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evolution
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in vertebrates, PtdIns4P is synthesized by four distinct PI4K enzymes that belong to either the type-II or type-III family, each having alpha- and beta-forms. The type-III PI4Ks are relatives of the PI 3-kinase family, while the smaller type-II enzymes form a separate family
malfunction
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depletion of PI4KIIalpha by siRNA-mediated knockdown reduces Wnt5a-triggered uptake and/or sorting of Fz4-eGFP into EEA1-positive endosomes. This effect is fully rescued by re-expression of siRNA-resistant PI4KIIalpha
malfunction
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depletion of PIK1 results in a subsequent loss of intracellular 1-phosphatidyl-1D-myo-inositol 4-phosphate, and loss of Pik1 induces elongated growth, because knockdown of PIK1 results in the constitutive activation of Kss1, which subsequently drives elongated growth
malfunction
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hepatitis C virus, by recruiting PI4KIIIa in the RNA replication complex, hijacks phosphatidylinositol-4 phosphate metabolism, ultimately resulting in a markedly altered subcellular distribution of the PI4KIIIalpha product. Antiviral effect of 4-anilino quinazoline compounds is mediated by the inhibition of PI4KIIIalpha and the consequent depletion of 1-phosphatidyl-1D-myo-inositol 4-phosphate required for the HCV membranous web. Inhibition of PI4KIIIalpha by AL-9 induces the formation of large viral NS5A protein clusters
malfunction
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in PI4KII mutants, mucin-containing glue granules fail to reach normal size, with glue protein aberrantly accumulating in enlarged Rab7-positive late endosomes. PI4KIIDELTA mutants reveal small glue granules of grossly normal morphology, PI4KIIDELTA cells also exhibited large vacuolated structures not observed in wild-type, phenotype, overview. Retromer localization and dynamics are altered in PI4KIIDELTA mutants
malfunction
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Inhibitors of phosphatidylinositol 4-phosphate synthesis or depletion of PI4KIIIalpha, a phosphatidylinositol 4-kinase localized to the endoplasmic reticulum and Golgi, prevents the recruitment of GBF1 to Golgi membranes
malfunction
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knockdown of isozyme phosphatidylinositol 4-kinase IIIbeta inhibits SARS-CoV S-mediated entry into VeroE6 cells
malfunction
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mitophagy is defective in the absence of Pik1 activity, and Atg9 and Atg27 trafficking is defective in the pik1 mutant. Because Pik1 functions at the late Golgi, the defect in Atg93GFP localization to the phagophore assembly site reflects accumulation of this protein in the trans-Golgi network
malfunction
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phosphatidic acid resulting from the phosphoinositide-dependent phospholipase C pathway is significantly lowered in a pi4kIIIbeta1beta2 double mutant exposed to cold stress, phenotype, overview. The root growth in the double mutant is 5fold reduced at 12°C
malfunction
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PI4KIIalpha knockdown causes enlarged LAMP-1-positive endosomal structures in fixed cells. Acute depletion of phosphatidylinositol 4-phosphate in the Golgi causes accumulation of LIMP-2 in this compartment, and PI4KIIIbeta is responsible for controlling the exit of LIMP-2 from the Golgi. In contrast, depletion of PI4KIIalpha blocks trafficking at a post-Golgi compartment, leading to accumulation of LIMP-2 in enlarged endosomal vesicles. PI4KIIalpha depletion also causes secretion of missorted GBA into the medium, which is attenuated by limiting LIMP-2/GBA exit from the Golgi by PI4KIIIbeta inhibitors, overview
malfunction
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silencing of isozyme PI4KIIIbeta, but not ofisozyme PI4KIIIa strongly inhibits SARS CoV spike-mediated entry
malfunction
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silencing of the PI 4-kinase PI4KA leads to abberrant membranous web morphology, and PI4KB silencing inhibits HCV infection, overview. PI4KA silencing-induced membrane clustering depends on HCV polyprotein cleavage but does not require integrity of the endoplasmic reticulum-Golgi secretory pathway
malfunction
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siRNAs that reduce PI4KA accumulation appear to perturb membranous web formation. Cell viral polyprotein expression results in enhanced cytoplasmic phosphatidylinositol 4-phosphate production. Increased phosphatidylinositol 4-phosphate accumulation following hepatitis C virus protein expression is precluded by silencing the expression of isozyme PI4KA, but not the related isozyme PI4KB. Silencing PI4KA also results in aberrant agglomeration of viral replicase proteins, including NS5A, NS5B, and NS3. NS5A alone, but not other viral proteins, stimulates phosphatidylinositol 4-phosphate production in vivo and enhanced PI4KA kinase activity in vitro
malfunction
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an enzyme-deficient mutant displays defects in vegetative growth, deoxynivalenol production and pathogenicity. Furthermore, the deletion mutant also exhibits increased resistance to osmotic (NaCl, KCl and sorbitol), oxidative (H2O2) and cell wall (Congo Red and SDS) stresses
malfunction
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an enzyme-deficient mutant presents serrated leaves, which is resulted from the accelerated cell division and increased auxin concentration at serration tips
malfunction
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downregulation of enzyme expression negatively affects chilli leaf curl virus pathogenesis in Nicotiana benthamiana
malfunction
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enzyme knockdown of isoform PI4KIIalpha -but not PI4KIIbeta - impairs toll-interleukin 1 receptor domain-containing adaptor protein and toll-like receptor 4 localization to phagosomes, reduces proinflammatory cytokine secretion, abolishes phagosomal tubule formation, and impairs major histocompatibility complex II presentation
malfunction
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loss of the PI4K2B allele and underexpression of isoform PI4KIIbeta mRNA are associated with human cancers. Depletion of isoform PI4KIIbeta is sufficient to confer an aggressive invasive phenotype on minimally invasive HeLa and MCF-7 cell lines. Loss of isoform PI4KIIbeta induces the formation of invadopodia and leads to increased exocytic trafficking of membrane type I matrix metalloproteinase
malfunction
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the pi4kbeta1beta2 double mutant constitutively accumulates a high salicylic acid level via isochorismate synthase 1/SID2 and this has considerable impact on other hormone levels and is associated with an increased resistance to several plant pathogens (P. syringae, H. arabidopsidis, Botrytis cinerea)
malfunction
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mitophagy is defective in the absence of Pik1 activity, and Atg9 and Atg27 trafficking is defective in the pik1 mutant. Because Pik1 functions at the late Golgi, the defect in Atg93GFP localization to the phagophore assembly site reflects accumulation of this protein in the trans-Golgi network
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malfunction
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an enzyme-deficient mutant displays defects in vegetative growth, deoxynivalenol production and pathogenicity. Furthermore, the deletion mutant also exhibits increased resistance to osmotic (NaCl, KCl and sorbitol), oxidative (H2O2) and cell wall (Congo Red and SDS) stresses
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metabolism
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alterations to phosphatidylinositol 4-kinase expression levels can modulate MAP kinase and Akt signalling, and are important for chemoresistance, tumour angiogenesis and the suppression of apoptosis and metastases
metabolism
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formation of PI4KII-containing endosomal tubules is independent of retromer or AP-3 function, but retromer dynamics at LEs depends on PI4KII
metabolism
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regulation of the Golgi system and 1-phosphatidyl-1D-myo-inositol 4-phosphate levels involving the enzyme, overview
metabolism
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regulation of the Golgi system and 1-phosphatidyl-1D-myo-inositol 4-phosphate levels involving the enzyme, overview
metabolism
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the enzyme catalyzes the first step in generating the phosphoinositides hydrolyzed by phosphoinositide-dependent phospholipase C, EC 3.1.4.11, that produces diacylglycerol which can be phosphorylated to phosphatidic acid. Type-III PIK activity is upstream of the phosphoinositide-dependent phospholipase C activity
metabolism
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the enzyme interacts with hepatitis C virus nonstructural protein 5A
metabolism
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the enzyme interacts with peroxiredoxin-1, Nedd4-1, and vesicle-mediated transport proteins such as clathrin heavy chain and the pallidin subunit of BLOC-1
physiological function
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Arabidopsis thaliana type-III phosphatidylinositol 4-kinases beta1 and beta2 are upstream of the phospholipase C pathway triggered by cold exposure, overview. De novo synthesis of 1-phosphatidyl-1D-myo-inositol 4-phosphate by PI4Ks occurs in parallel to phosphoinositide-dependent phospholipase C activation
physiological function
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distinct phosphatidylinositol 4-kinases play important roles at multiple steps in the trafficking pathway of the LIMP-2/GBA complex. The phosphatidylinositol 4-kinases control lysosomal delivery of the Gaucher disease enzyme, beta-glucocerebrosidase, overview. Catalytic activity of PI4KIIIbeta in Golgi exit of the LIMP-2/GBA complex, which is followed by PI4KIIalpha-mediated trafficking to lysosomes. PI4KIalpha is involved in post-Golgi trafficking of LIMP-2 along the degradative pathway
physiological function
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isozyme phosphatidylinositol 4-kinase IIIbeta is required for severe acute respiratory syndrome coronavirus spike-mediated cell entry, overview
physiological function
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isozyme phosphatidylinositol 4-kinase IIIbeta is required for severe acute respiratory syndrome coronavirus spike-mediated cell entry. PI4P plays an essential role in SARS-CoV spike-mediated entry, which is regulated by the PI4P lipid microenvironment, overview
physiological function
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isozyme PI4KA plays an essential role in hepatitis C virus membranous webs formation and colocalizes with the hepatitis C virus membranous webs, which show phosphatidylinositol 4-phosphate enrichment, while isozyme PI4KB supports the HCV life cycle but does not localize to or generate phosphatidylinositol 4-phosphate at membranous webs
physiological function
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key role of isozyme PI4KIIalpha in TGN/endosomal membrane traffic, isozyme PI4KIIalpha regulates Wnt signalling, endosomal sorting of signalling receptors, and promotes adaptor protein recruitment to endosomes and the trans-Golgi network. E3 ubiquitin ligase Itch is a binding partner and regulator of PI4KIIa function. Itch directly associates with and ubiquitinates PI4KIIalpha, and both proteins co-localize on endosomes containing Wnt-activated frizzled 4 receptor. Itch and PI4KIIalpha reciprocally regulate each other
physiological function
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phosphatidylinositol 4-kinase IIalpha is required for oxysterol binding protein-dependent activation of sphingomyelin synthesis in the Golgi apparatus, overview
physiological function
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phosphatidylinositol 4-kinase IIalpha is required for oxysterol binding protein-dependent activation of sphingomyelin synthesis in the Golgi apparatus, overview
physiological function
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phosphatidylinositol 4-kinases regulate vesicle mediate export from the Golgi apparatus via phosphatidylinositol 4-phosphate binding effector proteins that control vesicle budding reactions and regulate membrane dynamics. Function of phosphatidylinositol 4-phosphate at the Golgi Membrane biogenesis and lipid homeostasis
physiological function
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phosphatidylinositol 4-kinases regulate vesicle mediate export from the Golgi apparatus via phosphatidylinositol 4-phosphate binding effector proteins that control vesicle budding reactions and regulate membrane dynamics. Function of phosphatidylinositol 4-phosphate at the Golgi Membrane biogenesis and lipid homeostasis
physiological function
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phosphatidylinositol 4-phosphate is a key regulator of membrane trafficking. Specific requirement for PI4KII emerged in larval salivary glands. In the Golgi, PI4KII is required for sorting of glue granule cargo and the granule-associated SNARE Snap24. In endosomes, it is required for normal retromer dynamics and for formation of tubular endosomes that are likely to be involved in retrieving Snap24 and lysosomal enzyme receptor protein from late endosomes to the trans-Golgi network. PI4KII in flies thus reveals a role for PI4KII in regulating the fidelity of granule protein trafficking in secretory tissues, PI4KII catalytic activity is required for granule biogenesis and normal endosome size, overview
physiological function
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phosphatidylinositol 4-phosphate, synthesized by phosphatidylinositol 4-kinase isozyme PI4KIIIalpha, is required for recruitment of the guanine nucleotide exchange factor GBF1 to Golgi membranes, where it is bound and activates Arf1. Activated Arf1 is required for formation of trafficking vesicles in the Golgi apparatus, overview. Rab1 contributes to the specificity and timing of GBF1 recruitment by activating PI4KIIIalpha
physiological function
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PI4KIIalpha recruits clathrin adaptors AP1, AP3 and GGAs to the trans-Golgi network, and controls fate of endocytic vesicles, PI4KIIalpha promotes EGF receptor degradation, and supports Wnt signaling. PI4KIIIbeta regulates exit of certain cargos from the Golgi, and supports CERT-mediated ceramide transport to the trans-Golgi. PI4KIIIalpha supplies PtdIns(4,5)P2 for the plasma membrane and regulates the endoplasmic reticulum exit. Phosphatidylinositide 4-phosphate lipids are involved in viral replications. They can be used as replication platforms in the host membranes that are hijacked by RNA viruses including the endoplasmic reticulum, Golgi apparatus, trans-Golgi network, endosomes, plasma membrane and mitochondrial outer membrane. Viral replication machinery is assembled on these platforms as a supramolecular complex and PtdIns4P lipids regulate viral RNA synthesis, detailed overview. Throughout infection, the viral replication membrane platforms contain high levels of the host enzyme phosphatidylinositol 4-kinase IIIbeta, PI4KIIIbeta, that generates PtdIns4P at these membranes. PI4KIIIbeta or PI4KIIIalpha, independently from making PtdIns4P lipids, can also serve as scaffolds to recruit other host proteins to the replication platform
physiological function
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PI4KIIIalpha is a host factor for hepatitis C virus. Isozyme PI4KIIIbet is involved in the entry of SARS coronavirus. PI4KIIIbeta is not required for virus binding and internalization, but plays a role at, or before, virus fusion with the late endosomes. Modes of recruitment of PI4KIIIs to the replication complexes of hepattis C virus, enteroviruses, and the Aichi virus, overview
physiological function
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PI4KIIIalpha is responsible for the phosphatidylinositol-4 phosphate pool present in the plasma membrane. Antiviral effect of 4-anilino quinazoline compounds is mediated by the inhibition of PI4KIIIalpha and the consequent depletion of 1-phosphatidyl-1D-myo-inositol 4-phosphate required for the HCV membranous web
physiological function
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PI4KIIIbeta localised to the Golgi complex through GTP-bound Arf1 binding, can be activated by protein kinase D phosphorylation, and also through interactions with neuronal calcium sensor 1. 1-Phosphatidyl-1D-myo-inositol 4-phosphate PI4P is an essential phospholipid substrate for two phosphoinositide-dependent signalling pathways that control cell migration and proliferation. It induces expression of Girdin in several cancers, and its translocation to the plasma membrane where it activates heterotrimeric Gai proteins to stimulate PI(3,4,5)P3 synthesis by PI 3-kinase, overview. The enzyme shows a potential role for a plasma membrane pool of PI4P in regulating Girdin targeting and EGFR signalling. PI4KIIIa may have an underappreciated function in the constitutive chemoresistance of cancers which are recalcitrant to apoptotic induction. PI4KIIbeta isoform migh exhibit an anti-metastatic role in hepatocellular carcinoma
physiological function
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Pik1, a phosphatidylinositol 4-kinase that localizes primarily to the Golgi, is required for proper pheromone signaling acting independently of Ste5, overview. It also regulates MAP kinase specificity but does so independently of Ste5. Pik1 is required for full activation of the MAP kinases Fus3 and Hog1 and represses activation of Kss1. Pik1 likely regulates Ste11 and Ste50, components shared by all three MAP kinase pathways, through their interaction with the scaffold protein Opy2. Pik1 acts as a regulator of signaling specificity functioning at endomembranes rather than at the plasma membrane. Pik1 is required for full Fus3 activation and inhibits Kss1 activation. Pik1 acts via Ste11 or a pathway component downstream of Ste11, overview
physiological function
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PtdIns 4-kinase Pik1 is involved in Atg9 trafficking through the Golgi and is involved in both nonselective and selective types of autophagy, overview. The Golgi-localized Pik1 is essential for secretory vesicle exit from the trans-Golgi network. The plasma membrane-localized Stt4 is involved in the Slt2 MAP kinase cascade and is required for autophagy. Isozymes Pik1 and Stt4 are responsible for the synthesis of the majority of cellular PtdIns4P, while isozyme Lsb6 is not essential
physiological function
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Stt4p supplies PtdIns(4,5)P2 for the plasma membrane, regulates Pkc1 pathways and sphingolipid synthesis, and is required for cell wall integrity, Stt4p controls mitotic checkpoints. Pik1p is essentially required for late Golgi to plasma membrane secretion, and involved in cytokinesis and translation.Lsb6p can partially reverse Stt4p but not Pik1p defects, and regulates actin binding and movements of endosomes. Phosphatidylinositide 4-phosphate lipids are involved in viral replications. They can be used as replication platforms in the host membranes that are hijacked by RNA viruses including the endoplasmic reticulum, Golgi apparatus, trans-Golgi network, endosomes, plasma membrane and mitochondrial outer membrane. Viral replication machinery is assembled on these platforms as a supramolecular complex and PtdIns4P lipids regulate viral RNA synthesis, detailed overview. Throughout infection, the viral replication membrane platforms contain high levels of the host enzyme Pik1p, that generates PtdIns4P at these membranes
physiological function
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whereas the palmitoylated membrane-bound pool is catalytically active, the cytosolic kinase is inactive
physiological function
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isoform PI4Kgamma3 is essential for salt stress tolerance, necessary for reinforcement of plant response to abiotic stresses and delay of the floral transition. Isoform PI4Kgamma3 is activated by DNA demethylation and regulates the reactive oxygen species accumulation induced by high salt or abscisic acid treatment
physiological function
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the enzyme is associated with actin cytoskeleton and cell adhesion, required for CD3 receptor induced calcium release, and a key component in early T cell activation signaling cascades
physiological function
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isoform PI4Kgamma5 interacts with ANAC078 to negatively regulate auxin synthesis and hence influences cell proliferation and leaf development
physiological function
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isoform PI4KIIalpha is an essential regulator of phagosomal toll-like receptor signaling in dendritic cells by ensuring optimal toll-interleukin 1 receptor domain-containing adaptor protein recruitment to phagosomes
physiological function
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isoform PI4KIIbeta synthesizes a pool of 1-phosphatidyl-1D-myo-inositol 4-phosphate that maintains membrane type I matrix metalloproteinase traffic in the degradative pathway and suppresses the formation of invadopodia
physiological function
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the enzyme is a susceptible factor, which is required by chilli leaf curl virus for pathogenesis
physiological function
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the enzyme plays an important role for in the CO2 signal transduction pathway, that mediates PATROL1 dynamics
physiological function
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the enzyme plays an important role in endocytosis and is involved in the pathogenicity of Fusarium graminearum. The enzyme contributes significantly to the production of deoxynivalenol and phosphatidylinositol 4-phosphate on endosomes
physiological function
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PtdIns 4-kinase Pik1 is involved in Atg9 trafficking through the Golgi and is involved in both nonselective and selective types of autophagy, overview. The Golgi-localized Pik1 is essential for secretory vesicle exit from the trans-Golgi network. The plasma membrane-localized Stt4 is involved in the Slt2 MAP kinase cascade and is required for autophagy. Isozymes Pik1 and Stt4 are responsible for the synthesis of the majority of cellular PtdIns4P, while isozyme Lsb6 is not essential
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physiological function
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the enzyme plays an important role in endocytosis and is involved in the pathogenicity of Fusarium graminearum. The enzyme contributes significantly to the production of deoxynivalenol and phosphatidylinositol 4-phosphate on endosomes
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additional information
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hepatitis C virus stimulates the phosphatidylinositol 4-kinase III alpha-dependent phosphatidylinositol 4-phosphate production that is essential for its replication, overview. PI4KA is also implicated in HCV replication complex formation
additional information
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molecular chaperone Hsp90 is a binding partner of isozyme PI4KIIbeta, PI4KIIbeta contains an Hsp90 interaction site, which most likely resides in the N-terminal lobe of the catalytic domain. PI4KIIbeta must bind to Hsp90 and is highly sensitive to its release, perhaps because a substantial portion of this isoform is cytosolic. Hsp90 selectively stabilizes the cytosolic pool of PI4KIIbeta.. Hsp90 protects PI4KIIbeta from degradation by the proteasome. Geldanamycin, a specific Hsp90 inhibitor, disrupts the Hsp90-PI4KIIbeta interaction and destabilizes PI4KIIbeta, reducing its half-life by 40% and increasing its susceptibility to ubiquitylation and proteasomal degradation. Cytosolic PI4KIIbeta is much more sensitive to geldanamycin treatment than is the integrally membrane-associated species. Stimuli such as PDGF receptor activation that also induce recruitment of the kinase to membranes disrupt the Hsp90-PI4KIIbeta interaction to a similar extent as inhibitor treatment. Dissociation of PI4KIIbeta from Hsp90 by exposure to geldanamycin results in transient translocation to membranes and increased kinase activity
additional information
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molecular chaperone Hsp90 is no binding partner of isozyme PI4KIIalpha, although also PI4KIIalpha contains an Hsp90 interaction site, which most likely resides in the N-terminal lobe of the catalytic domain, but PI4KIIalpha apparently does not require stabilization by Hsp90 binding because it associates strongly with membranes, even in the absence of palmitoylation
additional information
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nuclear accumulation of Pik1 is promoted by nutrient, e.g. glucose, deprivation, a condition that also results in the release of PI4K effectors from Golgi membranes and slowing of the rate of secretion
additional information
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PI4KA interacts with viral protein NS5A in hepatitis C virus-infected cells