreck D., Dunham A., Scott C.E., Howe K.L., Woodfine K., Spencer C.C.A., Jones M.C., Gillson C., Searle S., Zhou Y., Kokocinski F., McDonald L., Evans R., Phillips K. , Atkinson A., Cooper R., Jones C., Hall R.E., Andrews T.D., Lloyd C., Ainscough R., Almeida J.P., Ambrose K.D., Anderson F., Andrew R.W., Ashwell R.I.S., Aubin K., Babbage A.K., Bagguley C.L., Bailey J., Beasley H., Bethel G., Bird C.P., Bray-Allen S., Brown J.Y., Brown A.J., Buckley D., Burton J., Bye J., Carder C., Chapman J.C., Clark S.Y., Clarke G., Clee C., Cobley V., Collier R.E., Corby N., Coville G.J., Davies J., Deadman R., Dunn M., Earthrowl M., Ellington A.G., Errington H., Frankish A., Frankland J., French L., Garner P., Garnett J., Gay L., Ghori M.R.J., Gibson R., Gilby L.M., Gillett W., Glithero R.J., Grafham D.V., Griffiths C., Griffiths-Jones S., Grocock R., Hammond S., Harrison E.S.I., Hart E., Haugen E., Heath P.D., Holmes S., Holt K., Howden P.J., Hunt A.R., Hunt S.E., Hunter G., Isherwood J., James R., Johnson C., Johnson D., Joy A., Kay M., Kershaw J.K., Kibukawa M., Kimberley A.M., King A., Knights A.J., Lad H., Laird G., Lawlor S., Leongamornlert D.A., Lloyd D.M., Loveland J., Lovell J., Lush M.J., Lyne R., Martin S., Mashreghi-Mohammadi M., Matthews L., Matthews N.S.W., McLaren S., Milne S., Mistry S., Moore M.J.F., Nickerson T., O'Dell C.N., Oliver K., Palmeiri A., Palmer S.A., Parker A., Patel D., Pearce A.V., Peck A.I., Pelan S., Phelps K., Phillimore B.J., Plumb R., Rajan J., Raymond C., Rouse G., Saenphimmachak C., Sehra H.K., Sheridan E., Shownkeen R., Sims S., Skuce C.D., Smith M., Steward C., Subramanian S., Sycamore N., Tracey A., Tromans A., Van Helmond Z., Wall M., Wallis J.M., White S., Whitehead S.L., Wilkinson J.E., Willey D.L., Williams H., Wilming L., Wray P.W., Wu Z., Coulson A., Vaudin M., Sulston J.E., Durbin R.M., Hubbard T., Wooster R., Dunham I., Carter N.P., McVean G., Ross M.T., Harrow J., Olson M.V., Beck S., Rogers J., Bentley D.R. Nature 441:315-321(2006) [PubMed: 16710414] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[6]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
[7]	"Autophosphorylation of p110 delta phosphoinositide 3-kinase: a new paradigm for the regulation of lipid kinases in vitro and in vivo." Vanhaesebroeck B., Higashi K., Raven C., Welham M., Anderson S., Brennan P., Ward S.G., Waterfield M.D. EMBO J. 18:1292-1302(1999) [PubMed: 10064595] [Abstract] Cited for: PROTEIN SEQUENCE OF 1031-1040, PHOSPHORYLATION AT SER-1039, MUTAGENESIS OF ARG-894 AND SER-1039.
[8]	"Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer." Rikova K., Guo A., Zeng Q., Possemato A., Yu J., Haack H., Nardone J., Lee K., Reeves C., Li Y., Hu Y., Tan Z., Stokes M., Sullivan L., Mitchell J., Wetzel R., Macneill J., Ren J.M. , Yuan J., Bakalarski C.E., Villen J., Kornhauser J.M., Smith B., Li D., Zhou X., Gygi S.P., Gu T.-L., Polakiewicz R.D., Rush J., Comb M.J. Cell 131:1190-1203(2007) [PubMed: 18083107] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-524, MASS SPECTROMETRY. Tissue: Lung carcinoma.
[9]	"Large-scale proteomics analysis of the human kinome." Oppermann F.S., Gnad F., Olsen J.V., Hornberger R., Greff Z., Keri G., Mann M., Daub H. Mol. Cell. Proteomics 8:1751-1764(2009) [PubMed: 19369195] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT TYR-484; SER-520; TYR-524 AND SER-1039, MASS SPECTROMETRY.
[10]	"PI3K p110delta regulates T-cell cytokine production during primary and secondary immune responses in mice and humans." Soond D.R., Bjorgo E., Moltu K., Dale V.Q., Patton D.T., Torgersen K.M., Galleway F., Twomey B., Clark J., Gaston J.S.H., Tasken K., Bunyard P., Okkenhaug K. Blood 115:2203-2213(2010) [PubMed: 20081091] [Abstract] Cited for: FUNCTION IN T-CELLS, ENZYME REGULATION.
[11]	"PI3K delta and PI3K gamma: partners in crime in inflammation in rheumatoid arthritis and beyond?" Rommel C., Camps M., Ji H. Nat. Rev. Immunol. 7:191-201(2007) [PubMed: 17290298] [Abstract] Cited for: REVIEW ON FUNCTION.
[12]	"Phosphoinositide 3-kinase delta (PI3Kdelta) in leukocyte signaling and function." Fung-Leung W.-P. Cell. Signal. 23:603-608(2011) [PubMed: 20940048] [Abstract] Cited for: REVIEW ON FUNCTION.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	Y10055 mRNA. Translation: CAA71149.2. U86453 mRNA. Translation: AAC25677.1. DQ263594 mRNA. Translation: ABB83814.1. AL691449 Genomic DNA. Translation: CAI15703.1. BC132919 mRNA. Translation: AAI32920.1. BC132921 mRNA. Translation: AAI32922.1.
IPI	IPI00298410.
RefSeq	NP_005017.3. NM_005026.3.
UniGene	Hs.518451.
3D structure databases
ProteinModelPortal	O00329.
SMR	O00329. Positions 109-1027.
ModBase	Search...
Protein-protein interaction databases
IntAct	O00329. 5 interactions.
MINT	MINT-7242357.
STRING	O00329.
PTM databases
PhosphoSite	O00329.
Proteomic databases
PRIDE	O00329.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000377346; ENSP00000366563; ENSG00000171608.
GeneID	5293.
KEGG	hsa:5293.
UCSC	uc001aqb.2. human.
Organism-specific databases
CTD	5293.
GeneCards	GC01P009711.
H-InvDB	HIX0028728.
HGNC	HGNC:8977. PIK3CD.
HPA	CAB015420.
MIM	602839. gene.
neXtProt	NX_O00329.
GenAtlas	Search...
Phylogenomic databases
eggNOG	prNOG11835.
HOVERGEN	HBG052721.
OrthoDB	EOG4XKV67.
PhylomeDB	O00329.
Enzyme and pathway databases
BioCyc	MetaCyc:ENSG00000171608-MONOMER.
BRENDA	2.7.1.137. 2681.
Pathway_Interaction_DB	pi3kcipathway. Class I PI3K signaling events. trail_pathway. TRAIL signaling pathway.
Reactome	REACT_6900. Immune System.
Gene expression databases
ArrayExpress	O00329.
Bgee	O00329.
CleanEx	HS_PIK3CD.
Genevestigator	O00329.
GermOnline	ENSG00000171608. Homo sapiens.
Family and domain databases
InterPro	IPR016024. ARM-type_fold. IPR008973. C2_Ca/lipid-bd_dom_CaLB. IPR011009. Kinase-like_dom. IPR000403. PI3/4_kinase_cat. IPR018936. PI3/4_kinase_CS. IPR002420. PI3K_C2. IPR003113. PI3K_p85-bd. IPR000341. PI3K_ras-bd. IPR015433. PI_Kinase. IPR001263. PInositide-3_kin_accessory_dom. [Graphical view]
Gene3D	G3DSA:1.10.1070.11. PI3/4_kinase_cat. 1 hit. G3DSA:1.25.40.70. PI3Ka. 1 hit.
KO	K00922.
PANTHER	PTHR10048. PI_Kinase. 1 hit.
Pfam	PF00454. PI3_PI4_kinase. 1 hit. PF00792. PI3K_C2. 1 hit. PF02192. PI3K_p85B. 1 hit. PF00794. PI3K_rbd. 1 hit. PF00613. PI3Ka. 1 hit. [Graphical view]
SMART	SM00142. PI3K_C2. 1 hit. SM00143. PI3K_p85B. 1 hit. SM00144. PI3K_rbd. 1 hit. SM00145. PI3Ka. 1 hit. SM00146. PI3Kc. 1 hit. [Graphical view]
SUPFAM	SSF48371. ARM-type_fold. 1 hit. SSF49562. C2_CaLB. 1 hit. SSF56112. Kinase_like. 1 hit.
PROSITE	PS00915. PI3_4_KINASE_1. 1 hit. PS00916. PI3_4_KINASE_2. 1 hit. PS50290. PI3_4_KINASE_3. 1 hit. PS51544. PI3K_ABD. 1 hit. PS51547. PI3K_C2. 1 hit. PS51546. PI3K_RBD. 1 hit. PS51545. PIK_HELICAL. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	20454.
SOURCE	Search...

Entry information

Entry name

PK3CD_HUMAN

Accession

Primary (citable) accession number: O00329
Secondary accession number(s): A6NCG0, O15445, Q5SR49

Entry history

Integrated into UniProtKB/Swiss-Prot:	July 15, 1998
Last sequence update:	June 7, 2005
Last modified:	January 25, 2012
This is version 110 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.