Information on EC 2.7.1.153 - phosphatidylinositol-4,5-bisphosphate 3-kinase

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The expected taxonomic range for this enzyme is: Eukaryota

EC NUMBER
COMMENTARY
2.7.1.153
-
RECOMMENDED NAME
GeneOntology No.
phosphatidylinositol-4,5-bisphosphate 3-kinase
REACTION
REACTION DIAGRAM
COMMENTARY
ORGANISM
UNIPROT
LITERATURE
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate = ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
-
-
-
-
REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phospho-group transfer
-
-
-
-
PATHWAY
BRENDA Link
KEGG Link
MetaCyc Link
3-phosphoinositide biosynthesis
-
-
Inositol phosphate metabolism
-
-
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.
SYNONYMS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
class I phosphoinositide 3-kinase
-
-
-
-
class I PI3K
-
-
-
-
kinase (phosphorylating), phosphatidylinositol 4,5-diphosphate 3-
-
-
-
-
p101-PI3K
-
-
-
-
p110delta
-
-
-
-
P120-PI3K
-
-
-
-
phosphatidylinositol (4,5)-bisphosphate 3-hydroxykinase
-
-
-
-
phosphatidylinositol 3-hydroxyl kinase
-
-
-
-
PI3K
-
-
-
-
PI3Kbeta
-
-
-
-
PI3Kgamma
-
-
-
-
PtdIns(4,5)P2 3-OH kinase
-
-
-
-
PtdIns-3-kinase p101
-
-
-
-
PtdIns-3-kinase p110
-
-
-
-
PtdInsP 3-OH-kinase
-
-
-
-
type I phosphoinositide 3-kinase
-
-
-
-
CAS REGISTRY NUMBER
COMMENTARY
103843-30-7
-
115926-52-8
cf. EC 2.7.1.137
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
-
SwissProt
Manually annotated by BRENDA team
catalytic subunit alpha isoform
SwissProt
Manually annotated by BRENDA team
catalytic subunit beta isoform
SwissProt
Manually annotated by BRENDA team
catalytic subunit delta isoform
SwissProt
Manually annotated by BRENDA team
catalytic subunit gamma isoform
SwissProt
Manually annotated by BRENDA team
catalytic subunit p110, alpha isoform
SwissProt
Manually annotated by BRENDA team
catalytic subunit p110, delta isoform
SwissProt
Manually annotated by BRENDA team
catalytic subunit p110, gamma isoform
SwissProt
Manually annotated by BRENDA team
gamma isoform
SwissProt
Manually annotated by BRENDA team
gene PIK3CA encoding for the catalytic subunit p110alpha of PI3K
-
-
Manually annotated by BRENDA team
gene PIK3CA enocding the PI3K catalytic subunit alpha
-
-
Manually annotated by BRENDA team
GFP-tag, expression in HEK cell
SwissProt
Manually annotated by BRENDA team
isoform p85/p110 phosphatidylinositol 3-kinase
-
-
Manually annotated by BRENDA team
Korean population, women with polycystic ovary syndrome
-
-
Manually annotated by BRENDA team
p110 catalytic subunit, gamma isoform
SwissProt
Manually annotated by BRENDA team
patients with acute myelogenous leukemia
-
-
Manually annotated by BRENDA team
phosphatidylinositol 4,5-bisphosphate 3-kinase 110 kDa catalytic subunit alpha
SwissProt
Manually annotated by BRENDA team
regulatory subunit alpha
UniProt
Manually annotated by BRENDA team
-
SwissProt
Manually annotated by BRENDA team
C57BL/6 mice, BALB/c mice, and CB-17/lcr-Prkdcscid/Crl, i.e. BALB/c SCID, mice
-
-
Manually annotated by BRENDA team
expression in CHO-K1 cells
-
-
Manually annotated by BRENDA team
K/BxN serum transfer model of arthritis, isoforms PI3Kdelta and PI3Kgamma
-
-
Manually annotated by BRENDA team
recombinant enzyme
SwissProt
Manually annotated by BRENDA team
strain C57BL/6 mice
-
-
Manually annotated by BRENDA team
two isozymes of the catalytic subunit, p110alpha and p110beta
-
-
Manually annotated by BRENDA team
Mus musculus C57BL/6
strain C57BL/6 mice
-
-
Manually annotated by BRENDA team
strain TU-1
-
-
Manually annotated by BRENDA team
beta-isoform
Swissprot
Manually annotated by BRENDA team
Wistar-Kyoto rats and spontaneously hypertensive rats
-
-
Manually annotated by BRENDA team
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
-
aberrant activation of the phosphatidylinositol 3-kinase pathway is involved in a wide range of cancers. Mutations in subunit isoform p110alpha are involved in development of bladder cancer, and are also common in the benign skin lesions seborrheic keratosis and epidermal nevi
malfunction
-
aberrant PI3K signaling has been found to play an important role in multiple aspects of tumorgenesis including uncontrolled proliferation, resistance to apoptosis, angiogenesis and metastatic capability. The PI3Kbeta isoform is implicated as necessary for transformation induced by the loss or inactivation of the PTEN tumor suppressor both in vitro and in vivo
malfunction
-
binding of thyroid receptor to p85alpha activates PI3K/AKT signaling promoting thyroid carcinogenesis by increasing cell proliferation and tumor metastasis
malfunction
-
chronic blockade of phosphatidylinositol 3-kinase in the nucleus tractus solitarii is prohypertensive in the spontaneously hypertensive rat
malfunction
-
constitutively activated phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin, mTOR, signaling is a common feature of T-cell acute lymphoblastic leukemia, where it strongly influences growth and survival
malfunction
-
deregulated signaling through phosphatidylinositol 3'-kinase pathway is common in many types of malignancies, including mantle cell lymphoma. PI3K catalytic subunit alpha gene amplification contributes to the pathogenesis of mantle cell lymphoma. Inhibition of PIK3CA induces apoptosis in mantle cell lymphoma cell lines
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
-
inhibition of PI3-kinase or expression of a dominant negative form of PI3-kinase cause inhibition of airway epithelial cell wound closure
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
-
PI3K signalling is involved in development of respiratory diseases, such as asthma and cystic fibrosis, and lung cancer, detailed overview. Inhibition of PI3Kdelta and gamma may provide a beneficial therapeutic strategy for the reduction of Th1/Th2 and Tc1 cells in respiratory disease. 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
-
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
-
PI3Ks constitute important regulators of various signaling pathways with relevance in cancer. Enhanced activation of p110A, the catalytic subunit of PI3K, woccurs in a high proportion of many human tumor types. Activation of PI3K by membrane localization of subunit p110alpha predisposes mammary glands to neoplastic transformation. Perturbation of the interaction of the CDK4/Rb/E2F cascade and the PI3K signaling occurs in many human cancers
malfunction
-
suppression of the PI3K catalytic subunit p110alpha inhibits the growth of ovarian cancer cells in vitro and in vivo, inhibiting decreased cell viability and induced cell apoptosis
metabolism
-
PI3K is part of the PI3K signaling pathway that is upregulated in cancer
metabolism
-
PI3K/Akt/mTOR signaling, overview
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
metabolism
-
the phosphatidylinositol 3-kinase pathway is a critical signal transduction pathway that regulatesmultiple cellular functions, class IA PI3K signalling pathway, overview
metabolism
-
the signaling cascade involving the enzyme is known as the PI3K/Akt/mTor axis
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
-
p110 isoforms alpha, beta, and gamma PI3K are involved in T-cell acute lymphoblastic leukemia cell survival, but not p110delta PI3K
physiological function
-
phosphatidylinositol 3-kinase activity and asymmetrical accumulation of F-actin are necessary for establishment of cell polarity in the early development of monospores from the marine red alga. Establishment of the anterior-posterior axis in migrating monospores is PI3K-dependent
physiological function
-
phosphatidylinositol 3-kinase is a key mediator of oncogenic K-ras
physiological function
-
phosphatidylinositol 3-kinase is involved in sperm-induced tyrosine kinase signaling in Xenopus egg fertilization. Inhibition of sperm-induced activation of the tyrosine kinase Src and a transient increase in the intracellular concentration of Ca2+ at fertilization, overview. PIP3 acts as a positive regulator of the Src signaling pathway in Xenopus fertilization
physiological function
-
phosphatidylinositol 3-kinase mediates non-opsonic phagocytosis of Legionella pneumophila by macrophages
physiological function
-
PI 3-kinase activated in response to cAMP or IGF-I stimulus plays important roles in increasing the translation rate or mRNA levels of cyclin D1, respectively. Activation of PI 3-kinase in response to cAMP or IGF-I are essential for marked increases in G1 CDK activities and DNA synthesis. cAMP-dependent PI 3-kinase activation plays an important role in the increase in cyclin D1 translation. In contrast, IGF-I-dependent PI 3-kinase activation is required for the increase in cyclin D1 mRNA levels and degradation of p27Kip1
physiological function
-
PI 3-kinase is an important enzyme in the early insulin signaling cascade and plays a key role in insulin-mediated glucose transport
physiological function
-
PI3-kinase regulates Rac1 activity through the guanosine exchange factor Tiam1. Expression of mutant CA-PI3K causes a significant increase in membrane-associated Tiam1
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 enzyme plays a pivotal role in the mechanism of CSF-1-induced Wiskott-Aldrich syndrome protein activation in vivo
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 p85alpha subunit of class IA phosphatidylinositol 3-kinase regulates the expression of multiple genes involved in osteoclast maturation and migration
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
-
Tiam1-mediated Rac1 activation and E-cadherin-mediated cell-cell adhesion are dependent on PI3K activity, regulation, overview. The signaling hierarchy leads from PI3K to Tiam1 to Rac to the actin cytoskeleton resulting in adherens junction formation. PI3K is involved in E-cadherin-dependent regulation of epithelial cell differentiation and polarity
physiological function
O00329
in tumor cell lines and primary patient samples representing multiple B-cell malignancies, constitutive phosphatidylinositol-3-kinase pathway activation is dependent on isoform PI3Kdelta. Inhibitor 3-phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one blocks constitutive phosphatidylinositol-3-kinase signaling, resulting in decreased phosphorylation of Akt and other downstream effectors, an increase in poly(ADP-ribose) polymerase and caspase cleavage and an induction of apoptosis
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
-
phosphatidylinositol 3-kinase is critical for the TLR2 downstream effects of glucocorticoids. Cells expressing a phosphatidylinositol 3-kinase p85 subunit deletion mutant and exposed to Pam3-Cys-Ser-Lys4 in the presence or absence of dexamethasone, show enhanced tumour necrosis factor TNFalpha expression while AP-1 and NF-kappaB transcriptional activity are repressed. Phosphatidylinositol 3-kinase physically interacts with the glucocorticoid receptor through two putative phosphatidylinositol 3-kinase recruitment consensus YxxM binding motifs in the glucocorticoid receptor. The phosphatidylinositol 3-kinase-glucocorticoid receptor interaction may contribute to the effects of glucocorticoids on the TLR2 pro-inflammatory signalling cascade
physiological function
P27986
phosphatidylinositol 3-kinase pathway inhibition is sufficient to reduce expression of Smad anchor for receptor activation protein, i.e. SARA. Phosphatidylinositol 3-kinase-dependent depletion of SARA is apparent within 6 h and does not occur at the mRNA or promoter level but is blocked by inhibition of proteasome-mediated degradation. It is a direct effect of phosphatidylinositol 3-kinase subunit alpha action, and coimmunoprecipitation of SARA and subunit alpha confirm that these proteins interact. Expression of GTPase-deficient Rab5 leads to endosomal enlargement and reduced SARA protein expression, similar to that seen with phosphatidylinositol 3-kinase inhibition
physiological function
-
suppressing phosphatidylinositol 3-kinase activity by inhibitors LY294002 and PI103 selectively reduces both the mRNA and protein levels of peroxisome proliferator-activated receptor gamma coactivator PGC-1beta but not PGC-1alpha. Reducing PGC-1b expression also leads to reduced mRNA expression levels of uncoupling protein 1, 2 and superoxide dismutase 2. Correspondingly, mitochondrial membrane potential and reactive oxygen species levels are increased
physiological function
Mus musculus C57BL/6
-
selective regulation of CD8 effector T cell migration by the p110gamma catalytic subunit isoform of phosphatidylinositol 3-kinase
-
metabolism
-
WASP activation downstream of CSF-1R is phosphatidylinositol 3-kinase- and Cdc42-dependent consistent with an involvement of these molecules in macrophage migration, regulation, overview
additional information
-
SHIP downregulates PI3-K-initiated signals by dephosphorylating PI-3,4,5-triphosphate
SUBSTRATE
PRODUCT                      
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
ATP + 1-phosphatidyl-1D-myo-inositol
ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate
show the reaction diagram
-
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol
ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate
show the reaction diagram
-
catalyzed by class I and III, and probably by class II enzymes, overview. PI3K is part of the plasma membrane E-cadherin signaling complex
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
-
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
O00329
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
-
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
-
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
-
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
-
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
P48736
-
-
-
-
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
-
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
-
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
show the reaction diagram
-
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
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
-
catalyzed by class I enzyme, overview. PI3K is part of the plasma membrane E-cadherin signaling complex
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-triphosphate
show the reaction diagram
-
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-triphosphate
show the reaction diagram
-
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-triphosphate
show the reaction diagram
-
-
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-triphosphate
show the reaction diagram
-
catalyzed by class I enzyme, overview. PI3K is part of the plasma membrane E-cadherin signaling complex
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4-phosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate
show the reaction diagram
-
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4-phosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate
show the reaction diagram
-
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4-phosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate
show the reaction diagram
-
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4-phosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate
show the reaction diagram
-
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4-phosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate
show the reaction diagram
-
catalyzed by class I enzyme, overview. PI3K is part of the plasma membrane E-cadherin signaling complex
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4-phosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate
show the reaction diagram
-
PIP3 acts as a positive regulator of the Src signaling pathway in Xenopus fertilization
-
-
?
ATP + Akt
ADP + Akt phosphate
show the reaction diagram
-
-
-
-
?
ATP + Akt
ADP + Akt phosphate
show the reaction diagram
-
phosphorylation at Ser473
-
-
?
ATP + p70S6K
ADP + p70S6K phosphate
show the reaction diagram
-
-
-
-
?
ATP + phosphatidylinositol
ADP + phosphatidylinositol 3-phosphate
show the reaction diagram
-
-
-
?
ATP + phosphatidylinositol
ADP + phosphatidylinositol 3-phosphate
show the reaction diagram
-
-
-
?
ATP + phosphatidylinositol
ADP + phosphatidylinositol 3-phosphate
show the reaction diagram
-
-
-
?
ATP + phosphatidylinositol
ADP + phosphatidylinositol 3-phosphate
show the reaction diagram
O00329
-
-
?
ATP + phosphatidylinositol
ADP + phosphatidylinositol 3-phosphate
show the reaction diagram
-
-
-
?
ATP + phosphatidylinositol
ADP + phosphatidylinositol 3-phosphate
show the reaction diagram
O00329
-
-
-
?
ATP + phosphatidylinositol 4-phosphate
ADP + phosphatidylinositol 4,5-diphosphate
show the reaction diagram
-
-
-
?
ATP + phosphatidylinositol 4-phosphate
ADP + phosphatidylinositol 4,5-diphosphate
show the reaction diagram
-
-
-
?
ATP + phosphatidylinositol 4-phosphate
ADP + phosphatidylinositol 4,5-diphosphate
show the reaction diagram
-
-
-
?
ATP + phosphatidylinositol 4-phosphate
ADP + phosphatidylinositol 4,5-diphosphate
show the reaction diagram
O00329
-
-
?
ATP + phosphatidylinositol 4-phosphate
ADP + phosphatidylinositol 4,5-diphosphate
show the reaction diagram
-
-
-
?
ATP + phosphatidylinositol-4,5-bisphosphate
ADP + phosphatidylinositol-3,4,5-trisphosphate
show the reaction diagram
-
-
-
-
?
ATP + phosphatidylinositol-4,5-bisphosphate
ADP + phosphatidylinositol-3,4,5-trisphosphate
show the reaction diagram
-
-
-
-
?
ATP + phosphatidylinositol-4,5-bisphosphate
ADP + phosphatidylinositol-3,4,5-trisphosphate
show the reaction diagram
-
-
-
-
?
ATP + phosphatidylinositol-4,5-bisphosphate
ADP + phosphatidylinositol-3,4,5-trisphosphate
show the reaction diagram
-
-
i.e. PIP3, PIP3 recruits protein dependent kinase 1, PDK1, and AKT, also known as protein kinase B, PKB, to the plasma membrane
-
?
ATP + phosphatidylinositol-4,5-bisphosphate
ADP + phosphatidylinositol-3,4,5-trisphosphate
show the reaction diagram
-
class I PI3Ks
the product allows for the recruitment to the plasma membrane of proteins containing a pleckstrin homology domain
-
?
additional information
?
-
-
-
-
-
-
additional information
?
-
-
enzyme interacts with active, GTP-bound Ras
-
-
-
additional information
?
-
O00329
p110delta does not phosphorylate the p85 adaptor but instead harbors an intrinsic autophosphorylation capacity
-
-
-
additional information
?
-
-
enzyme can promote proliferation
-
-
-
additional information
?
-
-
phosphoinositide 3-kinase and DNA synthesis
-
-
-
additional information
?
-
-
enzyme is involved in the synthesis of 3-phosphoinositides. Class I phosphoinositide 3-kinases are further subdivided into class IA and IB enzymes, which signal downstream of tyrosine kinase and heterotrimeric G protein-coupled receptors, respectively. All class I phosphoinositide 3-kinase members also bind to Ras, but the role of this interaction in physiological phosphoinositide 3-kinase signalling is not entirely clear
-
-
-
additional information
?
-
-
phosphoinositide 3-kinase and apoptosis
-
-
-
additional information
?
-
-
enzyme is activated by binding of osteopontin to integrin alphavbeta3
-
-
-
additional information
?
-
-
involvement of the enzyme in CD18-mediated adhesion of human neutrophils to fibrinogen
-
-
-
additional information
?
-
-
the adaptor subunits of the class IA enzymes bind phosphorylated Tyr residues, thereby linking the phosphoinositide 3-kinases catalytic subunit to tyr kinase signalling pathways
-
-
-
additional information
?
-
-
mechanism of signal down-regulation of insulin receptor substrate mediated by monomeric p85 enzyme regulatory subunit
-
-
-
additional information
?
-
P48736
subunit p101 is responsible for phosphatidylinositol-4,5-bisphosphate substrate selectivity of enzyme gamma isoform by sensitizing p110 gamma toward G-protein beta,gamma-subunits in the presence of phosphatidylinositol-4,5-bisphosphate
-
-
-
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
?
-
O35904
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
?
-
Q9JHG7
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
?
-
Q9JHG7
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
?
-
-
PI3K generates phosphatidylinositol 3,4,5 trisphosphate
-
-
-
additional information
?
-
-
the enzyme is activated and associated to E-cadherin complexes, the assembly is mediated by docking proteins, e.g. beta-catenin, gamma-catenin, and Dlg, and involves c-SRC. Cell-cell adhesion induces c-SRC recruitment and E-cadherin complex assembly as well as activity of PI3K, regulatory and molecular mechanism, overview. PI3K, stimulated by E-cadherin adhesion, activates PKB/Akt
-
-
-
additional information
?
-
-
the p85alpha subunit of phosphatidylinositol 3-kinase has GTPase-activating protein activity toward Rab5 and Rab4, small monomeric GTPases important in the regulation of RTK endocytosis, trafficking, and degradation pathways
-
-
-
additional information
?
-
-
a p110alpha/beta-subunit binds to a p85 regulatory subunit, and this heterodimer is recruited to the membrane through the association with phosphotyrosyl proteins, leading to production of phosphatidylinositol 3,4,5-triphosphate, PIP3, followed by activation of downstream signal pathway(s)
-
-
-
additional information
?
-
-
regulatory domain p85 interacts with RAS-GTP
-
-
-
additional information
?
-
-
the enzyme also catalyzes the reactions of EC 2.7.1.68, 1-phosphatidylinositol-4-phosphate 5-kinase, and EC 2.7.1.67, 1-phosphatidylinositol 4-kinase
-
-
-
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 SUBSTRATES
NATURAL PRODUCTS
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
LITERATURE
(Substrate)
COMMENTARY
(Product)
LITERATURE
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
ATP + 1-phosphatidyl-1D-myo-inositol
ADP + 1-phosphatidyl-1D-myo-inositol 3-phosphate
show the reaction diagram
-
catalyzed by class I and III, and probably by class II enzymes, overview. PI3K is part of the plasma membrane E-cadherin signaling complex
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
-
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
-
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
-
-
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
-
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
show the reaction diagram
-
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
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
show the reaction diagram
-
catalyzed by class I enzyme, overview. PI3K is part of the plasma membrane E-cadherin signaling complex
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4,5-bisphosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4,5-triphosphate
show the reaction diagram
-
-
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-triphosphate
show the reaction diagram
-
catalyzed by class I enzyme, overview. PI3K is part of the plasma membrane E-cadherin signaling complex
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4-phosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate
show the reaction diagram
-
catalyzed by class I enzyme, overview. PI3K is part of the plasma membrane E-cadherin signaling complex
-
-
?
ATP + 1-phosphatidyl-1D-myo-inositol 4-phosphate
ADP + 1-phosphatidyl-1D-myo-inositol 3,4-bisphosphate
show the reaction diagram
-
PIP3 acts as a positive regulator of the Src signaling pathway in Xenopus fertilization
-
-
?
ATP + Akt
ADP + Akt phosphate
show the reaction diagram
-
-
-
-
?
ATP + p70S6K
ADP + p70S6K phosphate
show the reaction diagram
-
-
-
-
?
ATP + phosphatidylinositol-4,5-bisphosphate
ADP + phosphatidylinositol-3,4,5-trisphosphate
show the reaction diagram
-
-
-
-
?
ATP + phosphatidylinositol-4,5-bisphosphate
ADP + phosphatidylinositol-3,4,5-trisphosphate
show the reaction diagram
-
-
-
-
?
ATP + phosphatidylinositol-4,5-bisphosphate
ADP + phosphatidylinositol-3,4,5-trisphosphate
show the reaction diagram
-
-
-
-
?
ATP + phosphatidylinositol-4,5-bisphosphate
ADP + phosphatidylinositol-3,4,5-trisphosphate
show the reaction diagram
-
-
i.e. PIP3, PIP3 recruits protein dependent kinase 1, PDK1, and AKT, also known as protein kinase B, PKB, to the plasma membrane
-
?
ATP + phosphatidylinositol-4,5-bisphosphate
ADP + phosphatidylinositol-3,4,5-trisphosphate
show the reaction diagram
-
class I PI3Ks
the product allows for the recruitment to the plasma membrane of proteins containing a pleckstrin homology domain
-
?
additional information
?
-
-
-
-
-
-
additional information
?
-
-
enzyme can promote proliferation
-
-
-
additional information
?
-
-
phosphoinositide 3-kinase and DNA synthesis
-
-
-
additional information
?
-
-
enzyme is involved in the synthesis of 3-phosphoinositides. Class I phosphoinositide 3-kinases are further subdivided into class IA and IB enzymes, which signal downstream of tyrosine kinase and heterotrimeric G protein-coupled receptors, respectively. All class I phosphoinositide 3-kinase members also bind to Ras, but the role of this interaction in physiological phosphoinositide 3-kinase signalling is not entirely clear
-
-
-
additional information
?
-
-
phosphoinositide 3-kinase and apoptosis
-
-
-
additional information
?
-
-
enzyme is activated by binding of osteopontin to integrin alphavbeta3
-
-
-
additional information
?
-
-
involvement of the enzyme in CD18-mediated adhesion of human neutrophils to fibrinogen
-
-
-
additional information
?
-
-
the adaptor subunits of the class IA enzymes bind phosphorylated Tyr residues, thereby linking the phosphoinositide 3-kinases catalytic subunit to tyr kinase signalling pathways
-
-
-
additional information
?
-
-
mechanism of signal down-regulation of insulin receptor substrate mediated by monomeric p85 enzyme regulatory subunit
-
-
-
additional information
?
-
P48736
subunit p101 is responsible for phosphatidylinositol-4,5-bisphosphate substrate selectivity of enzyme gamma isoform by sensitizing p110 gamma toward G-protein beta,gamma-subunits in the presence of phosphatidylinositol-4,5-bisphosphate
-
-
-
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
?
-
O35904
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
?
-
Q9JHG7
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
?
-
Q9JHG7
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
?
-
-
PI3K generates phosphatidylinositol 3,4,5 trisphosphate
-
-
-
additional information
?
-
-
the enzyme is activated and associated to E-cadherin complexes, the assembly is mediated by docking proteins, e.g. beta-catenin, gamma-catenin, and Dlg, and involves c-SRC. Cell-cell adhesion induces c-SRC recruitment and E-cadherin complex assembly as well as activity of PI3K, regulatory and molecular mechanism, overview. PI3K, stimulated by E-cadherin adhesion, activates PKB/Akt
-
-
-
additional information
?
-
-
the p85alpha subunit of phosphatidylinositol 3-kinase has GTPase-activating protein activity toward Rab5 and Rab4, small monomeric GTPases important in the regulation of RTK endocytosis, trafficking, and degradation pathways
-
-
-
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
-
-
INHIBITORS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
1-[2-methyl-3-(trifluoromethyl)benzyl]-2-methyl-7-(morpholin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one
-
-
1-[2-methyl-3-(trifluoromethyl)benzyl]-7-(morpholin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one
-
-
1-[2-methyl-3-(trifluoromethyl)benzyl]-7-[(2R)-2-methylmorpholin-2-yl]-6,7-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one
-
-
1-[4-[(4-methylpiperazin-1-yl)carbonyl]phenyl]-3-[4-[4-morpholin-4-yl-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d ]pyrimidin-2-yl]phenyl]urea
-
dual catalytic subunit alpha isoform/mTOR kinase inhibitor, demonstrates inhibition of tumor cell growth in vitro and in vivo and causes suppression of the pathway specific biomarkers in the human MDA-361 cell line
17-hydroxywortmannin
-
-
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
2-(difluoromethyl)-1-[4,6-di-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole
-
lead compound for structure-activity study
2-(methylsulfanyl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(morpholin-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one
-
-
2-methyl-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(2methylmorpholin-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one
-
-
2-methyl-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(morpholin-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one
-
-
2-[(6-amino-9H-purin-9-yl)methyl]-5-methyl-3-(2-methylphenyl)-4(3H)-quinazolinone
-
i.e. IC87114, selectively inhibits isoform p110delta
-
3-(2-morpholino-6-(2-(pyridin-4-yl)ethylamino)pyrimidin-4-yl)phenol
P42336
-
3-(2-morpholino-6-(pyridin-2-ylmethoxy)pyrimidin-4-yl)phenol
P42336
-
3-(4-morpholino-6-(pyridin-2-yl)pyrimidin-2-yl)phenol
P42336
-
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
3-phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one
O00329
i.e. CAL-101, highly selective and small molecule inhibitor of isoform PI3Kdelta. Inhibitor blocks constitutive phosphatidylinositol-3-kinase signaling, resulting in decreased phosphorylation of Akt and other downstream effectors, an increase in poly(ADP-ribose) polymerase and caspase cleavage and an induction of apoptosis
3-[4-(4-morpholinyl)thieno(3,2-d)pyrimidin-2-yl]-phenol
-
a p110 PI3K isoform selective inhibitor
3-[4-(morpholin-4-yl)pyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol
-
among the compounds tested, treatment with 3-[4-(morpholin-4-yl)thieno[3,2-d]pyrimidin-2-yl]phenol or 3-[4-(morpholin-4-yl)pyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol leads to the most efficient inhibition
3-[4-(morpholin-4-yl)thieno[3,2-d]pyrimidin-2-yl]phenol
-
among the compounds tested, treatment with 3-[4-(morpholin-4-yl)thieno[3,2-d]pyrimidin-2-yl]phenol or 3-[4-(morpholin-4-yl)pyrido[3',2':4,5]furo[3,2-d]pyrimidin-2-yl]phenol leads to the most efficient inhibition
4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine
-
not inhibitory to serine/threonine kinase mTOR; not inhibitory to serine/threonine kinase mTOR
4-[2-[(6-methoxypyridin-3-yl)amino]-5-phenylpyridin-3-yl]-6-methyl-1,3,5-triazin-2-amine
-
not inhibitory to serine/threonine kinase mTOR; not inhibitory to serine/threonine kinase mTOR
4-[4-(morpholin-4-yl)-5a,6-dihydro[1]benzofuro[3,2-d]pyrimidin-2-yl]phenol
-
i.e. PI103. Inhibitory to phosphatidylinositol 3-kinases, TORC1 and DNA protein kinase. PI103 potently inhibits proliferation and invasion of a wide variety of human cancer cells in vitro and shows biomarker modulation consistent with inhibition of phosphatidylinositide 3-kinase signaling
4-[4-(morpholin-4-yl)-5a,6-dihydro[1]benzofuro[3,2-d]pyrimidin-2-yl]phenol
-
i.e. PI-103. In human leukemic cell lines and in primary blast cells from acute myelogenous leukemia patients, PI-103 inhibits constitutive and growth factor-induced PI3K/Akt and mTORC1 activation. PI-103 is essentially cytostatic for cell lines and induces cell cycle arrest in the G1 phase. In blast cells, PI-103 inhibits leukemic proliferation, the clonogenicity of leukemic progenitors and induces mitochondrial apoptosis. PI-103 has additive proapoptotic effects with etoposide in blast cells and in immature leukemic cells. PI-103 does not induce apoptosis in normal CD34ž cells and has moderate effects on their clonogenic and proliferative properties
4-[5-(3,6-dihydro-2H-pyran-4-yl)-2-[(6-methoxypyridin-3-yl)amino]pyridin-3-yl]-6-methyl-1,3,5-triazin-2-amine
-
not inhibitory to serine/threonine kinase mTOR; not inhibitory to serine/threonine kinase mTOR
5-[2,2-difluoro-benzo(1,3)-dioxol-5-ylmethylene]-thiazolidine-2,4-dione
-
a p110 PI3K isoform selective inhibitor
6-amino-2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-4-methoxy-1H-benzimidazole
-
inhibitory against all three class Ia PI 3-kinase enzymes, i.e. p110alpha, p110beta, and p110delta, and also displays significant potency against two mutant forms of the p110alpha isoform, H1047R and E545K. In an in vivo U87MG human glioblastoma tumor xenograftmodel in Rag1-/- mice, and at a dose of 50mg/kg given by intraperitoneal injection it dramatically reduces cancer growth by 81% compared to untreated controls
7-methyl-2-(4-morpholinyl)-9-[1-(phenylamino)ethyl]-4H-pyrido[1,2-a]pyrimidin-4-one
-
i.e. TGX221, selectively inhibits isoform p110beta. Compound decreases secretion of vascular endothelial growth factor and interleukin-6 in nonasthmatic airway smooth muscle cells and lung fibroblasts
-
Baicalin
-
10 microM, 35.5% inhibition of isoform PI3Kalpha
CAL-101
-
a specific inhibitor of the PI3Kdelta isoform
CapG
-
nuclear actin-regulatory protein
-
IC87114
-
a specific inhibitor of the PI3Kdelta isoform, inhibits AML proliferation and augments the effects of a topoisomerase 2 inhibitor
IC87114
-
a selective PI3Kdelta inhibitor
luteolin
-
1 microM, 75.8% inhibition of isoform PI3Kalpha
LY294002
-
-
LY294002
-
inhibits sperm-induced activation of the tyrosine kinase Src and a transient increase in the intracellular concentration of Ca2+ at fertilization. LY294002 also has an inhibitory effect on the Ca2+-dependent breakdown of the Mos protein kinase and cyclin B2 as well as dephosphorylation of mitogenactivated protein kinase
LY294002
-
a PI3K-specific inhibitor
LY294002
-
specific inhibitor
LY294002
-
-
LY294002
-
a specific #PI3K inhibitor
LY294002
-
-
LY294002
-
a quercetin analogue
LY294002
-
-
myricetin
-
1 microM, almost complete inhibition of isoform PI3Kalpha
N-[(E)-(6-bromoimidazo[1,2-a]pyridin-3-yl)methylidene]-N,2-dimethyl-5-nitrobenzenesulfonohydrazide
-
i.e.PIK75, selectively inhibits isoform p110alpha. In cells stimulated with transforming growth factor-beta and/or 10% fetal bovine serum, compound attenuates transforming growth factor-induced fibronectin deposition in all cell types tested and decreases secretion of vascular endothelial growth factor and interleukin-6 in nonasthmatic airway smooth muscle cells and lung fibroblasts. Compound decreases cell survival in transforming growth factor-stimulated asthmatic, but not nonasthmatic, airway smooth muscle cells
-
N-[2-(dimethylamino)ethyl]-N-methyl-4-[([4-[4-morpholin-4-yl-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d ]pyrimidin-2-yl]phenyl]carbamoyl)amino]benzamide
-
dual catalytic subunit alpha isoform/mTOR kinase inhibitor, demonstrates inhibition of tumor cell growth in vitro and in vivo and causes suppression of the pathway specific biomarkers in the human MDA-361 cell line. Good in vivo efficacy in the MDA361 human breast tumor xenograft model
PI-103
-
a dual PI3K/mTOR inhibitor and a small synthetic molecule of the pyridofuropyrimidine class. PI-103 induces caspase activation and is cytotoxic to all T-cell acute lymphoblastic leukemia cell lines affecting PI3K/Akt/mTOR signaling, mechanism, overview
PI-103
-
shows increased efficacy in inhibiting the growth of glioma cells due to its activity against both the class I PI3Ks and the PIK family member mTor
PI103
-
suppressing phosphatidylinositol 3-kinase activity by inhibitors LY294002 and PI103 selectively reduces both the mRNA and protein levels of peroxisome proliferator-activated receptor gamma coactivator PGC-1beta but not PGC-1alpha. Reducing PGC-1b expression also leads to reduced mRNA expression levels of uncoupling protein 1, 2 and superoxide dismutase 2. Correspondingly, mitochondrial membrane potential and reactive oxygen species levels are increased
PX-866
-
irreversible PI3K inhibitor, shows selectivity for the alpha, delta, and gamma class I PI3K isoforms, inhibits the beta isoform at higher concentrations, and shows decreased selectivity for mTor
PX-866
-
a PI3K inhibitor, inhibits also the oncogenic K-ras-induced bronchioalveolar stem cell accumulation and tumor growth in vivo
quercetagetin
-
1 microM, almost complete inhibition of isoform PI3Kalpha
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
quercetin
-
1 microM, 54.1% inhibition of isoform PI3Kalpha
TGX-221
-
a p110 PI3K isoform selective inhibitor
TGX-221-R
-
R-enantiomer of inhibitor TGX-221, 100fold more potent as a PI3K-beta inhibitor than the S-enantiomer
WAY-266175
-
-
-
WAY-266176
-
-
Wortmannin
-
-
Wortmannin
P48736
in nanomolar range
Wortmannin
-
treatment prevents interleukin-13-induced hyper-responsiveness
Wortmannin
-
member of a class of steroidal furanoids, shows equally potent activity against all the class I PI3K enzymes, has antiproliferative effect
Wortmannin
-
-
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
XL147
-
targets only the class I PI3Ks
ZSTK474
-
a phosphatidylinositol 3-kinase inhibitor, inhibited phosphorylation of Ser65, Thr70 and Thr37/46 in 4E-BP1 by PI3K. Identification of the ZSTK474-sensitive phosphoproteins in A-549 cells, overview
[(4-[2-[(3-hydroxyphenyl)amino]-1H-benzimidazol-1-yl]-1,3,5-triazin-2-yl)amino]acetonitrile
-
lead compound for structure-based design of inhibitors, dual inhibitor of phosphatidylinositol 3-kinase and serine/threonine kinase mTOR; lead compound for structure-based design of inhibitors, dual inhibitor of phosphatidylinositol 3-kinase and serine/threonine kinase mTOR
[3-[4-morpholin-4-yl-7-(pyrrolidin-1-ylmethyl)-5H-pyrrolo-[3,2-d ]pyrimidin-2-yl]phenyl]methanol
-
selective for catalytic subunit alpha isoform
LY294002
-
suppressing phosphatidylinositol 3-kinase activity by inhibitors LY294002 and PI103 selectively reduces both the mRNA and protein levels of peroxisome proliferator-activated receptor gamma coactivator PGC-1beta but not PGC-1alpha. Reducing PGC-1b expression also leads to reduced mRNA expression levels of uncoupling protein 1, 2 and superoxide dismutase 2. Correspondingly, mitochondrial membrane potential and reactive oxygen species levels are increased
additional information
-
inhibition of PIK3CA induces apoptosis in mantle cell lymphoma cell lines
-
additional information
-
cyclic stretch causes a sustained decrease in activation of PI3-kinase and inhibits wound healing
-
additional information
-
pan-PI3K inhibition and inhibition of only PI3Kdelta results in attenuated vascular leakage, tissue eosinophilia, airway mucus production, and AHR as well as release of cytokines, chemokines and adhesion molecules
-
additional information
-
inhibitory activity of eighteen flavonoids and deduction of their structure-activity relationships. The number of hydroxyl groups in the A and B rings might promote the activity, while loss of C2-C3 double bond might reduce the activity. The results indicate that the flavonoids seem to exhibit more potent activity on PI3Kalpha and delta isoforms compared with that on PI3Kbeta and gamma isoforms
-
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
beta-catenin
-
tyrosine-phopshorylated
-
cAMP
-
PI 3-kinase is activated in response to cAMP or IGF-I, the PI 3-kinase activity bound to its p85 regulatory subunit increases by 1.7fold. cAMP-dependent PI 3-kinase activation plays an important role in the increase in cyclin D1 translation. In contrast, IGF-I-dependent PI 3-kinase activation is required for the increase in cyclin D1 mRNA levels and degradation of p27Kip1
Dlg
-
tyrosine-phopshorylated
-
G-protein alpha, beta and gamma subunit
P48736
strong
-
G-protein beta,gamma
P48736
in vivo, activation of enzyme by a mechanism assigning specific roles for both enzyme subunits, membrane recruitment via the noncatalytic p101 subunit, and direct stimulation of p110gamma
-
G-protein beta,gamma subunit
Q9Z1L0
purified from bovine brain, 16fold activitation at 0.016 mM
-
G-protein beta,gamma subunits
P48736
significant stimulation of enzyme beta and gamma isoforms in the presence as well as in the absence of non-catalytic subunits such as p85alpha or p101, stimulation of autophosphorylation of the catalytic subunit of enzyme
-
guanosine 5'-3-O-(thio)triphosphate
Q9Z1L0
up to 3fold increase in activity, activation is blocked by high concentrations of guanosine-5’-2-O-(thio)diphosphate
IGF-I
-
PI 3-kinase is activated in response to cAMP or IGF-I. cAMP-dependent PI 3-kinase activation plays an important role in the increase in cyclin D1 translation. In contrast, IGF-I-dependent PI 3-kinase activation is required for the increase in cyclin D1 mRNA levels and degradation of p27Kip1
-
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
-
Pasteurella multocida toxin
-
mediated by G protein betagamma-subunits and G protein alpha-subunit, EC 3.6.5.1
-
platelet-derived growth factor
-
stimulates synthesis of 1-phosphatidyl-1D-myo-inositol 3,4,5-trisphosphate
-
Ras
-
active RAs activates class 1 enzymes
-
RAS-GTP
-
regulatory domain p85 interacts with RAS-GTP. RAS binding is essential for oncogenic transformation by helical domain mutants of p110alpha
-
Thrombin
Q9Z1L0
activation of enzyme in intact cells, blocked by pertussis toxin
-
thyroid receptor
-
i.e. PV, nongenomic activation of phosphatidylinositol 3-kinase signaling by thyroid hormone receptors, overview. PI3Kactivation through thyroid recptor via protein–protein 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
-
TNF-alpha
-
activates PI3K
-
monocyte chemotactic peptide-1
-
i.e. MCP-1, stimulation can be inhibited by pertussis toxin, but not by wortmannin
-
additional information
-
stimulation of almost every receptor that induces tyrosine kinase activity also leads to class IA phosphatidylinositol-4,5-bisphosphate 3-kinase activation
-
additional information
-
activated receptor tyrosine kinases recruit the PI3 kinase complex to the membrane via the p85 regulatory subunit either directly or via insulin receptor substrate adapter proteins, activating the catalytic subunit p110
-
additional information
-
activation of phosphatidylinositol 3-kinase by membrane localization of subunit p110alpha
-
additional information
-
the enzyme is activated and associated to E-cadherin complexes, the assembly is mediated by docking proteins, e.g. beta-catenin, gamma-catenin, and Dlg, and involves c-SRC. Cell-cell adhesion induces c-SRC recruitment and E-cadherin complex assembly as well as activity of PI3K, regulatory and molecular mechanism, overview. Interaction of docking proteins via the p85 subunit of PI3K
-
additional information
-
wounding activates PI3-kinase by 4fold
-
additional information
-
the p110gamma isoform of PI3K is activated by G protein-coupled receptors and regulates neutrophil and macrophage chemotaxis
-
additional information
-
the PI3K/Akt pathway is directly activated through loss or inactivation of PTEN, a tumor suppressor. Inhibition of mTor has the ability to activate PI3K signaling either by feedback to growth factor receptors, or by promoting the formation of an alternative mTor complex with rictor, that may serve to phosphorylate Akt, seen in both cell models and clinical samples
-
additional information
-
Rac1 acts upstream of PI3K to activate downstream Akt and finally induce NF-kappaB activation and NO production, overview
-
additional information
-
virulent Legionella pneumophila infection activates PI3K 10fold in vivo, the avirulent bacteria strain Lp-14 activates 4fold in vivo
-
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
-
IC50 VALUE [mM]
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
0.000001
1-[2-methyl-3-(trifluoromethyl)benzyl]-2-methyl-7-(morpholin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one
-
pH not specified in the publication, temperature not specified in the publication
0.000003
1-[2-methyl-3-(trifluoromethyl)benzyl]-7-(morpholin-4-yl)-6,7-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one
-
pH not specified in the publication, temperature not specified in the publication
0.000001
1-[2-methyl-3-(trifluoromethyl)benzyl]-7-[(2R)-2-methylmorpholin-2-yl]-6,7-dihydroimidazo[1,2-a]pyrimidin-5(1H)-one
-
pH not specified in the publication, temperature not specified in the publication
0.0000024
1-[4-[(4-methylpiperazin-1-yl)carbonyl]phenyl]-3-[4-[4-morpholin-4-yl-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d ]pyrimidin-2-yl]phenyl]urea
-
pH not specified in the publication, temperature not specified in the publication
0.0000004
2-(methylsulfanyl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(morpholin-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one
-
beta isoform, pH not specified in the publication, temperature not specified in the publication
0.000025
2-(methylsulfanyl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(morpholin-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one
-
delta isoform, pH not specified in the publication, temperature not specified in the publication
0.00032
2-(methylsulfanyl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(morpholin-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one
-
alpha isoform, pH not specified in the publication, temperature not specified in the publication
0.0013
2-(methylsulfanyl)-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(morpholin-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one
-
gamma isoform, pH not specified in the publication, temperature not specified in the publication
0.0000003
2-methyl-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(2methylmorpholin-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one
-
beta isoform, pH not specified in the publication, temperature not specified in the publication
0.000004
2-methyl-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(2methylmorpholin-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one
-
delta isoform, pH not specified in the publication, temperature not specified in the publication
0.00006
2-methyl-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(2methylmorpholin-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one
-
gamma isoform, pH not specified in the publication, temperature not specified in the publication
0.00032
2-methyl-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(2methylmorpholin-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one
-
alpha isoform, pH not specified in the publication, temperature not specified in the publication
0.0000006
2-methyl-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(morpholin-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one
-
beta isoform, pH not specified in the publication, temperature not specified in the publication
0.00002
2-methyl-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(morpholin-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one
-
delta isoform, pH not specified in the publication, temperature not specified in the publication
0.00063
2-methyl-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(morpholin-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one
-
alpha isoform, pH not specified in the publication, temperature not specified in the publication
0.00079
2-methyl-3-[2-methyl-3-(trifluoromethyl)benzyl]-5-(morpholin-4-yl)[1,2,4]triazolo[1,5-a]pyrimidin-7(3H)-one
-
gamma isoform, pH not specified in the publication, temperature not specified in the publication
0.00014
3-(2-morpholino-6-(2-(pyridin-4-yl)ethylamino)pyrimidin-4-yl)phenol
P42336
isoform p110alpha, pH 7.4, 22°C
0.00074
3-(2-morpholino-6-(2-(pyridin-4-yl)ethylamino)pyrimidin-4-yl)phenol
P42336
isoform p110gamma, pH 7.4, 22°C
0.0016
3-(2-morpholino-6-(2-(pyridin-4-yl)ethylamino)pyrimidin-4-yl)phenol
P42336
isoform p110beta, pH 7.4, 22°C
0.00011
3-(2-morpholino-6-(pyridin-2-ylmethoxy)pyrimidin-4-yl)phenol
P42336
isoform p110alpha, pH 7.4, 22°C
0.00037
3-(2-morpholino-6-(pyridin-2-ylmethoxy)pyrimidin-4-yl)phenol
P42336
isoform p110beta, pH 7.4, 22°C
0.00073
3-(2-morpholino-6-(pyridin-2-ylmethoxy)pyrimidin-4-yl)phenol
P42336
isoform p110gamma, pH 7.4, 22°C
0.000044
3-(4-morpholino-6-(pyridin-2-yl)pyrimidin-2-yl)phenol
P42336
isoform p110gamma, pH 7.4, 22°C
0.000062
3-(4-morpholino-6-(pyridin-2-yl)pyrimidin-2-yl)phenol
P42336
isoform p110alpha, pH 7.4, 22°C
0.0001
3-(4-morpholino-6-(pyridin-2-yl)pyrimidin-2-yl)phenol
P42336
isoform p110beta, pH 7.4, 22°C
0.0000025
3-phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one
O00329
isoform PI3Kdelta, pH not specified in the publication, temperature not specified in the publication
0.000089
3-phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one
O00329
isoform PI3Kgamma, pH not specified in the publication, temperature not specified in the publication
0.000565
3-phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one
O00329
isoform PI3Kbeta, pH not specified in the publication, temperature not specified in the publication
0.00082
3-phenyl-2-[(S)-1-(9H-purin-6-ylamino)-propyl]-3H-quinazolin-4-one
O00329
isoform PI3Kalpha, pH not specified in the publication, temperature not specified in the publication
0.00058
3-[4-(4-morpholinyl)thieno(3,2-d)pyrimidin-2-yl]-phenol
-
versus p110alpha PI3K
0.000002
4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine
-
isoform delta, pH not specified in the publication, temperature not specified in the publication
0.000004
4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine
-
isoform gamma, pH not specified in the publication, temperature not specified in the publication
0.000005
4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine
-
isoform beta, pH not specified in the publication, temperature not specified in the publication
0.000009
4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine
-
isoform alpha, pH not specified in the publication, temperature not specified in the publication
0.000001
4-[2-[(6-methoxypyridin-3-yl)amino]-5-phenylpyridin-3-yl]-6-methyl-1,3,5-triazin-2-amine
-
isoform delta, pH not specified in the publication, temperature not specified in the publication
0.000002
4-[2-[(6-methoxypyridin-3-yl)amino]-5-phenylpyridin-3-yl]-6-methyl-1,3,5-triazin-2-amine
-
isoform beta, pH not specified in the publication, temperature not specified in the publication
0.000003
4-[2-[(6-methoxypyridin-3-yl)amino]-5-phenylpyridin-3-yl]-6-methyl-1,3,5-triazin-2-amine
-
isoform alpha, pH not specified in the publication, temperature not specified in the publication
0.000007
4-[2-[(6-methoxypyridin-3-yl)amino]-5-phenylpyridin-3-yl]-6-methyl-1,3,5-triazin-2-amine
-
isoform gamma, pH not specified in the publication, temperature not specified in the publication
0.000002
4-[5-(3,6-dihydro-2H-pyran-4-yl)-2-[(6-methoxypyridin-3-yl)amino]pyridin-3-yl]-6-methyl-1,3,5-triazin-2-amine
-
isoform delta, pH not specified in the publication, temperature not specified in the publication; isoform gamma, pH not specified in the publication, temperature not specified in the publication
0.000003
4-[5-(3,6-dihydro-2H-pyran-4-yl)-2-[(6-methoxypyridin-3-yl)amino]pyridin-3-yl]-6-methyl-1,3,5-triazin-2-amine
-
isoform beta, pH not specified in the publication, temperature not specified in the publication
0.000005
4-[5-(3,6-dihydro-2H-pyran-4-yl)-2-[(6-methoxypyridin-3-yl)amino]pyridin-3-yl]-6-methyl-1,3,5-triazin-2-amine
-
isoform alpha, pH not specified in the publication, temperature not specified in the publication
0.00025
5-[2,2-difluoro-benzo(1,3)-dioxol-5-ylmethylene]-thiazolidine-2,4-dione
-
about, versus p110gamma PI3K
0.00000022
6-amino-2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-4-methoxy-1H-benzimidazole
-
isoform p110alpha, pH not specified in the publication, temperature not specified in the publication
0.00000038
6-amino-2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-4-methoxy-1H-benzimidazole
-
isoform p110delta, pH not specified in the publication, temperature not specified in the publication
0.0000014
6-amino-2-(difluoromethyl)-1-[4,6-di(4-morpholinyl)-1,3,5-triazin-2-yl]-4-methoxy-1H-benzimidazole
-
isoform p110beta, pH not specified in the publication, temperature not specified in the publication
0.0000009
N-[2-(dimethylamino)ethyl]-N-methyl-4-[([4-[4-morpholin-4-yl-7-(2,2,2-trifluoroethyl)-7H-pyrrolo[2,3-d ]pyrimidin-2-yl]phenyl]carbamoyl)amino]benzamide
-
pH not specified in the publication, temperature not specified in the publication
0.00004
TGX-221
-
about, versus p110beta PI3K
0.000006
TGX-221-R
-
pH not specified in the publication, temperature not specified in the publication
0.0000025
Wortmannin
-
inhibition of bacterial entry into macrophages
0.000052
[(4-[2-[(3-hydroxyphenyl)amino]-1H-benzimidazol-1-yl]-1,3,5-triazin-2-yl)amino]acetonitrile
-
isoform delta, pH not specified in the publication, temperature not specified in the publication
0.00012
[(4-[2-[(3-hydroxyphenyl)amino]-1H-benzimidazol-1-yl]-1,3,5-triazin-2-yl)amino]acetonitrile
-
isoform gamma, pH not specified in the publication, temperature not specified in the publication
0.00019
[(4-[2-[(3-hydroxyphenyl)amino]-1H-benzimidazol-1-yl]-1,3,5-triazin-2-yl)amino]acetonitrile
-
isoform beta, pH not specified in the publication, temperature not specified in the publication
0.00035
[(4-[2-[(3-hydroxyphenyl)amino]-1H-benzimidazol-1-yl]-1,3,5-triazin-2-yl)amino]acetonitrile
-
isoform alpha, pH not specified in the publication, temperature not specified in the publication
0.000021
[3-[4-morpholin-4-yl-7-(pyrrolidin-1-ylmethyl)-5H-pyrrolo-[3,2-d ]pyrimidin-2-yl]phenyl]methanol
-
pH not specified in the publication, temperature not specified in the publication
0.008
LY294002
-
inhibition of bacterial entry into macrophages
additional information
additional information
-
IC50 value of inhbitor 4-[4-(morpholin-4-yl)-5a,6-dihydro[1]benzofuro[3,2-d]pyrimidin-2-yl]phenol is 2 nmol/l against recombinant isoform p110alpha, 3 nmol/l against recombinant isoform p110beta, 3 nmol/l against recombinant isoform p110delta, 15 nmol/l against recombinant isoform p110agamma
-
pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
7
-
assay at
7.4
-
assay at
7.5
-
assay at
7.5
-
assay at
7.5
-
assay at
7.6
-
assay at
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
22
-
assay at room temperature
25
-
assay at
30
-
assay at
37
-
assay at
37
-
assay at
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
-
an airway epithelial cell line
Manually annotated by BRENDA team
-
the cells are located at the terminal bronchi, and have the capacity to selfrenew and undergo multi-linage differentiation
Manually annotated by BRENDA team
-
CEM-S cell, CEM-R cell
Manually annotated by BRENDA team
-
recombinant isoforms PI3Kalpha, beta, delta and gamma
Manually annotated by BRENDA team
Q9JHG7
PI3Kgamma
Manually annotated by BRENDA team
P27986
renal proximal tubule epithelial cell
Manually annotated by BRENDA team
-
embryonic fibroblast cell culture
Manually annotated by BRENDA team
-
embryonic fibroblast cells
Manually annotated by BRENDA team
-
thyroid follicular cell line
Manually annotated by BRENDA team
-
PI3Kgamma, small amounts
Manually annotated by BRENDA team
P27986
renal proximal tubule epithelial cell
Manually annotated by BRENDA team
O00329
high expression
Manually annotated by BRENDA team
O00329
p110delta is exclusively localized in leukocytes
Manually annotated by BRENDA team
Q9JHG7
PI3Kgamma
Manually annotated by BRENDA team
-
PI3Kdelta is absolutely restricted to, and PI3Kgamma is largely restricted to leukocytes
Manually annotated by BRENDA team
O00329
high expression
Manually annotated by BRENDA team
O00329
high expression
Manually annotated by BRENDA team
-
bone marrow-derived macrophages
Manually annotated by BRENDA team
-
68% of clinical cases and the MCL cell lines harbor a gain of PIK3 catalytic subunit alpha gene copy number. In addition, cases with increased PIK3CA gene copy number have elevated PIK3CA mRNA levels
Manually annotated by BRENDA team
-
PI3Kdelta isoform is most prominently expressed in myeloid cells
Manually annotated by BRENDA team
-
p110delta is highly expressed. p110delta as an important signaling component for efficient axonal elongation in the developing and regenerating nervous system
Manually annotated by BRENDA team
-
a pivotal region in reflex regulation of arterial pressure in the brain stem. Quantitative determination of expression levels of specific class I PI3K subunits, p85alpha, p85beta, p110alpha, p110beta, p110delta, and p110gamma, in the nucleus tractus solitarii of spontaneously hypertensive rats, overview
Manually annotated by BRENDA team
-
osteoclasts express multiple regulatory subunits of class IA PI3-K, although the expression of the full-length form of p85alpha is most abundant
Manually annotated by BRENDA team
Q9Z1L0
rat osteosarcoma cell line
Manually annotated by BRENDA team
-
an epithelial ovarian cancer cell line SKOV3 with constitutively active PI3K
Manually annotated by BRENDA team
-
tracheal smooth muscle
Manually annotated by BRENDA team
-
all cell lines express the catalytic subunit isoforms p110alpha, p110beta, p110gamma, and p110delta
Manually annotated by BRENDA team
-
monocytic cell line
Manually annotated by BRENDA team
Homo sapiens PI3K-C2alpha
-
monocytic cell line
-
Manually annotated by BRENDA team
-
migrating plant cells
Manually annotated by BRENDA team
additional information
-
all mammalian cell types investigated express at least one class IA isoform, class IB isoform is present only in mammals, where it shows a restricted tissue distribution, being abundant only in white blood cells
Manually annotated by BRENDA team
additional information
P42338
expressed ubiquitously
Manually annotated by BRENDA team
additional information
-
PI3K p110delta is mainly expressed in cells of the immune system
Manually annotated by BRENDA team
additional information
-
PI3Kalpha and beta are ubiquitously expressed while the expression of PI3Kdelta is restricted to leukocytes
Manually annotated by BRENDA team
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
-
both nuclear membrane and soluble fraction, presence of an autonomous phosphoinositide 3-kinase cycle
Manually annotated by BRENDA team
additional information
-
activated receptor tyrosine kinases recruit the PI3 kinase complex to the membrane via the p85 regulatory subunit either directly or via insulin receptor substrate adapter proteins, activating the catalytic subunit p110
-
Manually annotated by BRENDA team
additional information
-
PI3K associates with E-cadherin and part of the E-cadherin signaling complex, which is intergrated into the plasma membrane, complex formation, overview
-
Manually annotated by BRENDA team
PDB
SCOP
CATH
ORGANISM
SUBUNITS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
?
O00329
x * 119471, p110delta subunit, can bind the p85 adaptor subunit, calculation from nucleotide sequence
?
O00329
x * 119505, calculated, x * 110000, SDS-PAGE
?
P48736
x * 120000, calculated, x * 110000, SDS-PAGE
dimer
-
class I PI3Ks exist as heterodimers consisting of one of four p110 catalytic subunit isoforms and one of two families of regulatory subunit forms. PI3K class III has only one member known as Vps34
dimer
-
PI3 kinases are heterodimers comprised of a regulatory subunit p85 and a catalytic subunit p110. Class IA subunit p110, i.e. PIK3CA, exists in three isoforms, p110alpha, p110beta, and p110gamma. All have similar structure with domains for binding to the adaptor protein subunit PIK3R1, p85, and to RAS
dimer
-
regulatory p85alpha and p85beta subunits of class IA PI3-K share near identity in the functional domains in the C-terminus, including the amino-SH2 and the carboxy-SH2 domains, which are critical for mediating association with other SH2-containing proteins as well as binding to the p110 catalytic subunit
heterodimer
-
a p110alpha/beta-subunit binds to a p85 regulatory subunit, and this heterodimer is recruited to the membrane through the association with phosphotyrosyl proteins, leading to production of phosphatidylinositol 3,4,5-triphosphate, PIP3, followed by activation of downstream signal pathway(s)
heterodimer
-
catalytic subunit p110 and regulatory subunit p85
heterodimer
-
catalytic subunit p110 and regulatory subunit p85
heterodimer
-
catalytic subunit p110 and regulatory subunit p85
heterodimer
-
catalytic subunit p110alpha and regulatory subunit p85. p85 binding to p110alpha is required for activity
heterodimer
-
PI3K is formed by a catalytic subunit p110, occuring in four isoforms p110alpha, p110beta, p110gamma, and p110delta, and a regulatory subunit p85
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
additional information
-
-
additional information
-
class I phosphoinositide 3-kinases are heterodimers made up of an catalytic subunit, called p110, of about 110000 Da and an adaptor/regulatory subunit. Class I phosphoinositide 3-kinases are further subdivided into class Ia and IB enzymes, which signal downstream of tyrosine kinase and heterotrimeric G protein-coupled receptors, respectively
additional information
-
a single type of catalytic/adaptor heterodimer: AGE-1/AAP-1
additional information
-
a single type of catalytic/adaptor heterodimer: Dp110/p60
additional information
-
three class IA p110 isoforms, p110alpha, beta and delta, which are encoded by three separate genes, at least seven adaptor proteins, which are generated by expression and alternative splicing of three different genes, namely p85alpha, p85beta and p55gamma. All these splice variants make functional complexes with p110 subunits
additional information
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three catalytic subunits: PIK1, PIK2 or PIK3
additional information
P42338
a 187 amino acid domain of regulatory subunit p85 mediates interaction with catalytic subunit p110 in vitro and in intact cells
additional information
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enzyme forms a complex with a phosphatidylinositol-(3,4,5)-triphosphate 5-phosphatase distinct from platelet 43 kDa and 75kDa 5-phosphatases
additional information
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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
O00329
forms a complex with regulatory subunit p85
additional information
P48736
G-protein beta,gamma recruits the enzyme from the cytosol to the mebrane by interaction with ist p101 subunit
additional information
P42337
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
P48736
no interaction with regulatory subunit p85
additional information
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p85 regulatory subunit forms cytosolic complexes with insulin receptor substrate
additional information
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specific interaction between GTPase Rab5 and enzyme catalytic subunit p110beta leading to efficient coupling of enzyme product to its downstream target, protein kinase B
additional information
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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
additional information
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p85alpha subunit of class I PI3K
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
P48736
stimulation of autophosphorylation of catalytic sunbunit by G-protein beta,gamma subunits
Crystallization/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
cocrystal strucutre of inhibitor 4-(2-((6-methoxypyridin-3-yl)amino)-5-((4-(methylsulfonyl)piperazin-1-yl)methyl)pyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine bound to catalytic subunit gamma isoform. Compound binds with two hydrogen bonds from the aminotriazine ring to the hinge, with the triazine methyl substituent oriented toward the Tyr867 side chain, and with the 4-methoxypyridine substituent projected into the affinity pocket. The methoxypyridine nitrogen atom makes a hydrogen bond to an ordered water molecule sitting between Tyr867 and Asp841, and the piperazine sulfonamide extended into the ribose pocket
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docking of inhibitor TGX-221-R into a homology model of the PI3K-beta enzyme. The morpholine-oxygen accepts an H-bond from the hinge region Val854 while the pyrido-pyrimidinone template core interacts in the central pocket lined by Met926 and Ile residues 803, 851 and 936 from the N and C-terminal of the kinase domain
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structure activity relationship study of inhibitor 2-(difluoromethyl)-1-[4,6-di-(4-morpholinyl)-1,3,5-triazin-2-yl]-1H-benzimidazole, i.e. ZSTK474, with catalytic subunit gamma isoform, PDB entry 2CHX
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Purification/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
recombinant tagged proteins by the specific affinity chromatographies
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recombinant tagged proteins by the specific affinity chromatographies
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Cloned/COMMENTARY
ORGANISM
UNIPROT
LITERATURE
expression of His-, FLAG-, or GSt-tagged p85beta in HEK-293T or A-549 cells
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expression in Saccharomyces cerevisiae
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expression of HA-tagged p85alpha in NIH 3T3 cells in a mouse cell model
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expression of P110delta in Sf9 insect cells
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expression of p85 constructus from a retroviral vector
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gene PIK3CA, encodes the catalytic subunit of PI3K, and resides in chromosomal area 3q26
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overexpression of the dominant negative PI3K mutant in J774A.1 cells
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PI 3-kinase genotyping
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expression in HEK-293T cell
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expression of His-, FLAG-, or GSt-tagged p85beta in HEK-293T or A-549 cells
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enzyme subunit isoform expression analysis in the nucleus tractus solitarii of the brain stem, overview
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EXPRESSION
ORGANISM
UNIPROT
LITERATURE
gain of copy number of PIK3CA gene by gene amplification in mantle cell lymphoma is one mechanism of oncogenic activation of PI3K. Expression of PIK3CA in mantle cell lymphoma correlates with gene copy numbers determined by real-time PCR, overview
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upregulation of class I PI3K isozymes in cancer cells
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virulent Legionella pneumophila infection induces PI3K in human macrophages, while PI3K and protein kinase B, PKB/Akt, activities are lower in macrophages infected with an avirulent bacterial strain
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upregulation of class I PI3K isozymes in cancer cells
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ENGINEERING
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
A1066V
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a common naturally occuring mutation involved in cancer development
D1017H
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a common naturally occuring somatic mutation involved in cancer development
D915A
P42336
complete loss of enzymic activity
D933A/F934A
P42336
complete loss of enzymic activity
E542K
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a common naturally occuring mutation in the helical domain, the mutation is involved in cancer development, the mutant requires RAS binding but bot p85 binding
E542K/E545K
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gain-of-function helical domain mutations result in upregulation of enzyme activity, Akt phosphorylation and cell transformation
E545K
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a common naturally occuring mutation in the helical domain, the mutation is involved in cancer development, the mutant requires RAS binding but bot p85 binding
E545K/H1047R
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gain-of-function helical domain mutations result in upregulation of enzyme activity, Akt phosphorylation and cell transformation
E970A
P42336
90% of wild-type activity
H1047R
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a common naturally occuring mutation of the kinase domain, that is involved in cancer development
H1047R
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gain-of-function mutation of subunit p110alpha, the H1047R mutation can substitute for RAS binding, but binding to p85 is essential for H1047R-induced cell transformation
K227E
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the mutaion reduces enzyme activity
M1043I
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a common naturally occuring somatic mutation involved in cancer development
P124L
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a common naturally occuring somatic mutation involved in cancer development. P124L lies in a region of four helices in the protein between the adapter-binding and RAS-binding domains
P124T
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a naturally occuring missense mutation in codon 124 from a colorectal cancer cell
Q643R
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a common naturally occuring somatic mutation involved in cancer development
R274A
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the GTPase-activating protein activity toward Rab5 and Rab4 of PI3K p85alpha subunit is abolished in the mutant. Expression of p85alpha-R274A results in increased platelet-derived growth factor receptor, PDGFR, activation and downstream signaling, via Akt and MAPK pathways, and in decreased PDGFR degradation. Disrupted RabGAP function of the p85 subunit of phosphatidylinositol 3-kinase results in cell transformation, co-expression of a dominant negative Rab5-S34N mutant attenuates these transformed properties
R922A
P42336
80% of wild-type activity
D910A
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site-directed mutagenesis of isoform p110delta, catalytically inactive. Interleukin is unable to induce hyper-responsiveness in tissues expressing the mutant
D910A
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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
M582V
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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
additional information
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construction of chimeras of 85alpha and p85beta iSH2 domain by overlapping PCR using mouse p85beta and bovine p85alpha as templates
V573M
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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
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a mutant with a deletion in the binding site of the p110 catalytic subunit is dominant negative
M326I
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a common naturally occuring polymorphism of the regulatory subunit p85alpha in women involved in the polycystic ovary syndrome, PCOS, genotyping in polycystic ovary syndrome patients from Korean female population
additional information
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a mutant with a deletion in the binding site of the p110 catalytic subunit is dominant negative
additional information
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construction of a constitutively active PI3-kinase, CA-PI3K, mutant, whose expression stimulates translocation of Tiam1 to the membrane, increases Rac1 activity, and increases wound healing of airway epithelial cells, phenotype, overview. Expression of a dominant negative form of PI3-kinase,using an adenoviral vector, causes inhibition of airway epithelial cell wound closure, overview
additional information
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construction of a dominant negative PI3K mutant by PCR cloning. Legionella pneumophila entry into macrophages expressing the mutant is reduced
additional information
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deficiency of PI3-K regulatory subunit p85alpha in vivo results in a significantly greater number of trabeculae and significantly lower spacing between trabeculae as well as increased bone mass in both males and females compared to their sex-matched wild-type controls. p85-/- osteoclast progenitors show impaired growth and differentiation, which is associated with reduced activation of Akt and mitogen-activated protein kinase Erk1/Erk2 in vitro, and a significant reduction in the ability of p85-/- osteoclasts to adhere to as well as to migrate via integrin alphanybeta3. Restoring the expression of the full-length form of p85alpha but not the version with a deletion of the Src homology-3 domain restores the maturation of p85-/- osteoclasts to wild-type levels, overview. Phenotypes, overview
additional information
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genetic abolition of PI3Kdelta signalling by insertion of a kinase-dead p110delta catalytic subunit results in impaired B cell and T cell antigen receptor signalling
additional information
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helical domain and kinase domain mutations in p110alpha of phosphatidylinositol 3-kinase induce gain of function by different mechanisms, overview. About 30% of prostate, breast, cervix, and endometrium tumors show catalytic subunit p110alpha mutations, the most prominent single amino acid substitutions in the helical or kinase domain result in a gain of enzymatic function, activate AKT signaling, and induce oncogenic transformation, analysis of hot-spot mutations in gene PIK3CA. The gain of function induced by helical domain mutations is independent of binding to p85 but requires interaction with RAS-GTP. In contrast, the kinase domain mutation is active in the absence of RAS-GTP binding but is highly dependent on the interaction with p85. Truncation reduce the activities of all enzymes, truncated wild-type and mutant, overview. Phenotypes, overview
additional information
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mutations in PIK3CA are also found commonly in the benign skin lesions seborrheic keratosis and epidermal nevi
additional information
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sequencing of cancer cell p85alpha subunits reveal four mutational alterations, three colonic and one ovarian: one with an early stop codon after Asp605 and three containing small in-frame deletions, DELTALeu570-Gln572, DELTALeu570-Asp578, and DELTAMet582-Asp605. These deletions are located near the negative regulatory phosphorylation site Ser608 within p85alpha. All mutations lead to increased enzyme activity
additional information
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suppression of the PI3K catalytic subunit p110alpha inhibits the growth of ovarian cancer cells in vitro and in vivo
additional information
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the most common sites for hotspot mutations of PI3Kalpha are around amino acid 1047 in the kinase domain, and amino acid 545 in the helical domain, the mutations are involved in breast and colon tumorigenesis
M582V
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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
additional information
P42337
expression of regulatory protein p85 102 amino acid binding domain plus catalytic subunit p110 leads to fully active enzyme complex
additional information
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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
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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
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construction of chimeras of 85alpha and p85beta iSH2 domain by overlapping PCR using mouse p85beta and bovine p85alpha as templates
additional information
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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
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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
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mRNA translation of IFN-responsive genes is defective in cells with targeted disruption of both the p85alpha and p85beta subunits of PI3K
additional information
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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
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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
V573M
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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
Mus musculus C57BL/6
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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
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APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
analysis
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low-cost bioassay that readily measures phosphatidylinositol 3-kinase inhibition. The in vivo assay is based on the fact that the overproduction of phosphatidylinositol 3-kinase is toxic in yeast, and uses the ability of commercial phosphatidylinositol 3-kinase inhibitors to rescue cell growth. The use of 0.003% sodium dodecyl sulfate and the elimination of the Snq2 detoxification pump, optimize the bioassay by enhancing its sensitivity. From 9600 extracts tested, 0.6% lead to a recovery of yeast growth reproducibly, selectively, and in a dose-dependent manner
medicine
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in human leukemic cell lines and in primary blast cells from acute myelogenous leukemia patients, inhibitor 4-[4-(morpholin-4-yl)-5a,6-dihydro[1]benzofuro[3,2-d]pyrimidin-2-yl]phenol/PI-103 inhibits constitutive and growth factor-induced PI3K/Akt and mTORC1 activation. PI-103 is essentially cytostatic for cell lines and induces cell cycle arrest in the G1 phase. In blast cells, PI-103 inhibits leukemic proliferation, the clonogenicity of leukemic progenitors and induces mitochondrial apoptosis. PI-103 has additive proapoptotic effects with etoposide in blast cells and in immature leukemic cells. PI-103 does not induce apoptosis in normal CD34ž cells and has moderate effects on their clonogenic and proliferative properties
medicine
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inhibitor 4-[4-(morpholin-4-yl)-5a,6-dihydro[1]benzofuro[3,2-d]pyrimidin-2-yl]phenol, i.e. PI103 is inhibitory to phosphatidylinositol 3-kinases, TORC1 and DNA protein kinase. PI103 potently inhibits proliferation and invasion of a wide variety of human cancer cells in vitro and shows biomarker modulation consistent with inhibition of phosphatidylinositide 3-kinase signaling. PI103 is extensively metabolized, but distributed rapidly to tissues and tumors. This results in tumor growth delay in eight different human cancer xenograft models with various phosphatidylinositide 3-kinase pathway abnormalities. Decreased phosphorylation of AKT is observed in U87MG gliomas, consistent with drug levels achieved
medicine
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application of PI3K/Akt/mTOR inhibitors in T-cell acute lymphoblastic leukemia, T-ALL
pharmacology
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the PI3Kgamma signaling pathway may represent a suitable target for the development of therapeutic strategies for human diseases characterized by vascular leakage
medicine
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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
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p110delta may be a good target for pharmaceutical intervention of T cell-dependent autoimmune pathologies
medicine
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therapeutic target for Th2-mediated airway disease
medicine
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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
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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