O00329 · PK3CD_HUMAN
- ProteinPhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
- GenePIK3CD
- StatusUniProtKB reviewed (Swiss-Prot)
- Organism
- Amino acids1044 (go to sequence)
- Protein existenceEvidence at protein level
- Annotation score5/5
Function
function
Phosphoinositide-3-kinase (PI3K) phosphorylates phosphatidylinositol (PI) and its phosphorylated derivatives at position 3 of the inositol ring to produce 3-phosphoinositides (PubMed:9235916).
Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) (PubMed:15135396).
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. Plays 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. Plays 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. Isoform 2 may be involved in stabilizing total RAS levels, resulting in increased ERK phosphorylation and increased PI3K activity.
Uses ATP and PtdIns(4,5)P2 (phosphatidylinositol 4,5-bisphosphate) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3) (PubMed:15135396).
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. Plays 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. Plays 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. Isoform 2 may be involved in stabilizing total RAS levels, resulting in increased ERK phosphorylation and increased PI3K 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, inflammation and allergy (PubMed:17290298, PubMed:20940048).
Catalytic activity
- a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-4,5-bisphosphate) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3,4,5-trisphosphate) + ADP + H+This reaction proceeds in the forward direction.
- 1-octadecanoyl-2-(5Z,8Z,11Z,14Z)-eicosatetraenoyl-sn-glycero-3-phospho-1D-myo-inositol 4,5-bisphosphate + ATP = 1-octadecanoyl-2-(5Z,8Z,11Z,14Z-eicosatetraenoyl)-sn-glycero-3-phospho-(1D-myo-inositol 3,4,5-triphosphate) + ADP + H+This reaction proceeds in the forward direction.
Activity 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 uM. IC87114 blocks T-cell receptor signaling in naive and memory T-cells and reduces cytokine production by memory T-cells.
Pathway
Phospholipid metabolism; phosphatidylinositol phosphate biosynthesis.
GO annotations
Keywords
- Molecular function
- Biological process
- Ligand
Enzyme and pathway databases
Chemistry
Names & Taxonomy
Protein names
- Recommended namePhosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform
- EC number
- Short namesPI3-kinase subunit delta; PI3K-delta; PI3Kdelta; PtdIns-3-kinase subunit delta
- Alternative names
Gene names
Organism names
- Organism
- Taxonomic lineageEukaryota > Metazoa > Chordata > Craniata > Vertebrata > Euteleostomi > Mammalia > Eutheria > Euarchontoglires > Primates > Haplorrhini > Catarrhini > Hominidae > Homo
Accessions
- Primary accessionO00329
- Secondary accessions
Proteomes
Organism-specific databases
Subcellular Location
Disease & Variants
Involvement in disease
Immunodeficiency 14A with lymphoproliferation, autosomal dominant (IMD14A)
- Note
- DescriptionA disorder characterized by recurrent respiratory infections, progressive airway damage, lymphopenia, increased circulating transitional B cells, increased immunoglobulin M, reduced immunoglobulin G2 levels in serum, and impaired vaccine responses.
- See alsoMIM:615513
Natural variants in IMD14A
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_070918 | 1021 | E>K | in IMD14A; results in gain of function causing enhanced membrane association and kinase activity; dbSNP:rs397518423 |
Immunodeficiency 14B, autosomal recessive (IMD14B)
- Note
- DescriptionAn autosomal recessive, primary immunodeficiency characterized by recurrent sinopulmonary infections apparent in early childhood. Some patients may develop inflammatory bowel disease or osteomyelitis. Immunological features include hypogammaglobulinemia, decreased levels of B cells, and evidence of impaired immune-mediated cytotoxicity and defective T-cell function.
- See alsoMIM:619281
Roifman-Chitayat syndrome (ROCHIS)
- Note
- DescriptionAn autosomal recessive digenic disorder characterized by global developmental delay, variable neurologic features such as seizures and ataxia, optic atrophy, dysmorphic facial features, distal skeletal anomalies, and recurrent invasive infections due to combined immunodeficiency.
- See alsoMIM:613328
Natural variants in ROCHIS
Variant ID | Position(s) | Change | Description | |
---|---|---|---|---|
VAR_085590 | 721-1044 | missing | in ROCHIS; no protein can be detected by Western blot in patient cells |
Features
Showing features for natural variant, mutagenesis.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Natural variant | VAR_085590 | 721-1044 | in ROCHIS; no protein can be detected by Western blot in patient cells | |||
Sequence: Missing | ||||||
Mutagenesis | 894 | Abolishes lipid and protein kinase activities. | ||||
Sequence: R → P | ||||||
Natural variant | VAR_070918 | 1021 | in IMD14A; results in gain of function causing enhanced membrane association and kinase activity; dbSNP:rs397518423 | |||
Sequence: E → K | ||||||
Mutagenesis | 1039 | Abolishes autophosphorylation, no effect on lipid kinase activity. | ||||
Sequence: S → A | ||||||
Mutagenesis | 1039 | Abolishes autophosphorylation, reduced lipid kinase activity. | ||||
Sequence: S → D or E |
Variants
We now provide the "Disease & Variants" viewer in its own tab.
The viewer provides 784 variants from UniProt as well as other sources including ClinVar and dbSNP.
Keywords
- Disease
Organism-specific databases
Miscellaneous
Chemistry
Genetic variation databases
PTM/Processing
Features
Showing features for chain, modified residue (large scale data), modified residue.
Type | ID | Position(s) | Source | Description | |||
---|---|---|---|---|---|---|---|
Chain | PRO_0000088790 | 1-1044 | UniProt | Phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform | |||
Sequence: MPPGVDCPMEFWTKEENQSVVVDFLLPTGVYLNFPVSRNANLSTIKQLLWHRAQYEPLFHMLSGPEAYVFTCINQTAEQQELEDEQRRLCDVQPFLPVLRLVAREGDRVKKLINSQISLLIGKGLHEFDSLCDPEVNDFRAKMCQFCEEAAARRQQLGWEAWLQYSFPLQLEPSAQTWGPGTLRLPNRALLVNVKFEGSEESFTFQVSTKDVPLALMACALRKKATVFRQPLVEQPEDYTLQVNGRHEYLYGSYPLCQFQYICSCLHSGLTPHLTMVHSSSILAMRDEQSNPAPQVQKPRAKPPPIPAKKPSSVSLWSLEQPFRIELIQGSKVNADERMKLVVQAGLFHGNEMLCKTVSSSEVSVCSEPVWKQRLEFDINICDLPRMARLCFALYAVIEKAKKARSTKKKSKKADCPIAWANLMLFDYKDQLKTGERCLYMWPSVPDEKGELLNPTGTVRSNPNTDSAAALLICLPEVAPHPVYYPALEKILELGRHSECVHVTEEEQLQLREILERRGSGELYEHEKDLVWKLRHEVQEHFPEALARLLLVTKWNKHEDVAQMLYLLCSWPELPVLSALELLDFSFPDCHVGSFAIKSLRKLTDDELFQYLLQLVQVLKYESYLDCELTKFLLDRALANRKIGHFLFWHLRSEMHVPSVALRFGLILEAYCRGSTHHMKVLMKQGEALSKLKALNDFVKLSSQKTPKPQTKELMHLCMRQEAYLEALSHLQSPLDPSTLLAEVCVEQCTFMDSKMKPLWIMYSNEEAGSGGSVGIIFKNGDDLRQDMLTLQMIQLMDVLWKQEGLDLRMTPYGCLPTGDRTGLIEVVLRSDTIANIQLNKSNMAATAAFNKDALLNWLKSKNPGEALDRAIEEFTLSCAGYCVATYVLGIGDRHSDNIMIRESGQLFHIDFGHFLGNFKTKFGINRERVPFILTYDFVHVIQQGKTNNSEKFERFRGYCERAYTILRRHGLLFLHLFALMRAAGLPELSCSKDIQYLKDSLALGKTEEEALKHFRVKFNEALRESWKTKVNWLAHNVSKDNRQ | |||||||
Modified residue (large scale data) | 520 | PRIDE | Phosphoserine | ||||
Sequence: S | |||||||
Modified residue | 524 | UniProt | Phosphotyrosine | ||||
Sequence: Y | |||||||
Modified residue | 1039 | UniProt | Phosphoserine; by autocatalysis | ||||
Sequence: S | |||||||
Modified residue (large scale data) | 1039 | PRIDE | Phosphoserine | ||||
Sequence: S |
Post-translational modification
Autophosphorylation on Ser-1039 results in the almost complete inactivation of the lipid kinase activity.
Keywords
- PTM
Proteomic databases
PTM databases
Expression
Tissue specificity
In humans, the highest levels of expression are seen in peripheral blood mononuclear cells, spleen, and thymus, and low levels of expression in testes, uterus, colon, and small intestine but not in other tissues examined including prostate, heart, brain, and liver (PubMed:9235916).
Isoform 2 is expressed in normal thymus, lung and spleen tissues, and is detected at low levels in normal lysates from colon and ovarian biopsies, at elevated levels in lysates from colorectal tumors and is abundantly expressed in some ovarian tumors (at protein level). Both isoform 1 and isoform 2 are widely expressed. Isoform 1 is expressed predominantly in leukocytes.
Isoform 2 is expressed in normal thymus, lung and spleen tissues, and is detected at low levels in normal lysates from colon and ovarian biopsies, at elevated levels in lysates from colorectal tumors and is abundantly expressed in some ovarian tumors (at protein level). Both isoform 1 and isoform 2 are widely expressed. Isoform 1 is expressed predominantly in leukocytes.
Gene expression databases
Organism-specific databases
Interaction
Subunit
Heterodimer of a catalytic subunit PIK3CD and a p85 regulatory subunit (PIK3R1, PIK3R2 or PIK3R3). Interacts with ERAS (By similarity).
Interacts with HRAS
Interacts with HRAS
Binary interactions
Type | Entry 1 | Entry 2 | Number of experiments | Intact | |
---|---|---|---|---|---|
BINARY | O00329 | HRAS P01112 | 2 | EBI-718309, EBI-350145 | |
BINARY | O00329 | PIK3R1 P27986 | 9 | EBI-718309, EBI-79464 | |
BINARY | O00329 | PIK3R1 P27986-2 | 3 | EBI-718309, EBI-9090282 | |
BINARY | O00329 | PIK3R3 Q92569 | 6 | EBI-718309, EBI-79893 | |
BINARY | O00329-2 | HRAS P01112 | 2 | EBI-6470902, EBI-350145 |
Protein-protein interaction databases
Chemistry
Miscellaneous
Structure
Family & Domains
Features
Showing features for domain, region.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Domain | 16-105 | PI3K-ABD | ||||
Sequence: ENQSVVVDFLLPTGVYLNFPVSRNANLSTIKQLLWHRAQYEPLFHMLSGPEAYVFTCINQTAEQQELEDEQRRLCDVQPFLPVLRLVARE | ||||||
Domain | 187-278 | PI3K-RBD | ||||
Sequence: NRALLVNVKFEGSEESFTFQVSTKDVPLALMACALRKKATVFRQPLVEQPEDYTLQVNGRHEYLYGSYPLCQFQYICSCLHSGLTPHLTMVH | ||||||
Region | 287-312 | Disordered | ||||
Sequence: DEQSNPAPQVQKPRAKPPPIPAKKPS | ||||||
Domain | 319-476 | C2 PI3K-type | ||||
Sequence: LEQPFRIELIQGSKVNADERMKLVVQAGLFHGNEMLCKTVSSSEVSVCSEPVWKQRLEFDINICDLPRMARLCFALYAVIEKAKKARSTKKKSKKADCPIAWANLMLFDYKDQLKTGERCLYMWPSVPDEKGELLNPTGTVRSNPNTDSAAALLICLP | ||||||
Domain | 497-674 | PIK helical | ||||
Sequence: HSECVHVTEEEQLQLREILERRGSGELYEHEKDLVWKLRHEVQEHFPEALARLLLVTKWNKHEDVAQMLYLLCSWPELPVLSALELLDFSFPDCHVGSFAIKSLRKLTDDELFQYLLQLVQVLKYESYLDCELTKFLLDRALANRKIGHFLFWHLRSEMHVPSVALRFGLILEAYCRG | ||||||
Domain | 745-1027 | PI3K/PI4K catalytic | ||||
Sequence: CVEQCTFMDSKMKPLWIMYSNEEAGSGGSVGIIFKNGDDLRQDMLTLQMIQLMDVLWKQEGLDLRMTPYGCLPTGDRTGLIEVVLRSDTIANIQLNKSNMAATAAFNKDALLNWLKSKNPGEALDRAIEEFTLSCAGYCVATYVLGIGDRHSDNIMIRESGQLFHIDFGHFLGNFKTKFGINRERVPFILTYDFVHVIQQGKTNNSEKFERFRGYCERAYTILRRHGLLFLHLFALMRAAGLPELSCSKDIQYLKDSLALGKTEEEALKHFRVKFNEALRESW | ||||||
Region | 751-757 | G-loop | ||||
Sequence: FMDSKMK | ||||||
Region | 890-898 | Catalytic loop | ||||
Sequence: GIGDRHSDN | ||||||
Region | 909-935 | Activation loop | ||||
Sequence: HIDFGHFLGNFKTKFGINRERVPFILT |
Sequence similarities
Belongs to the PI3/PI4-kinase family.
Phylogenomic databases
Family and domain databases
Sequence & Isoform
- Sequence statusComplete
This entry describes 2 isoforms produced by Alternative splicing.
O00329-1
This isoform has been chosen as the canonical sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
- Name1
- Synonymsp110-delta
- Length1,044
- Mass (Da)119,479
- Last updated2005-06-07 v2
- ChecksumA38B5D1A1081A3D0
O00329-2
- Name2
- Synonymsp37-delta
Computationally mapped potential isoform sequences
There are 7 potential isoforms mapped to this entry
Entry | Entry name | Gene name | Length | ||
---|---|---|---|---|---|
B7ZM44 | B7ZM44_HUMAN | PIK3CD | 1043 | ||
F8W9P4 | F8W9P4_HUMAN | PIK3CD | 1068 | ||
A0A8V8TNW9 | A0A8V8TNW9_HUMAN | PIK3CD | 1012 | ||
A0A8V8TNP1 | A0A8V8TNP1_HUMAN | PIK3CD | 197 | ||
A0A8V8TM62 | A0A8V8TM62_HUMAN | PIK3CD | 996 | ||
A0A8V8TML5 | A0A8V8TML5_HUMAN | PIK3CD | 51 | ||
A0A8V8TMM0 | A0A8V8TMM0_HUMAN | PIK3CD | 1040 |
Features
Showing features for alternative sequence, sequence conflict.
Type | ID | Position(s) | Description | |||
---|---|---|---|---|---|---|
Alternative sequence | VSP_044409 | 201-300 | in isoform 2 | |||
Sequence: ESFTFQVSTKDVPLALMACALRKKATVFRQPLVEQPEDYTLQVNGRHEYLYGSYPLCQFQYICSCLHSGLTPHLTMVHSSSILAMRDEQSNPAPQVQKPR → VSPCVACGIQAALSMGSTSSVKLLSHPQAPLPQWHQMVFARCLCMCGAQLNVPPGELHLPGVHQGRAAGADGLCPAEEGHSVPAAAGGAAGRLHAAGERQ | ||||||
Sequence conflict | 253 | in Ref. 3; AAC25677 | ||||
Sequence: S → N | ||||||
Alternative sequence | VSP_044410 | 302-1044 | in isoform 2 | |||
Sequence: Missing |
Keywords
- Coding sequence diversity
- Technical term
Sequence databases
Nucleotide Sequence | Protein Sequence | Molecule Type | Status | |
---|---|---|---|---|
Y10055 EMBL· GenBank· DDBJ | CAA71149.2 EMBL· GenBank· DDBJ | mRNA | ||
U86453 EMBL· GenBank· DDBJ | AAC25677.1 EMBL· GenBank· DDBJ | mRNA | ||
JN190435 EMBL· GenBank· DDBJ | AEK81610.1 EMBL· GenBank· DDBJ | mRNA | ||
DQ263594 EMBL· GenBank· DDBJ | ABB83814.1 EMBL· GenBank· DDBJ | mRNA | ||
AL691449 EMBL· GenBank· DDBJ | - | Genomic DNA | No translation available. | |
BC132919 EMBL· GenBank· DDBJ | AAI32920.1 EMBL· GenBank· DDBJ | mRNA | ||
BC132921 EMBL· GenBank· DDBJ | AAI32922.1 EMBL· GenBank· DDBJ | mRNA |