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evolution
PI3K type III is the only type of PI3K identified in plants
evolution
RT0135 contains conserved residues within the catalytic and activation loops of the diverse PI3/PI4 family effectors
evolution
vacuolar protein sorting 34 (Vps34) is a member of the phosphoinositide 3-kinase (PI3K) family of lipid kinases. Vps34 and its functions are highly conserved from yeast to mammals
evolution
vacuolar protein sorting 34 (Vps34) is a member of the phosphoinositide 3-kinase (PI3K) family of lipid kinases. Vps34 and its functions are highly conserved from yeast to mammals. The domain organization of Vps34 and Vps15 are highly conserved between yeast and humans
evolution
vacuolar protein sorting 34 (Vps34) is a member of the phosphoinositide 3-kinase (PI3K) family of lipid kinases. Vps34 and its functions are highly conserved from yeast to mammals. The domain organization of Vps34 and Vps15 are highly conserved between yeast and humans
evolution
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RT0135 contains conserved residues within the catalytic and activation loops of the diverse PI3/PI4 family effectors
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evolution
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RT0135 contains conserved residues within the catalytic and activation loops of the diverse PI3/PI4 family effectors
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malfunction
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Co-treatment of NB4 cells with either LY294002 to inhibit PI3Ks or PD98059 in order to suppress MEK activity lead to significant reduction of CD11b surface expression during all-trans-retinoic acid, 9-cis-retinoic acid or retinoic acid receptor agonist Ro40-6055 dependent NB4 cells granulocyte differentiation
malfunction
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disruption of PDGFRbeta-PI3K signaling in mice reduces atherosclerosis. Disorganization of the actin cytoskeleton in LRP1-deficient smooth muscle cells is prevented by blocking PI3K activation by PDGFRbeta
malfunction
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gene PIK3CA, encoding the catalytic subunit p110alpha of PI3K, is mutated in about 12% of all human cancers, as single point mutations of hot-spot mutation with exchange of three positions, overview
malfunction
inhibition of TcVps34 with specific PI3K inhibitors, such as wortmannin and LY294000, result in reduced regulatory volume decrease after hyposmotic stress
malfunction
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phosphatidylinositol 3-kinase signaling is involved in progression of hepatic fibrosis in hepatic stellate cells. Inhibition of phosphatidylinositol 3-kinase signaling in hepatic stellate cells, by either a pharmacological or by a genetic approach, blocks the progression of hepatic fibrosis inhibiting extracellular matrix deposition, including synthesis of type I collagen, and reducing expression of profibrogenic factors, mechanism, overview. Inhibition of PI3K signaling is also associated with reduced activation of Akt, p70 S6 kinase, and extracellular regulated kinase signaling as well as reduced cyclin D1 expression
malfunction
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PI3K is part of the PI3K/Akt pathway, e.g. responsible for promoting motility and invasion of gastric cancer cells in epithelial-mesenchymal transition and metastasis, after activation and signaling by bone morphogenetic protein 2, BMP-2, with Snail induction, E-cadherin delocalization and down-regulation, and up-regulation of mesenchymal and invasiveness markers, overview
malfunction
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the phosphatidylinositol 3-kinase/Akt signaling pathway is crucial to sustain the pathophysiology of medulloblastoma, a primitive neuroectodermal tumor and the most common malignant pediatric brain tumor. Small-molecule inhibitors of phosphatidylinositol 3-kinase/Akt signaling inhibit Wnt/beta-catenin pathway cross-talk and suppress medulloblastoma growth. The inhibitors affect beta-catenin signaling by inhibition of GSK-3beta activity, resulting in cytoplasmic retention of beta-catenin and reduced expression of its target genes cyclin D1 and c-Myc
malfunction
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upregulation of expression of the close homologue of adhesion molecule L1, CHL1, by reactive astrocytes in the glial scar requires the activation of PI3K/PKCdelta-dependent pathways reduces axonal regeneration and inhibits functional recovery after spinal cord injury, overview
malfunction
deletion of a key endosomal trafficking regulator, the class 3 phosphatidylinositol (PtdIns) 3-kinase vacuolar protein sorting 34 (Vps34), in podocytes results in aberrant endosomal membrane morphology and podocyte dysfunction. The vacuolation phenotype in cultured Vps34-deficient podocytes is caused by the absence of a substrate for the Vps34 downstream effector PtdIns 3-phosphate 5-kinase, which phosphorylates Vps34-generated PtdIns(3)P to produce PtdIns (3,5)P2
malfunction
enzyme mutations are involved in bilateral perisylvian polymicrogyria (BPP), the most common form of regional polymicrogyria, that causes the congenital bilateral perisylvian syndrome, featuring oromotor dysfunction, cognitive impairment, and epilepsy. Constitutional and mosaic mutations in the PIK3R2 gene are associated with developmental brain disorders ranging from BPP with a normal head size to the MPPH syndrome. They occur primarily in the caucasian white genotype, phenotypes, overview
malfunction
treatment with PI3K inhibitors or downregulation of AtVPS34 gene expression further suppressed V-ATPase activation in methyl jasmonate-induced leaf senescence. Downregulation of PI3K activity accelerates methyl jasmonate-induced leaf senescence. Vacuolar pH and the stomatal aperture also increased in the pi3k mutant and in treatments with PI3K inhibitors
malfunction
Arabidopsis thaliana pollen development is abnormal in knockout mutants for shared components of two VPS34 complexes (VPS34, VPS15, and ATG6/VPS30)
malfunction
consistent with a regulatory role for Ser90 phosphorylation, induction of autophagy by amino acid starvation is reduced in cells expressing S90A Beclin-1
malfunction
downregulation of PI3K activity accelerates leaf senescence induced by methyl jasmonate (MeJA) and suppresses the activation of vacuolar H+-ATPase (VATPase)
malfunction
PARQ3 knockdown in cells or knockout in mice leads to reductions in Atg14-associated Beclin-1, Vps34 and Vps15
malfunction
pretreatment of Rickettsia with Risk1-specific antibody for various lengths of time shows that neutralization of Risk1 significantly reduces Rickettsia typhi internalization, which is consequently resulting in an increase in bacterial adherence. In contrast, pretreatment of Rickettsia typhi with an alphaIgG isotype control Ab shows no reduction in bacterial internalization, indicating that the reduction in Rickettsia typhi infectivity is the result of direct inhibition of Risk1 functionality and not due to steric hindrance induced by the Fc portion of the alphaRisk1 Ab. Cells overexpressing wild-type Risk1 have an about 2.5fold higher bacterial burden than cells expressing either vector or Risk1 H297A mutant. Inhibition of PI3K activity negatively affects Rickettsia typhi internalization and the colocalization of Risk1 with Rab5 and EEA. Cells transfected with Risk1 H297A display a significant increase in apoptosis1
malfunction
the deletion of Vps34, Vps15 or Vps30 affects both autophagy and vacuolar protein sorting. The deletion of Vps34 or Vps15 results in a reduced mRNA production from G + C-rich coding sequences (CDS). Vps34 and Vps15 can enhance the efficiency of transcription elongation based on their physical proximity to nuclear pores and transcribed chromatin
malfunction
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pretreatment of Rickettsia with Risk1-specific antibody for various lengths of time shows that neutralization of Risk1 significantly reduces Rickettsia typhi internalization, which is consequently resulting in an increase in bacterial adherence. In contrast, pretreatment of Rickettsia typhi with an alphaIgG isotype control Ab shows no reduction in bacterial internalization, indicating that the reduction in Rickettsia typhi infectivity is the result of direct inhibition of Risk1 functionality and not due to steric hindrance induced by the Fc portion of the alphaRisk1 Ab. Cells overexpressing wild-type Risk1 have an about 2.5fold higher bacterial burden than cells expressing either vector or Risk1 H297A mutant. Inhibition of PI3K activity negatively affects Rickettsia typhi internalization and the colocalization of Risk1 with Rab5 and EEA. Cells transfected with Risk1 H297A display a significant increase in apoptosis1
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malfunction
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inhibition of TcVps34 with specific PI3K inhibitors, such as wortmannin and LY294000, result in reduced regulatory volume decrease after hyposmotic stress
-
malfunction
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pretreatment of Rickettsia with Risk1-specific antibody for various lengths of time shows that neutralization of Risk1 significantly reduces Rickettsia typhi internalization, which is consequently resulting in an increase in bacterial adherence. In contrast, pretreatment of Rickettsia typhi with an alphaIgG isotype control Ab shows no reduction in bacterial internalization, indicating that the reduction in Rickettsia typhi infectivity is the result of direct inhibition of Risk1 functionality and not due to steric hindrance induced by the Fc portion of the alphaRisk1 Ab. Cells overexpressing wild-type Risk1 have an about 2.5fold higher bacterial burden than cells expressing either vector or Risk1 H297A mutant. Inhibition of PI3K activity negatively affects Rickettsia typhi internalization and the colocalization of Risk1 with Rab5 and EEA. Cells transfected with Risk1 H297A display a significant increase in apoptosis1
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malfunction
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upregulation of expression of the close homologue of adhesion molecule L1, CHL1, by reactive astrocytes in the glial scar requires the activation of PI3K/PKCdelta-dependent pathways reduces axonal regeneration and inhibits functional recovery after spinal cord injury, overview
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metabolism
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a signaling network regulates interleukin-8 production in response to proteasome activation or inactivation also involving PI3K, detailed overview
metabolism
mammalian cells have at least two distinct class III PI3-kinase complexes, which may function in different membrane trafficking pathways
metabolism
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phosphatidylinositol 3-kinase is closely associated with TGFbeta3 production/secretion in astrocytes. Microglia-derived plasminogen or plasmin facilitates the production/secretion of TGFbeta3 in astrocytes through both PAR-1 and the subsequent signaling cascade including PI3K and Akt
metabolism
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PI3K is part of the PI3K/Akt pathway, e.g. responsible for promoting motility and invasion of gastric cancer cells in epithelial-mesenchymal transition and metastasis, after activation and signaling by bone morphogenetic protein 2, BMP-2, with Snail induction, E-cadherin delocalization and down-regulation, and up-regulation of mesenchymal and invasiveness markers, overview
metabolism
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the enzyme is part of the phosphatidylinositol 3-kinase-Akt pathway, which plays a role in the adenosine 5'-triphosphate-sensitive K+ channel function, overview
metabolism
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the enzyme is part of the phosphatidylinositol 3-kinase/Akt signaling pathway
metabolism
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the phosphatidylinositol 3'-kinase-Akt/protein kinase B axis is a pro-survival pathway which prevents apoptosis through defined anti-apoptotic mechanisms in a variety of cancer cells
metabolism
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the PI3-K/Akt pathway plays a pivotal role in controlling the survival of neurons, although this activity declines during the aging process. NGF receptors and the PI3-K signaling pathway strongly influence cell survival
metabolism
no association between Beclin-1 and Risk1 or Bcl-2 is observed after prolonged Rickettsia typhi infection
metabolism
PI3K type III plays a vital role in the trafficking of proteins to and from vacuoles. Interactions between VHA-B2 and PI3K are possibly promoted the translocation of VHA-B2 from the TNG to the vacuole and thus improve the assembly of V-ATPase, resulting in increased V-ATPase activity
metabolism
regulation by accessory proteins for Vps34 Complex I and II, and regulation of Vps34 complexes by phosphorylation during starvation, mechanisms, overview. In yeast, targeting of Vps34 to the pre-autophagosomal structure (PAS) requires Atg14 (although targeting of Vps15 to the PAS is Atg14-independent)
metabolism
regulation by accessory proteins for Vps34 Complex I and II, e.g. Beclin-1, mechanisms, overview. Members of Vps34 Complex I and II are regulated by a number of selective degradation systems. Regulation of Vps34 complexes by phosphorylation during starvation, overview
metabolism
regulation of Vps34 complexes by phosphorylation during starvation, overview
metabolism
together with Vps34, Vps15 and Vps30 it forms the PIK3C3-Complex II, which is mainly found at endosomal membranes, modulation of PIK3C3 complex function through different subunit compositions, overview. The Vps15 kinase domain intercts with the Vps34 activation loop, which might regulate the activity of Vps34
metabolism
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no association between Beclin-1 and Risk1 or Bcl-2 is observed after prolonged Rickettsia typhi infection
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metabolism
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no association between Beclin-1 and Risk1 or Bcl-2 is observed after prolonged Rickettsia typhi infection
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physiological function
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Atg6/Beclin 1, the phosphatidylinositol 3-kinase Vps34, and associated proteins Atg6 and Vps15 have direct or indirect roles in autophagic pathways. Roles of PI3K complex proteins and PpUvrag in autophagy, autophagy-related and the VPS pathways, overview. PpUvrag is required for the vacuolar sorting of PpCPY and in its absence PpCPY is mis-sorted
physiological function
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differentiation in C6 cells by panaxydol, isolated from the lipophilic fractions of Tienchi ginseng, Panax notoginseng, might be mediated through a PI 3-K-dependent pathway. Treatment of C6 cells with panaxydol causes marked inhibition of growth that is abolished by wortmannin, a PI 3-K inhibitor
physiological function
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involvement of PI 3-kinase in the Nrf2 pathway during muscle differentiation. Nrf2 is transcriptionally up-regulated and translocated to the nucleus during myogenesis, but does not affect the PI 3-kinase activity acting downstream of it, overview
physiological function
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involvement of PI3K in all-trans-retinoic acid or Ro40-6055, a retinoic acid receptor alpha specific agonist, dependent granulocyte differentiation of NB4 cells, overview
physiological function
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NF-kappaB and phosphatidylinositol 3-kinase activity mediate the human cytomegalovirus, HCMV, induced atypical M1/M2 polarization of monocytes, overview. PI3K activity is involved in the upregulation of about 12% of M1-associated genes following infection with HCMV. And the enzyme is involved increased motility of HCMV-infected native cells by about 5.5fold compared to uninfected cells treated with mock-infected cell supernatants
physiological function
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phosphatidylinositol 3-kinase and xanthine oxidase regulate nitric oxide and reactive oxygen species productions by apoptotic lymphocyte microparticles in endothelial cells. PI3K inhibition reduces the effects of microparticles on endothelial NO synthase, but not on caveolin-1, whereas it enhances the effects of microparticles on reactive oxygen species production. Microparticles stimulated ERK1/2 phosphorylation via a PI3K-depedent mechanism
physiological function
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phosphatidylinositol 3-kinase is a key mediator of central sensitization, induced by intraplantar formalin, the spinal cord phenomenon associated with persistent afferent inputs and contributing to chronic pain states, in painful inflammatory conditions
physiological function
phosphatidylinositol 3-kinase is essential for normal growth and is essential for vacuole reorganization and nuclear division during pollen development
physiological function
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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
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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
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PI-3-K and the PI-3-K signaling pathway, besides the MAPK signaling pathway, are involved in the signaling mechanism underlying the neuroprotection of brain-derived neurotrophic factor against hypoxic insult, molecular mechanisms, overview. ERK but not PI-3-K pathway induce CREB phosphorylation
physiological function
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PI3-K is involved in the intracellular signal transduction pathways in the regulation of fowl sperm motility, the calcium-regulated maintenance of flagellar movement, and in reversible temperature-dependent immobilization at 40°C, but PI3K is probably not involved in regulation of Ca2+ mobilization
physiological function
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PI3K activity is involved in interleukin-8 production in retinal pigment epithelial cells, independent of 3-phosphoinositide-dependent protein kinase 1, PDK1, and Akt
physiological function
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PI3K is involved in LPS-induced signaling in glial cells inducing the lipopolysaccharide-stimulated expression of adhesion molecule L1, CHL1. PI3K/PKCdelta-mediated nuclear translocation of NF-kappaB
physiological function
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PI3K is involved in regulation of actin polymerization and cell movement
physiological function
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PI3K isozymes play selective roles in ischemic preconditioning, a potent cellular protective mechanism whereby brief periods of sublethal ischemia protect the myocardium from prolonged ischemia-induced injury, overview
physiological function
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PI3K plays a role in root hair growth
physiological function
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PI3K specifically interacts with retinoblastoma protein through the unique NH2 terminus of its regulatory subunit p55PIK, N24, which is critical for cell proliferation and cell cycle progression
physiological function
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PI3K-dependent phosphorylation of Akt1 activates it to phosphorylate p40phox and p40phox-p67phox complex, causing platelet-activating factor-mediated endosome formation required for the membrane translocation of p40phox and p67phox in neutrophils. Platelet-activating factor elicites an interaction between PI3K and p40phox and to a lesser extent between PI3K and phosphorylated p40phox, pathway overview
physiological function
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protein kinase Syk associates with clathrin and mediates phosphatidylinositol 3-kinase activation during human rhinovirus internalization in leukocytes, PI3K activity is required for HRV internalization, regulation and signaling mechanism, overview
physiological function
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role of crosstalk between phosphatidylinositol 3-kinase and extracellular signal-regulated kinase/mitogen-activated protein kinase pathways in artery-vein specification, mechanism of artery-vein specification during embryogenesis, the developmental process involves several protein factors, overview. PI3K is involved in the PI3K-ATK pathway, activated by the vascular endothelial growth factor, VEGF
physiological function
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role of PI3K/AKT signaling in expression of the MOR gene in CEM x 174 cells. Phosphatidylinositol 3-kinase pathway mediated up-regulation of the mu opioid receptor in lymphocytes, mechanisms, overview
physiological function
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the enzyme activates Akt signaling
physiological function
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the PI3-K/Akt pathway plays a pivotal role in controlling the survival of neurons, although this activity declines during the aging process. NGF receptors and the PI3-K signaling pathway strongly influence cell survival
physiological function
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the PI3K signaling pathway regulates several aspects of hepatic stellate cell activation in vitro, including collagen synthesis and cell proliferation, overview. Inhibition of PI3K decreases expression of alpha1(I)collagen in hepatic stellate cells mediated in part by inhibiting gene transcription, mechanism, overview
physiological function
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the thiazolidinedione pioglitazone acutely stimulates adiponectin secretion from mouse and human adipocytes via activation of the phosphatidylinositol 3-kinase
physiological function
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the thiazolidinedione pioglitazone acutely stimulates adiponectin secretion from mouse and human adipocytes via activation of the phosphatidylinositol 3-kinase
physiological function
the Trypanosoma cruzi phosphatidylinositol 3-kinase, TcVps34, is involved in osmoregulation and receptor-mediated endocytosis. TcVps34 participates in the endocytic pathway, fluid phase uptake of BSA and receptor-mediated endocytosis of transferrin. Multiple roles for TcVps34, schematic overview
physiological function
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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
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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
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Vps34 appears to be important in endocytosis and vesicular trafficking, and is also implicated in Toll-like receptor signalling
physiological function
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epidermal growth factor and fibroblast growth factor inhibit insulin-like growth factor-I-stimulated tyrosine phosphorylation of insulin receptor substrate-1 and the subsequent insulin-like growth factor-I-induced phosphatidylinositol 3-kinase activity. These epidermal growth factor and fibroblast growth factor inhibitory effects are dependent on both phosphatidylinositol 3-kinase and protein kinase D1 signaling pathways. Specific inhibition of either phosphatidylinositol 3-kinase or protein kinase D1 totally impairs epidermal growth factor- or fibroblast growth factor-induced inhibition of insulin-like growth factor-I-stimulated insulin receptor substrate-1 tyrosine phosphorylation. The negative regulation of IRS-1 requires the coordinated action of phosphatidylinositol 3-kinase and protein kinase D1
physiological function
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insulin-like growth factor-I stimulation leads to prolonged association of phosphatidylinositol 3-kinase with insulin-like growth factor-I receptor. Phosphatidylinositol 3-kinase activity is present in this complex in thyrocytes and fibroblasts. Insulin-like growth factor-I withdrawal in mid-G1 phase impairs the association of phosphatidylinositol 3-kinase with insulin-like growth factor-I receptor and suppresses DNA synthesis the same as when phosphatidylinositol 3-kinase inhibitor is added. Residues Tyr1316-X-X-Met of insulin-like growth factor-I receptor function as a phosphatidylinositol 3-kinase binding sequence when this tyrosine is phosphorylated. In cells expressing exogenous mutant insulin-like growth factor-I receptor in which Tyr1316 is substituted with Phe, insulin-like growth factor-I stimulation induces tyrosine phosphorylation of insulin-like growth factor-I receptor and insulin receptor substrates-1/2, but mutated insulin-like growth factor-IR fails to bind phosphatidylinositol 3-kinase and to induce maximal phosphorylation of GSK3 and cell proliferation in response to insulin-like growth factor-I. Phosphatidylinositol 3-kinase activity bound to insulin-like growth factor-I receptor, which is continuously sustained by insulin-like growth factor-I stimulation, is required for insulin-like growth factor-I-induced cell proliferation
physiological function
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intracerebroventricular injection of leptin significantly increases phosphodiesterase 3B activity by twofold in the hypothalamus. Previous administration of wortmannin, a specific PI3K inhibitor, completely reverses the stimulatory effect of leptin on phosphodiesterase 3B activity in the hypothalamus. PI3K but not Akt acts as an upstream regulator of the PDE3B pathway of leptin signalling in the rat hypothalamus
physiological function
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PI3K regulates NADPH oxidase activity through modulating the recruitment of Rac-1 to plasma membrane and accelerates the process of rice seed germination
physiological function
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enzyme PI3K can modify the PI3K-related kinases (PIKKs) in response to radiation. PIKKs interact with PI3K and contribute to radioresistance in thyroid-carcinomas
physiological function
enzyme PIK3C3 plays a role, such as endocytic trafficking, in synapses
physiological function
phosphatidylinositol 3-kinase, PI3K, binds to VHA-B2 and promotes the activation of V-ATPase, resulting in vacuolar acidification and stomatal closure, thereby delaying methyl jasmonate-induced leaf senescence. PI3K is involved in the regulation of dark-induced senescence but does not function through the regulation of V-ATPase activity. PI3K regulates the activity of V-ATPase in MeJA-induced leaf senescence but not in dark-induced leaf senescence
physiological function
PI3K-III (or PIK3C3) represents the most conserved PI3K class. It is the sole PI3K in yeast and plants. The catalytic subunit of the PI3K complex is Vps34, which exclusively utilizes PtdIns as substrate. It phosphorylates PtdIns at the 3-hydoxyl group of the inositol ring in order to generate PtdIns3P. Class III phosphatidylinositol 3-kinase Vps34 (vacuolar protein sorting 34) catalyzes for the formation of the signaling lipid phosphatidylinositol-3-phopsphate, which is a central factor in the regulation of autophagy, endocytic trafficking and vesicular transport. The Vps15 kinase domain interacts with the Vps34 activation loop, which might regulate the activity of Vps34. Regulation of Vps34 function by G-protein signaling. Vps34 and Vps15 act as suppressors of Gpa1 (Galpha)-mediated transcriptional responses involved in pheromone signaling. Direct link between trimeric G-proteins and Vps34p function in yeast
physiological function
pivotal role of phosphatidylinositol 3-kinase in delaying of methyl jasmonate-induced leaf senescence. Phosphatidylinositol 3-kinase (PI3K) and its product PI3P are involved in plant development and stress responses. PI3K type III plays a vital role in the trafficking of proteins to and from vacuoles. The vacuolar acidification is regulated by the PI3K-V-ATPase pathway in the methyl jasmonate-induced leaf senescence
physiological function
Risk1 is a phosphatidylinositol 3-kinase (PI3K) and a secreted effector involved in Rickettsia typhi host cell invasion, a T4SS effector, and the first bacterial secretory kinase with both class I and III PI3K activities. The rickettsial effector phosphatidylinositol 3-kinase (PI3K) has a dual specificity for phosphoinositides. Risk1 is a phosphatidylinositol 3-kinase with class I and III activities critical for Rickettsia typhi invasion. During infection, Risk1 targets the Rab5-EEA1-phosphatidylinositol 3-phosphate [PI(3)P] signaling axis to promote bacterial phagosomal escape. binding to Rab5 requires the kinase activity of Risk1. Subsequently, Rickettsia typhi undergoes ubiquitination and induces host autophagy. Maturation to autolysosomes is subverted to support intracellular growth. Only enzymatically active Risk1 binds the Beclin-1 core complex and contributes to Rickettsia typhi-induced autophagosome formation. Risk1, with dual class I and class III PI3K activities, alters host PI metabolism and consequently subverts intracellular trafficking to facilitate intracellular growth of Rickettsia typhi. Risk1 targets endosomal trafficking and Rickettsia typhi-induced autophagy to promote intracellular growth. Risk1, via its kinase activity, contributes to a nonapoptotic cell rounding phenotype
physiological function
the Class III phosphoinositide 3-kinase Vps34 (vacuolar protein sorting 34) plays important roles in endocytic trafficking, macroautophagy, phagocytosis, cytokinesis and nutrient sensing. Vps34 acts in a complex with a probable pseudokinase, Vps15, and signals to downstream effectors through the production of phosphatidylinositol 3-phosphate (PI[3]P). This lipid supplies a binding site for proteins containing appropriate lipid-binding domains, e.g. FYVE [Fab1, YOTB, Vac1, EEA1 (early endosomal antigen 1)] and PX (Phox homology) domain. Vps34 is recruited by the binding of the WD40 domain of Vps15 to activated Rab5. Production of PI[3]P synergizes with Rab5 in the recruitment of EEA1 and Rabenosyn5 to drive endosomal tethering and fusion. Vps34-Vps15 also binds to Rab7 in late endosomess. Vps34 acts in tetrameric complexes containing Vps15, Beclin-1 and either Atg14 (Vps34 complex I) or UVRAG (Vps34 complex II). Vps34 acts by producing PI[3]P in intracellular membranes. Vps34 regulates the fusion and maturation of Rab5-positive early endosomes (EE) and their maturation into Rab7-positive late endosomes (LE). PI[3]P produced by Vps34 recruits the retromer complex, which mediates endosome to Golgi retrograde trafficking, and the ESCRT complex, which produces ILVs in multivesicular bodies (MVB). Vps34 is recruited to phagosomes after sealing to direct phagosomal maturation. It functions in the endoplasmic reticulum and in maturing autophagosomes, where it drives autophagosomal initiation and maturation. Vps34 is required for the function of the retromer complex, which drives the retrograde trafficking of endocytic cargo to the Golgi. Mechanisms of Vps34 regulation, e.g. by phosphorylation under nutrient-replete conditions or during growth factor stimulation. Vps34 can act as an upstream regulator of mTORC1 regulation
physiological function
the Class III phosphoinositide 3-kinase Vps34 (vacuolar protein sorting 34) plays important roles in endocytic trafficking, macroautophagy, phagocytosis, cytokinesis and nutrient sensing. Vps34 acts in a complex with a probable pseudokinase, Vps15, and signals to downstream effectors through the production of phosphatidylinositol 3-phosphate (PI[3]P). This lipid supplies a binding site for proteins containing appropriate lipid-binding domains, e.g. FYVE [Fab1, YOTB, Vac1, EEA1 (early endosomal antigen 1)] and PX (Phox homology) domain. Vps34 is recruited by the binding of the WD40 domain of Vps15 to activated Rab5. Production of PI[3]P synergizes with Rab5 in the recruitment of EEA1 and Rabenosyn5 to drive endosomal tethering and fusion. Vps34-Vps15 also binds to Rab7 in late endosomess. Vps34 acts in tetrameric complexes containing Vps15, Beclin-1 and either Atg14 (Vps34 complex I) or UVRAG (Vps34 complex II). Vps34 acts by producing PI[3]P in intracellular membranes. Vps34 regulates the fusion and maturation of Rab5-positive early endosomes (EE) and their maturation into Rab7-positive late endosomes (LE). PI[3]P produced by Vps34 recruits the retromer complex, which mediates endosome to Golgi retrograde trafficking, and the ESCRT complex, which produces ILVs in multivesicular bodies (MVB). Vps34 is recruited to phagosomes after sealing to direct phagosomal maturation. It functions in the endoplasmic reticulum and in maturing autophagosomes, where it drives autophagosomal initiation and maturation. Vps34 is required for the function of the Retromer complex, which drives the retrograde trafficking of endocytic cargo to the Golgi. Mechanisms of Vps34 regulation, e.g. by phosphorylation under nutrient-replete conditions or during growth factor stimulation
physiological function
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intracerebroventricular injection of leptin significantly increases phosphodiesterase 3B activity by twofold in the hypothalamus. Previous administration of wortmannin, a specific PI3K inhibitor, completely reverses the stimulatory effect of leptin on phosphodiesterase 3B activity in the hypothalamus. PI3K but not Akt acts as an upstream regulator of the PDE3B pathway of leptin signalling in the rat hypothalamus
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physiological function
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Risk1 is a phosphatidylinositol 3-kinase (PI3K) and a secreted effector involved in Rickettsia typhi host cell invasion, a T4SS effector, and the first bacterial secretory kinase with both class I and III PI3K activities. The rickettsial effector phosphatidylinositol 3-kinase (PI3K) has a dual specificity for phosphoinositides. Risk1 is a phosphatidylinositol 3-kinase with class I and III activities critical for Rickettsia typhi invasion. During infection, Risk1 targets the Rab5-EEA1-phosphatidylinositol 3-phosphate [PI(3)P] signaling axis to promote bacterial phagosomal escape. binding to Rab5 requires the kinase activity of Risk1. Subsequently, Rickettsia typhi undergoes ubiquitination and induces host autophagy. Maturation to autolysosomes is subverted to support intracellular growth. Only enzymatically active Risk1 binds the Beclin-1 core complex and contributes to Rickettsia typhi-induced autophagosome formation. Risk1, with dual class I and class III PI3K activities, alters host PI metabolism and consequently subverts intracellular trafficking to facilitate intracellular growth of Rickettsia typhi. Risk1 targets endosomal trafficking and Rickettsia typhi-induced autophagy to promote intracellular growth. Risk1, via its kinase activity, contributes to a nonapoptotic cell rounding phenotype
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physiological function
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the Trypanosoma cruzi phosphatidylinositol 3-kinase, TcVps34, is involved in osmoregulation and receptor-mediated endocytosis. TcVps34 participates in the endocytic pathway, fluid phase uptake of BSA and receptor-mediated endocytosis of transferrin. Multiple roles for TcVps34, schematic overview
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physiological function
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Risk1 is a phosphatidylinositol 3-kinase (PI3K) and a secreted effector involved in Rickettsia typhi host cell invasion, a T4SS effector, and the first bacterial secretory kinase with both class I and III PI3K activities. The rickettsial effector phosphatidylinositol 3-kinase (PI3K) has a dual specificity for phosphoinositides. Risk1 is a phosphatidylinositol 3-kinase with class I and III activities critical for Rickettsia typhi invasion. During infection, Risk1 targets the Rab5-EEA1-phosphatidylinositol 3-phosphate [PI(3)P] signaling axis to promote bacterial phagosomal escape. binding to Rab5 requires the kinase activity of Risk1. Subsequently, Rickettsia typhi undergoes ubiquitination and induces host autophagy. Maturation to autolysosomes is subverted to support intracellular growth. Only enzymatically active Risk1 binds the Beclin-1 core complex and contributes to Rickettsia typhi-induced autophagosome formation. Risk1, with dual class I and class III PI3K activities, alters host PI metabolism and consequently subverts intracellular trafficking to facilitate intracellular growth of Rickettsia typhi. Risk1 targets endosomal trafficking and Rickettsia typhi-induced autophagy to promote intracellular growth. Risk1, via its kinase activity, contributes to a nonapoptotic cell rounding phenotype
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physiological function
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PI3K isozymes play selective roles in ischemic preconditioning, a potent cellular protective mechanism whereby brief periods of sublethal ischemia protect the myocardium from prolonged ischemia-induced injury, overview
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physiological function
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PI3K is involved in LPS-induced signaling in glial cells inducing the lipopolysaccharide-stimulated expression of adhesion molecule L1, CHL1. PI3K/PKCdelta-mediated nuclear translocation of NF-kappaB
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additional information
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hyperactivation of the PI3K/AKT/mTOR signaling pathway is common in cancer, and PI3K and mTOR act synergistically in promoting tumor growth, survival, and resistance to chemotherapy
additional information
domain organization of yeast Vps30, Atg14 and Vps38, structures of Complex I and II, crystal structure analysis of yeast Vps34 Complex II, overview
additional information
in yeast and mammals, Vps34 homologues are found in at least two distinct PI 3-kinase complexes. The Vps34 complex I, consisting of Vps34, Vps15, autophagy-related 6 (Atg6)/Vps30, and Atg14, regulates an early step of autophagy at the site of autophagosome formation, whereas the Vps34 complex II containing Vps34, Vps15, Atg6/ Vps30, and Vps38 (or UVRAG in mammals) is involved in vacuolar protein sorting and localized to the endosome
additional information
the major domains of Vps34 are found in all PI3Ks, and include a C2 domain, a helical domain and a kinase domain. Vps15 contains an N-terminally myristoylated kinase-like domain, a helical domain containing a series of internal HEAT [huntingtin, elongation factor 3, the PR65/A subunit of protein phosphatase 2A and TOR (target of rapamycin)] repeats and a C-terminal WD40 domain that forms a beta-propeller structure. The kinase domain has an atypical ATP-binding site. Domain organization of mammalian Vps34, Vps15, Beclin-1, Atg14 and UVRAG, structures of Complex I and II, cryo-EM structure of human Vps34 Complex I, overview