UniProt functional annotation for O00329



	UniProt functional annotation for O00329

UniProt code: O00329.

Organism: Homo sapiens (Human).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.

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. {ECO:0000269|PubMed:15135396, ECO:0000269|PubMed:20081091, ECO:0000269|PubMed:22020336, ECO:0000269|PubMed:9235916}.

Catalytic activity: Reaction=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(+); Xref=Rhea:RHEA:21292, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:57836, ChEBI:CHEBI:58456, ChEBI:CHEBI:456216; EC=2.7.1.153; Evidence={ECO:0000269|PubMed:15135396}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:21293; Evidence={ECO:0000305|PubMed:15135396};

Catalytic activity: Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + ADP + H(+); Xref=Rhea:RHEA:12709, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:57880, ChEBI:CHEBI:58088, ChEBI:CHEBI:456216; EC=2.7.1.137; Evidence={ECO:0000269|PubMed:9235916}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12710; Evidence={ECO:0000305|PubMed:9235916};

Catalytic activity: Reaction=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(+); Xref=Rhea:RHEA:43396, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:77137, ChEBI:CHEBI:83243, ChEBI:CHEBI:456216; Evidence={ECO:0000305|PubMed:15135396}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:43397; Evidence={ECO:0000305|PubMed:15135396};

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. {ECO:0000269|PubMed:20081091}.

Pathway: Phospholipid metabolism; phosphatidylinositol phosphate biosynthesis. {ECO:0000305|PubMed:15135396, ECO:0000305|PubMed:9113989}.

Subunit: Heterodimer of a catalytic subunit PIK3CD and a p85 regulatory subunit (PIK3R1, PIK3R2 or PIK3R3). Interacts with ERAS (By similarity). Interacts with HRAS. {ECO:0000250, ECO:0000269|PubMed:22020336}.

Subcellular location: Cytoplasm {ECO:0000269|PubMed:22020336}.

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. {ECO:0000269|PubMed:22020336, ECO:0000269|PubMed:9235916}.

Ptm: Autophosphorylation on Ser-1039 results in the almost complete inactivation of the lipid kinase activity. {ECO:0000269|PubMed:10064595}.

Disease: Activated PI3K-delta syndrome (APDS) [MIM:615513]: A 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. {ECO:0000269|PubMed:24136356}. Note=The disease is caused by variants affecting the gene represented in this entry.

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:20940048; PubMed:17290298).

Similarity: Belongs to the PI3/PI4-kinase family. {ECO:0000255|PROSITE- ProRule:PRU00877, ECO:0000255|PROSITE-ProRule:PRU00879, ECO:0000255|PROSITE-ProRule:PRU00880}.

Annotations taken from UniProtKB at the EBI.


Organism:		Homo sapiens (Human).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo.



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. {ECO:0000269\|PubMed:15135396, ECO:0000269\|PubMed:20081091, ECO:0000269\|PubMed:22020336, ECO:0000269\|PubMed:9235916}.


Catalytic activity:		Reaction=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(+); Xref=Rhea:RHEA:21292, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:57836, ChEBI:CHEBI:58456, ChEBI:CHEBI:456216; EC=2.7.1.153; Evidence={ECO:0000269\|PubMed:15135396}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:21293; Evidence={ECO:0000305\|PubMed:15135396};
Catalytic activity:		Reaction=a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol) + ATP = a 1,2-diacyl-sn-glycero-3-phospho-(1D-myo-inositol-3-phosphate) + ADP + H(+); Xref=Rhea:RHEA:12709, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:57880, ChEBI:CHEBI:58088, ChEBI:CHEBI:456216; EC=2.7.1.137; Evidence={ECO:0000269\|PubMed:9235916}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:12710; Evidence={ECO:0000305\|PubMed:9235916};
Catalytic activity:		Reaction=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(+); Xref=Rhea:RHEA:43396, ChEBI:CHEBI:15378, ChEBI:CHEBI:30616, ChEBI:CHEBI:77137, ChEBI:CHEBI:83243, ChEBI:CHEBI:456216; Evidence={ECO:0000305\|PubMed:15135396}; PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:43397; Evidence={ECO:0000305\|PubMed:15135396};
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. {ECO:0000269\|PubMed:20081091}.
Pathway:		Phospholipid metabolism; phosphatidylinositol phosphate biosynthesis. {ECO:0000305\|PubMed:15135396, ECO:0000305\|PubMed:9113989}.
Subunit:		Heterodimer of a catalytic subunit PIK3CD and a p85 regulatory subunit (PIK3R1, PIK3R2 or PIK3R3). Interacts with ERAS (By similarity). Interacts with HRAS. {ECO:0000250, ECO:0000269\|PubMed:22020336}.
Subcellular location:		Cytoplasm {ECO:0000269\|PubMed:22020336}.
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. {ECO:0000269\|PubMed:22020336, ECO:0000269\|PubMed:9235916}.
Ptm:		Autophosphorylation on Ser-1039 results in the almost complete inactivation of the lipid kinase activity. {ECO:0000269\|PubMed:10064595}.
Disease:		Activated PI3K-delta syndrome (APDS) [MIM:615513]: A 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. {ECO:0000269\|PubMed:24136356}. Note=The disease is caused by variants affecting the gene represented in this entry.
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:20940048; PubMed:17290298).
Similarity:		Belongs to the PI3/PI4-kinase family. {ECO:0000255\|PROSITE- ProRule:PRU00877, ECO:0000255\|PROSITE-ProRule:PRU00879, ECO:0000255\|PROSITE-ProRule:PRU00880}.