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Information on EC 2.7.1.153 - phosphatidylinositol-4,5-bisphosphate 3-kinase and Organism(s) Mus musculus and UniProt Accession P42337
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2.7.1.153 phosphatidylinositol-4,5-bisphosphate 3-kinaseIUBMB Comments
This enzyme also catalyses the phosphorylation of PtdIns4P to PtdIns(3,4)P2, and of PtdIns to PtdIns3P. Four mammalian isoforms are known to exist.
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Word Map
- 2.7.1.153
- wortmannin
- pten
- mapks
- mtor
- rapamycin
- endothelial
- erk
- colorectal
-
signal-regulated
- subtypes
-
insulin-like
- pkc
- tumour
- adenocarcinoma
- phospholipase
- akt1
-
insulin-stimulated
- irs-1
- erbb2
-
mitogen
- adipocytes
- integrins
-
tensin
-
insulin-induced
- 3-kinases
-
dominant-negative
-
platelet-derived
-
hotspot
-
pi3k-akt
-
progression-free
- substrate-1
- igf-i
- sh2
-
ctnnb1
-
tyrosine-phosphorylated
-
phosphatidylinositol-3
-
pleckstrin
-
cdkn2a
- rac1
-
pi3k-dependent
-
her2-negative
- cetuximab
-
phosphatidylinositol-3-kinase
-
everolimus
-
anti-egfr
-
pdgfra
- trastuzumab
-
her2-positive
-
phospho-akt
-
endometrioid
- medicine
- pharmacology
- analysis
The taxonomic range for the selected organisms is: Mus musculus
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
Synonyms
pik3ca, phosphoinositide 3-kinase, pi 3-kinase, pi3-kinase, pi3-k, pi-3k, pik3r1, phosphatidylinositol 3'-kinase, p110alpha, pi 3-k, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
class I phosphoinositide 3-kinase
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-
-
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class I PI3K
kinase (phosphorylating), phosphatidylinositol 4,5-diphosphate 3-
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-
-
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p101-PI3K
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-
-
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p110delta
P120-PI3K
-
-
-
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phosphatidylinositol (4,5)-bisphosphate 3-hydroxykinase
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-
-
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phosphatidylinositol 3-hydroxyl kinase
-
-
-
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phosphatidylinositol 3-kinase gamma
PI3K
PI3Kbeta
-
-
-
-
PI3Kgamma
PtdIns(4,5)P2 3-OH kinase
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-
-
-
PtdIns-3-kinase p101
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-
-
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PtdIns-3-kinase p110
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-
-
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PtdInsP 3-OH-kinase
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-
-
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type I phosphoinositide 3-kinase
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-
-
-
additional information
-
class I PI3Ks can be further subtyped depending on their associated catalytic subunit into class IA p110alpha, p110beta and p110delta and class IB p110gamma
class I PI3K
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-
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p110delta
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-
-
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PI3K
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-
-
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PI3Kgamma
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-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phospho-group transfer
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-
-
-
SYSTEMATIC NAME
IUBMB Comments
ATP:1-phosphatidyl-1D-myo-inositol-4,5-bisphosphate 3-phosphotransferase
This enzyme also catalyses the phosphorylation of PtdIns4P to PtdIns(3,4)P2, and of PtdIns to PtdIns3P. Four mammalian isoforms are known to exist.
CAS REGISTRY NUMBER
COMMENTARY
103843-30-7
-
115926-52-8
cf. EC 2.7.1.137
SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol
ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate
-
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-triphosphate
-
-
phosphatidylinositol-3,4,5-triphosphate is a major product of active PI3K, and recruits Akt/PKB to the plasma membrane and the phosphorylation of Akt occurs
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
ATP + phosphatidylinositol-4,5-bisphosphate
ADP + phosphatidylinositol-3,4,5-trisphosphate
-
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
-
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
p110delta controls a critical checkpoint in peripheral T cell differentiation and clonal expansion
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
PI3Kp110delta is the main source of production of 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate following antigen recognition by B cells, T cells and mast cells
-
-
?
additional information
?
-
-
mechanism of signal down-regulation of insulin receptor substrate mediated by monomeric p85 enzyme regulatory subunit
-
-
?
additional information
?
-
-
p110delta is an important signaling component for efficient axonal elongation in the developing and regenerating nervous system
-
-
?
additional information
?
-
p110delta isoform of PI 3-kinase negatively controls RhoA and PTEN
-
-
?
additional information
?
-
PI3K p110delta contributes to cellular and humoral immunity. PI3K p110delta regulates the diffentiation of peripheral helper T-cells towards the Th1 and Th2 lineages. PI3K p110delta is critical to regulatory T-cell development and function
-
-
?
additional information
?
-
PI3K p110delta play a role in the regulation of RAG gene expression and thereby LC allelic/isotype exclusion
-
-
?
additional information
?
-
PI3Kgamma plays an important role in neutrophil emigration but not rolling and limited adhesion in postcapillary venules in vivo. The leukocyte but not the endothelial PI3Kgamma is critically involved in the early neutrophil emigration into the inflamed tissues. The delayed neutrophil emigration in response to neutrophil chemokines is independent of the function of PI3Lgamma but is PI3Kdelta dependent
-
-
?
additional information
?
-
PI3Kgamma plays an important role in neutrophil emigration but not rolling and limited adhesion in postcapillary venules in vivo. The leukocyte but not the endothelial PI3Kgamma is critically involved in the early neutrophil emigration into the inflamed tissues. The delayed neutrophil emigration in response to neutrophil chemokines is independent of the function of PI3Lgamma but is PI3Kdelta dependent
-
-
?
additional information
?
-
role of the phosphoinositide 3-kinase p110delta in generation of type 2 cytokine responses and allergic airway inflammation
-
-
?
additional information
?
-
the delayed neutrophil emigration in response to neutrophil chemokines is independent of the function of PI3Lgamma but is PI3Kdelta dependent
-
-
?
additional information
?
-
the delayed neutrophil emigration in response to neutrophil chemokines is independent of the function of PI3Lgamma but is PI3Kdelta dependent
-
-
?
additional information
?
-
-
function of class IA phosphatidylinositol 3-kinases in the pre-T-cell receptor-controlled developmental transition of CD4-/CD8- double-negative to CD4+/CD8+ double-positive thymocytes
-
-
?
additional information
?
-
-
molecular model for the regulation of PI3K signaling by NCoR, a receptor corepressor and regulator of thyroid receptor-activated PI3K signaling
-
-
?
additional information
?
-
-
the single class 1B catalytic isoform p110gamma binds to either p101 or p84/p87 adaptors, which function to potentiate activation by betagamma-subunits of heterotrimeric GTP-binding proteins which facilitate intracellular signalling from G-protein coupled receptors
-
-
?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-triphosphate
-
-
phosphatidylinositol-3,4,5-triphosphate is a major product of active PI3K, and recruits Akt/PKB to the plasma membrane and the phosphorylation of Akt occurs
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
ATP + phosphatidylinositol-4,5-bisphosphate
ADP + phosphatidylinositol-3,4,5-trisphosphate
-
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
-
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
p110delta controls a critical checkpoint in peripheral T cell differentiation and clonal expansion
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
PI3Kp110delta is the main source of production of 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate following antigen recognition by B cells, T cells and mast cells
-
-
?
additional information
?
-
-
mechanism of signal down-regulation of insulin receptor substrate mediated by monomeric p85 enzyme regulatory subunit
-
-
?
additional information
?
-
-
p110delta is an important signaling component for efficient axonal elongation in the developing and regenerating nervous system
-
-
?
additional information
?
-
p110delta isoform of PI 3-kinase negatively controls RhoA and PTEN
-
-
?
additional information
?
-
PI3K p110delta contributes to cellular and humoral immunity. PI3K p110delta regulates the diffentiation of peripheral helper T-cells towards the Th1 and Th2 lineages. PI3K p110delta is critical to regulatory T-cell development and function
-
-
?
additional information
?
-
PI3K p110delta play a role in the regulation of RAG gene expression and thereby LC allelic/isotype exclusion
-
-
?
additional information
?
-
PI3Kgamma plays an important role in neutrophil emigration but not rolling and limited adhesion in postcapillary venules in vivo. The leukocyte but not the endothelial PI3Kgamma is critically involved in the early neutrophil emigration into the inflamed tissues. The delayed neutrophil emigration in response to neutrophil chemokines is independent of the function of PI3Lgamma but is PI3Kdelta dependent
-
-
?
additional information
?
-
PI3Kgamma plays an important role in neutrophil emigration but not rolling and limited adhesion in postcapillary venules in vivo. The leukocyte but not the endothelial PI3Kgamma is critically involved in the early neutrophil emigration into the inflamed tissues. The delayed neutrophil emigration in response to neutrophil chemokines is independent of the function of PI3Lgamma but is PI3Kdelta dependent
-
-
?
additional information
?
-
role of the phosphoinositide 3-kinase p110delta in generation of type 2 cytokine responses and allergic airway inflammation
-
-
?
additional information
?
-
the delayed neutrophil emigration in response to neutrophil chemokines is independent of the function of PI3Lgamma but is PI3Kdelta dependent
-
-
?
additional information
?
-
the delayed neutrophil emigration in response to neutrophil chemokines is independent of the function of PI3Lgamma but is PI3Kdelta dependent
-
-
?
additional information
?
-
-
function of class IA phosphatidylinositol 3-kinases in the pre-T-cell receptor-controlled developmental transition of CD4-/CD8- double-negative to CD4+/CD8+ double-positive thymocytes
-
-
?
additional information
?
-
-
molecular model for the regulation of PI3K signaling by NCoR, a receptor corepressor and regulator of thyroid receptor-activated PI3K signaling
-
-
?
COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
-
i.e. LY294002, treatment prevents interleukin-13-induced hyper-responsiveness
2-(6-aminopurin-9-ylmethyl)-5-methyl-3-O-tolyl-3H-quinazolin-4-one
-
i.e.IC87114, selective for isoform p110delta. Treatment prevents interleukin-13-induced hyper-responsiveness
3-Methyladenine
-
treatment in full medium for a prolonged period of time leads to marked increases of the autophagic markers in cells. The increase of autophagic markers is the result of enhanced autophagic flux. The autophagy promotion activity is due to its differential temporal effects on class I and class III PI3K enzymes. 3-Methyladenine blocks class I PI3K persistently, whereas its suppressive effect on class III PI3K is transient. Treatment with 3-methyladenine in full medium significantly reduces the level of phosphatidylinositol 3-phosphate, the product of class III PI3K, at early time points, but almost completely blocks the product of phosphatidylinositol 3,4,5-trisphosphate up to 9 h
PX-866
-
a PI3K inhibitor, inhibits also the oncogenic K-ras-induced bronchioalveolar stem cell accumulation and tumor growth in vivo
quercetin
-
from red wine extract, quercetin and red wine polyphenol extract inhibit the phosphorylation of Akt in vivo and show inhibitory effects on TNF-alpha-induced upregulation of MMP-9 and on the migratory phenotype of JB6 P+ mouse epidermal, mediated by suppression of the phosphorylation of Akt and the transactivation of activator protein-1 and nuclear factor-kappaB. Red wine extract and quercetin suppress TNF-alpha-induced PI3K activity by binding specifically to PI3K
AS605240
-
a specific PI3Kgamma inhibitor, significantly delays lethality in Plasmodium berghei-infected wild-type micer
Wortmannin
-
treatment with wortmannin results in sustained reduction of phosphatidylinositol 3-phosphate and a transient effect on production of phosphatidylinositol 3,4,5-trisphosphate with recovery after 9 h
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
influenza A virus NS1 protein
-
influenza A virus infection activates the PI3K/Akt pathway by binding influenza A virus NS1 protein to Val573 of the inter-SH2 domain of the p85beta, but not the p85alpha, regulatory subunit of PI3K. NS1-p85-p110 forms a complex in the cells. The interaction is mediated by the interaction interface between the NS1 SH3 binding motif 1, amino acids 164-167, p85beta Val573, and amino acids 137-142 of NS1, molecular modeling and mechanism, overview. Mutant virus PR8-NS1-141/142 is not able to activate Akt phosphorylation
-
interleukin-13
-
treatment of tracheal tissue is associated with an early activation of phosphoinositide 3-kinase
-
platelet-derived growth factor
-
stimulates synthesis of 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
-
thyroid receptor
-
i.e. PV, nongenomic activation of phosphatidylinositol 3-kinase signaling by thyroid hormone receptors, overview. PI3Kactivation through thyroid recptor via proteinprotein interaction, i.e. binding to regulatory subunit p85alpha. The thyroid receptorbeta mutant physically interacts with the regulatory p85alpha subunit of PI3K to activate the downstream AKT-mammalian target of rapamycin and p70S6K and PI3K-integrin-linked kinase-matrix metalloproteinase-2 signaling pathways. PI3K activation results in increased cell proliferation, motility, migration, and metastasis. Nuclear receptor corepressor, NCoR, is a regulator of thyroid receptor-activated PI3K signaling
-
additional information
-
activation of phosphatidylinositol 3-kinase by membrane localization of subunit p110alpha
-
additional information
-
class IA are activated by cell surface expressed receptor tyrosine kinases, such as growth factors, insulin and cytokines, while class IB are activated by G-protein coupled receptors. The single class 1B catalytic isoform p110gamma binds to either p101 or p84/p87 adaptors, which function to potentiate activation by betagamma-subunits of heterotrimeric GTP-binding proteins which facilitate intracellular signalling from G-protein coupled receptors
-
additional information
-
Rac1 acts upstream of PI3K to activate downstream Akt and finally induce NF-kappaB activation and NO production, overview
-
additional information
-
the p110gamma isoform of PI3K is activated by G protein-coupled receptors and regulates neutrophil and macrophage chemotaxis
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
the cells are located at the terminal bronchi, and have the capacity to selfrenew and undergo multi-linage differentiation
-
p110delta is highly expressed. p110delta as an important signaling component for efficient axonal elongation in the developing and regenerating nervous system
additional information
-
PI3Kdelta is absolutely restricted to, and PI3Kgamma is largely restricted to leukocytes
additional information
expression and platelet-derived growth factor beta receptor (betaPDGFR) binding of p110 isoforms in smooth muscle cells (SMCs), overview
additional information
expression and platelet-derived growth factor beta receptor (betaPDGFR) binding of p110 isoforms in smooth muscle cells (SMCs), overview
additional information
-
expression and platelet-derived growth factor beta receptor (betaPDGFR) binding of p110 isoforms in smooth muscle cells (SMCs), overview
additional information
PI3K p110delta is mainly expressed in cells of the immune system
additional information
-
PI3Kalpha and beta are ubiquitously expressed while the expression of PI3Kdelta is restricted to leukocytes
additional information
expression and platelet-derived growth factor beta receptor (betaPDGFR) binding of p110 isoforms in smooth muscle cells (SMCs), overview
additional information
expression and platelet-derived growth factor beta receptor (betaPDGFR) binding of p110 isoforms in smooth muscle cells (SMCs), overview
additional information
-
expression and platelet-derived growth factor beta receptor (betaPDGFR) binding of p110 isoforms in smooth muscle cells (SMCs), overview
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
physiological function
class Ia phosphatidylinositol 3-kinase isoform p110alpha is crucial for receptor tyrosine kinases signaling, thus affecting proliferation, migration, and survival of smooth muscle cells, Receptor tyrosine kinasesinduced phosphatidylinositol 3'-kinase signaling via the p110alpha isoform plays a central role for vascular remodeling
malfunction
metabolism
-
Rac1 regulates peptidoglycan-induced nuclear factor-kappaB activation and cyclooxygenase-2 expression in RAW 264.7 macrophages by activating the phosphatidylinositol 3-kinase/Akt pathway
physiological function
malfunction
-
binding of thyroid receptor to p85alpha activates PI3K/AKT signaling promoting thyroid carcinogenesis by increasing cell proliferation and tumor metastasis
malfunction
-
individual class I PI3K isoforms are strongly linked with the regulation of oncogenes and tumorigenesis. PI3Ka is upregulated and/or mutated in a variety of carcinomas, and in particular lung tumours, and is associated with an elevation in activation and signalling of the serine-threonine kinase Akt, overview
malfunction
-
PI3K is involved in non-small cell lung cancer and is PI3K is required for malignant progression in lung cancer, regulation mechanisms, overview
malfunction
-
PI3Ks constitute important regulators of various signaling pathways with relevance in cancer. Activation of PI3K by membrane localization of subunit p110alpha predisposes mammary glands to neoplastic transformation
malfunction
p110delta deficiency did not affect vascular remodeling in vivo
malfunction
-
Plasmodium berghei ANKA-infected PI3Kgamm knockout mice show greater survival despite similar parasitemia levels in comparison with infected wild-type mice. Histopathological analysis demonstrates reduced hemorrhage, leukocyte accumulation and vascular obstruction in the brain of infected PI3Kgamma null mice. PI3Kgamma deficiency also causes lower microglial activation and T cell cytotoxicity in the brain. On day 6 post-infection, CD3+/CD8+ T cells are significantly reduced in the brain of infected PI3Kgamma null mice when compared to infected wild-type mice and expression of CD44 in CD8+ T cell population in the brain tissue and levels of phospho-IkappaB-alpha in the whole brain are also markedly lower in infected PI3Kgamma null mice, phenotype, overview
physiological function
-
activation of phosphatidylinositol 3-kinase is required for tumor necrosis factor-alpha-induced upregulation of matrix metalloproteinase-9
physiological function
-
isozyme PI3Kgamma is involved in inteleukin-8-induced increase of endothelial monolayer permeability and is able to limit neovascularization and choroidal edema, as well as macrophage infiltration, therefore contributes to reduce laser-induced retinal damage
physiological function
-
phosphatidylinositol 3-kinase is a key mediator of oncogenic K-ras
physiological function
-
PI3K activation results in increased cell proliferation, motility, migration, and metastasis. Inhibition of PI3K signaling delays tumor progression and blocks metastasis of thyroid cancer
physiological function
-
PI3K, via p85alpha and p85beta subunit isoforms, plays dual regulatory roles in the induction of IFN responses by controlling both IFNalpha- and IFNgamma-dependent transcriptional regulation of IFN-sensitive genes and simultaneously regulating the subsequent initiation of mRNA translation for such genes
physiological function
-
selective regulation of CD8 effector T cell migration by the p110gamma catalytic subunit isoform of phosphatidylinositol 3-kinase
physiological function
-
the p110gamma isoform of phosphatidylinositol 3-kinase regulates chemokine receptor-mediated migration of effector CD4 T lymphocytes into peripheral inflammatory sites. Although p110gamma does not regulate antigen-dependent CD4 T cell activation and proliferation, it plays a crucial role in regulating CD4 effector T cell migration, overview
physiological function
-
the signalling pathways regulated by class 1 PI3K signalling are central in many of the fundamental cellular processes associated with PI3K signalling including cell growth, proliferation, migration and survival, signaling pathway overview
physiological function
-
isoform PI3Kdelta is responsible for phosphorylation of colony-stimulating factor CSF-1 receptor phosphorylation in response to CSF-1 added to intact cells or isolated nuclei and its triggering of the phosphorylation of Akt and p27 inside the nucleus. Translocation of exogenous CSF-1 to the nucleus-associated CSF-1 receptors correlates with a prominent role of isoform PI3Kdelta in activation of the Rab5 GTPase
physiological function
class Ia phosphatidylinositol 3-kinase isoform p110delta is disensible for receptor tyrosine kinases signaling, p110delta exerts noncatalytic functions in smooth muscle cell proliferation, but had no effect on migration
physiological function
non-canonical regulation of phosphatidylinositol 3-kinase gamma isoform activity in retinal rod photoreceptor cells. The interaction between the gamm isozyme and alpha subunit of cyclic nucleotide-gated channel, CNGA1, through its RA domain does not appear to play a role in regulation of CNG channel activity, but phosphatidylinositol 3-kinase gamma uses CNGA1 as an anchoring module to achieve close proximity to its substrate to generate D3-phosphoinositides. CNGA1-associated PI3Kgamma activity is independent of dark and light conditions, as well as insulin receptor impairment in rods. The RA domain of isozyme PI3Kgamma interacts strongly with CTR-CNGA1, compared with the RA domain of isozyme PI3Kalpha in retinal photoreceptor cells
physiological function
-
phosphatidylinositol 3-kinase gamma is central in signaling diverse cellular functions. Relevance of isozyme PI3Kgamma for the outcome and the neuroinflammatory process triggered by Plasmodium berghei ANKA infection
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). PK3CA_MOUSE
1068
0
124412
Swiss-Prot
Secretory Pathway (Reliability: 5)
PDB
SCOP
CATH
UNIPROT
ORGANISM
MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
heterodimer
1 * 110000, subunit p110, + 1 * 85000, subunit p85, class IA PI3K isoforms are heterodimers consisting of a catalytic subunit (p110alpha) and a smaller regulatory subunit (p85)
heterodimer
additional information
heterodimer
-
the catalytic subunits of the class IA PI3Ks form heterodimers with one of five Src-homology 2, SH2, domain-containing regulatory subunits p85alpha, p85beta, p55alpha, p55gamma and p50alpha, which bind with high affinity to phosphorylated tyrosines of receptor tyrosine kinases
heterodimer
1 * 110000, subunit p110, + 1 * 85000, subunit p85, class IA PI3K isoforms are heterodimers consisting of a catalytic subunit (p110delta) and a smaller regulatory subunit (p85)
additional information
interactive domains in subunits p85 and p110 responsible for binding to each other are less than 103 and 124 amino acids, respectively. Association of subunits is critical for enzyme activity
additional information
-
interactive domains in subunits p85 and p110 responsible for binding to each other are less than 103 and 124 amino acids, respectively. Association of subunits is critical for enzyme activity
additional information
-
enzyme is comprised of p110 catalytic subunit and a regulatory subunit often derived of p85. In wild-type cells, p85 subunit is more abundant than p110
additional information
-
p85 regulatory subunit forms cytosolic complexes with insulin receptor substrate
additional information
-
regulatory p85 and catalytic p110 subunits are present in equimolar amounts in mammalian cell lines and tissues. No evidence for free p85 or p110 subunits could be obtained. Cell lines contain 10,000-15,000 p85/p110 complexes per cell, with p110beta and p110delta being the most prevalent catalytic subunits in nonleukocytes and leukocytes, respectively
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
D910A
M582V
-
site-directed mutagenesis, the full-length p85alpha isoform inter-SH2 domain mutation enables the mutant PI3K to bind influenza A virus NS1 protein leading to activation of the mutant PI3K enzyme activity, molecular modeling, overview
V573M
-
site-directed mutagenesis, the p85beta isoform inter-SH2 domain mutation abrogates mutant PI3K binding to influenza A virus NS1 protein, molecular modeling, overview
additional information
D910A
-
site-directed mutagenesis of isoform p110delta, catalytically inactive. Interleukin is unable to induce hyper-responsiveness in tissues expressing the mutant
D910A
-
mice with an inactivating knock-in mutation in the p110delta isoform of PI3K, p110deltaD910A, generated on Leishmanina major resistant and susceptible genetic backgrounds. The mutant mice show severely impaired T cell responses, but the mutant mice also show more robust resistance to Leishmanina major infection manifested as significantly reduced lesion size and accelerated parasite clearance. Cells from p110D910A mice were significantly impaired in their ability to make cytokines, particularly IFN-gamma, interleukin-10, and TNF, phenotypes, overview
additional information
expression of regulatory protein p85 102 amino acid binding domain plus catalytic subunit p110 leads to fully active enzyme complex
additional information
-
expression of regulatory protein p85 102 amino acid binding domain plus catalytic subunit p110 leads to fully active enzyme complex
additional information
generation of a mouse model of smooth muscle cellspecific p110alpha deficiency. Targeted deletion of p110alpha in sm-p110alpha-/- mice blunts growth factorinduced cellular responses and abolishes neointima formation after balloon injury of the carotid artery in mice. p110 Subunit knockdown via specific siRNA application
additional information
generation of a mouse model of smooth muscle cellspecific p110alpha deficiency. Targeted deletion of p110alpha in sm-p110alpha-/- mice blunts growth factorinduced cellular responses and abolishes neointima formation after balloon injury of the carotid artery in mice. p110 Subunit knockdown via specific siRNA application
additional information
-
generation of a mouse model of smooth muscle cellspecific p110alpha deficiency. Targeted deletion of p110alpha in sm-p110alpha-/- mice blunts growth factorinduced cellular responses and abolishes neointima formation after balloon injury of the carotid artery in mice. p110 Subunit knockdown via specific siRNA application
additional information
-
heterozygous disruption of p85alpha regulatory subunit, increase in enzyme activity and decrease in apoptosis by insulin-like growth factor 1 through upregulated phosphatidylinositol (3,4,5)-triphosphate production. Complete depletion of regulatory subunit p85alpha results in significantly increased apoptosis due to reduced enzyme-dependent signaling
additional information
-
genetic deletion or selective inhibition of isoform PI3Kdelta diminishes joint erosion to a level comparable to its PI3Kgamma counterpart. The induction and progression of joint destruction is profoundly reduced in the absence of both PI3K isoforms and correlates with a limited ability of neutrophils to migrate into tissue in response to leukotriene B4. fMLP-induced neutrophil extravasation is primarily reliant on PI3Kgamma
additional information
-
construction of chimeras of 85alpha and p85beta iSH2 domain by overlapping PCR using mouse p85beta and bovine p85alpha as templates
additional information
-
generation of different transgenic lines expressing myristoylated p110A protein under the control of the epithelial-specific mouse mammary tumor virus promoter, i.e. myrp110A transgenic mice. The membrane localization of p110alpha predisposes mammary glands to neoplastic transformation, young female mutant mice show delayed mammary gland involution and morphologic changes of the mammary ducts, which is more pronounced in old animals, especially in mutiparous females, in which increased ductal branching, alveolar hyperplasia, and intraductal neoplasia are observed, phenotype, overview
additional information
-
generation of p110gamma knockout mice. p110gamma-deficient effector CD8 T cells exhibit impaired migration in vitro and exhibit reduced migration into the inflamed peritoneum following vaccinia virus challenge in vivo. Furthermore, p110gamma-/- mice exhibit reduced influx in response to virus-induced peritonitis and exhibit increased susceptibility to vaccinia virus infection when compared with wild-type mice, phenotype, overview
additional information
-
mRNA translation of IFN-responsive genes is defective in cells with targeted disruption of both the p85alpha and p85beta subunits of PI3K
additional information
-
mutations in catalytic subunit PI3Kdelta, PI3KdD910/A910 mice display impaired B cell development and differentiation including a reduction in B cell progenitor cells and an increase in the ratio of pre-(CD43-IgM+) to pro-(CD43+ IgM-) B cells. T cell differentiation into Th1, Th2 and Treg lineages are also impaired in PI3KdD910/A910 mice by a mechanism involving reduced T cell receptor activation of Akt and FOXO
additional information
-
p110-/- CD4 lymphocytes are phenotypically identical to their wild-type counterparts and do not exhibit any defects in TCR-mediated calcium mobilization or Erk activation. p110gamma-deficient CD4 OT.II T cells become activated and proliferate comparably with WT cells in response to antigen in vivo. But antigen-experienced p110gamma-deficient CD4 OT.II lymphocytes exhibit dramatic defects in their ability to traffic to peripheral inflammatory sites in vivo and exhibit impaired F-actin polarization and migration in response to stimulation ex vivo with the CCR4 ligand CCL22
additional information
generation of a mouse model of smooth muscle cellspecific p110delta deficiency. Targeted deletion of p110delta doe not affect vascular remodeling in vivo. p110 Subunit knockdown via specific siRNA application
additional information
generation of a mouse model of smooth muscle cellspecific p110delta deficiency. Targeted deletion of p110delta doe not affect vascular remodeling in vivo. p110 Subunit knockdown via specific siRNA application
additional information
-
generation of a mouse model of smooth muscle cellspecific p110delta deficiency. Targeted deletion of p110delta doe not affect vascular remodeling in vivo. p110 Subunit knockdown via specific siRNA application
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
-
reduction of regulatory subunit p85alpha as a therapeutic target for enhancing insulin-like growth factor 1/insulin signaling, prolongation of cell survival, and protection against apoptosis
medicine
p110delta may be a good target for pharmaceutical intervention of T cell-dependent autoimmune pathologies
medicine
-
genetic deletion or selective inhibition of isoform PI3Kdelta diminishes joint erosion to a level comparable to its PI3Kgamma counterpart. The induction and progression of joint destruction is profoundly reduced in the absence of both PI3K isoforms and correlates with a limited ability of neutrophils to migrate into tissue in response to leukotriene B4. fMLP-induced neutrophil extravasation is primarily reliant on PI3Kgamma
medicine
-
transition of CD4-/CD8- double-negative to CD4+/CD8+ double-positive thymocytes triggered by anti-CD3 monoclonal antibodies is significantly impaired in mice lacking both major reglulatory subunit p85alpha of phosphatidylinositol 3-kinases and Rag-2 compared with p85alpha+/- Rag-2-/- mice. Inhibition by IC87114 of the major class IA phosphatidylinositol 3-kinase catalytic subunit expressed in lymphocytes, p110, blocks transition of CD4-/CD8- double-negative to CD4+/CD8+ double-positive cells in embryonic day 14.5 fetal thymic organ culture without affecting cell viability
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Hawkins, P.T.; Jackson, T.R.; Stephens, L.R.
Platelet-derived growth factor stimulates synthesis of PtdIns(3,4,5)P3 by activating a PtdIns(4,5)P2 3-OH kinase
Nature
358
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1992
Mus musculus
Klippel, A.; Escobedo, J.A.; Hirano, M.; Williams, L.T.
The interaction of small domains between the subunits of phosphatidylinositol 3-kinase determines enzyme activity
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Mus musculus (P42337), Mus musculus
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Mus musculus
Ueki, K.; Fruman, D.A.; Brachmann, S.M.; Tseng, Y.H.; Cantley, L.C.; Kahn, C.R.
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Mus musculus (O35904)
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Mus musculus (O35904), Mus musculus (Q9JHG7)
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Mus musculus (O35904)
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Eur. J. Immunol.
37
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Mus musculus (O35904)
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J. Immunol.
177
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2006
Mus musculus (O35904)
Llorian, M.; Stamataki, Z.; Hill, S.; Turner, M.; Martensson, I.L.
The PI3K p110delta is required for down-regulation of RAG expression in immature B cells
J. Immunol.
178
1981-1985
2007
Mus musculus (O35904)
Eickholt, B.J.; Ahmed, A.I.; Davies, M.; Papakonstanti, E.A.; Pearce, W.; Starkey, M.L.; Bilancio, A.; Need, A.C.; Smith, A.J.; Hall, S.M.; Hamers, F.P.; Giese, K.P.; Bradbury, E.J.; Vanhaesebroeck, B.
Control of axonal growth and regeneration of sensory neurons by the p110delta PI 3-kinase
PLoS ONE
2
e869
2007
Mus musculus
Okkenhaug, K.; Ali, K.; Vanhaesebroeck, B.
Antigen receptor signalling: a distinctive role for the p110delta isoform of PI3K
Trends Immunol.
28
80-87
2007
Mus musculus (O35904)
Randis, T.M.; Puri, K.D.; Zhou, H.; Diacovo, T.G.
Role of PI3Kdelta and PI3Kgamma in inflammatory arthritis and tissue localization of neutrophils
Eur. J. Immunol.
38
1215-1224
2008
Mus musculus
Shiroki, F.; Matsuda, S.; Doi, T.; Fujiwara, M.; Mochizuki, Y.; Kadowaki, T.; Suzuki, H.; Koyasu, S.
The p85alpha regulatory subunit of class IA phosphoinositide 3-kinase regulates beta-selection in thymocyte development
J. Immunol.
178
1349-1356
2007
Mus musculus
Farghaly, H.S.; Blagbrough, I.S.; Medina-Tato, D.A.; Watson, M.L.
Interleukin 13 increases contractility of murine tracheal smooth muscle by a phosphoinositide 3-kinase p110delta-dependent mechanism
Mol. Pharmacol.
73
1530-1537
2008
Mus musculus
Geering, B.; Cutillas, P.R.; Nock, G.; Gharbi, S.I.; Vanhaesebroeck, B.
Class IA phosphoinositide 3-kinases are obligate p85-p110 heterodimers
Proc. Natl. Acad. Sci. USA
104
7809-7814
2007
Mus musculus
Renner, O.; Blanco-Aparicio, C.; Grassow, M.; Canamero, M.; Leal, J.F.; Carnero, A.
Activation of phosphatidylinositol 3-kinase by membrane localization of p110alpha predisposes mammary glands to neoplastic transformation
Cancer Res.
68
9643-9653
2008
Homo sapiens, Mus musculus
Hwang, M.K.; Song, N.R.; Kang, N.J.; Lee, K.W.; Lee, H.J.
Activation of phosphatidylinositol 3-kinase is required for tumor necrosis factor-alpha-induced upregulation of matrix metalloproteinase-9: its direct inhibition by quercetin
Int. J. Biochem. Cell Biol.
41
1592-1600
2009
Mus musculus
Li, Y.; Anderson, D.H.; Liu, Q.; Zhou, Y.
Mechanism of influenza A virus NS1 protein interaction with the p85beta, but not the p85alpha, subunit of phosphatidylinositol 3-kinase (PI3K) and up-regulation of PI3K activity
J. Biol. Chem.
283
23397-23409
2008
Bos taurus, Mus musculus
Martin, A.L.; Schwartz, M.D.; Jameson, S.C.; Shimizu, Y.
Selective regulation of CD8 effector T cell migration by the p110 gamma isoform of phosphatidylinositol 3-kinase
J. Immunol.
180
2081-2088
2008
Mus musculus, Mus musculus C57BL/6
Kaur, S.; Sassano, A.; Joseph, A.M.; Majchrzak-Kita, B.; Eklund, E.A.; Verma, A.; Brachmann, S.M.; Fish, E.N.; Platanias, L.C.
Dual regulatory roles of phosphatidylinositol 3-kinase in IFN signaling
J. Immunol.
181
7316-7323
2008
Mus musculus
Liu, D.; Zhang, T.; Marshall, A.J.; Okkenhaug, K.; Vanhaesebroeck, B.; Uzonna, J.E.
The p110delta isoform of phosphatidylinositol 3-kinase controls susceptibility to Leishmania major by regulating expansion and tissue homing of regulatory T cells
J. Immunol.
183
1921-1933
2009
Mus musculus
Thomas, M.S.; Mitchell, J.S.; DeNucci, C.C.; Martin, A.L.; Shimizu, Y.
The p110gamma isoform of phosphatidylinositol 3-kinase regulates migration of effector CD4 T lymphocytes into peripheral inflammatory sites
J. Leukoc. Biol.
84
814-823
2008
Mus musculus
Gavard, J.; Hou, X.; Qu, Y.; Masedunskas, A.; Martin, D.; Weigert, R.; Li, X.; Gutkind, J.S.
A role for a CXCR2/phosphatidylinositol 3-kinase gamma signaling axis in acute and chronic vascular permeability
Mol. Cell. Biol.
29
2469-2480
2009
Homo sapiens, Mus musculus
Chen, B.C.; Kang, J.C.; Lu, Y.T.; Hsu, M.J.; Liao, C.C.; Chiu, W.T.; Yeh, F.L.; Lin, C.H.
Rac1 regulates peptidoglycan-induced nuclear factor-kappaB activation and cyclooxygenase-2 expression in RAW 264.7 macrophages by activating the phosphatidylinositol 3-kinase/Akt pathway
Mol. Immunol.
46
1179-1188
2009
Mus musculus
Yang, Y.; Iwanaga, K.; Raso, M.G.; Wislez, M.; Hanna, A.E.; Wieder, E.D.; Molldrem, J.J.; Wistuba, I.I.; Powis, G.; Demayo, F.J.; Kim, C.F.; Kurie, J.M.
Phosphatidylinositol 3-kinase mediates bronchioalveolar stem cell expansion in mouse models of oncogenic K-ras-induced lung cancer
PLoS ONE
3
e2220
2008
Mus musculus
Furuya, F.; Lu, C.; Guigon, C.J.; Cheng, S.Y.
Nongenomic activation of phosphatidylinositol 3-kinase signaling by thyroid hormone receptors
Steroids
74
628-634
2009
Mus musculus
Marwick, J.A.; Chung, K.F.; Adcock, I.M.
Phosphatidylinositol 3-kinase isoforms as targets in respiratory disease
Ther. Adv. Respir. Dis.
2009
1-16
2010
Homo sapiens, Mus musculus
Zwaenepoel, O.; Tzenaki, N.; Vergetaki, A.; Makrigiannakis, A.; Vanhaesebroeck, B.; Papakonstanti, E.A.
Functional CSF-1 receptors are located at the nuclear envelope and activated via the p110delta isoform of PI 3-kinase
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26
691-706
2012
Mus musculus
Wu, Y.; Tan, H.; Shui, G.; Bauvy, C.; Huang, Q.; Wenk, M.; Ong, C.; Codogno, P.; Shen, H.
Dual role of 3-methyladenine in modulation of autophagy via different temporal patterns of inhibition on class I and III phosphoinositide 3-kinase
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285
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Homo sapiens, Mus musculus
Vantler, M.; Jesus, J.; Leppaenen, O.; Scherner, M.; Berghausen, E.M.; Mustafov, L.; Chen, X.; Kramer, T.; Zierden, M.; Gerhardt, M.; Ten Freyhaus, H.; Blaschke, F.; Sterner-Kock, A.; Baldus, S.; Zhao, J.J.; Rosenkranz, S.
Class IA phosphatidylinositol 3-kinase isoform p110alpha mediates vascular remodeling
Arterioscler. Thromb. Vasc. Biol.
35
1434-1444
2015
Rattus norvegicus, Rattus norvegicus (A0A0G2K344), Rattus norvegicus (Q9Z1L0), Homo sapiens (O00329), Homo sapiens (P42336), Homo sapiens (P42338), Homo sapiens, Mus musculus (O35904), Mus musculus (P42337), Mus musculus
Gupta, V.K.; Rajala, A.; Rajala, R.V.
Non-canonical regulation of phosphatidylinositol 3-kinase gamma isoform activity in retinal rod photoreceptor cells
Cell Commun. Signal.
13
7-7
2015
Mus musculus (Q9JHG7)
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