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evolution
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in Dictyostelium discoideum, the IP7 target Ser is conserved, but the neighboring Asp and Glu residues are replaced with Thr. These Thr residues may undergo phosphorylation to mimic Asp/Glu and create a consensus site for diphosphorylation
evolution
IP6Ks are members of a wider inositol phosphate kinase family (Pfam PF03770) that includes IPMKs and IP3Ks. These enzymes all share a PxxxDxKxG, PDKG, catalytic motif. Phylogenetic analysis indivates that this kinase family arose from a primordial IP6K precursor
evolution
the absence of diphosphorylation in the IC(1-70)fragment suggests that the Ser-Pro cluster (residues 71-111) is required to facilitate pyrophosphorylation on Ser51. The site of diphosphorylation in mouse IC-2C is well conserved in human and rat, suggesting that the effect of IP7 on dynein is likely to be conserved in these species
evolution
the absence of diphosphorylation in the IC(1-70)fragment suggests that the Ser-Pro cluster (residues 71-111) is required to facilitate pyrophosphorylation on Ser51. The site of diphosphorylation in mouse IC-2C is well conserved in human and rat, suggesting that the effect of IP7 on dynein is likely to be conserved in these species
evolution
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the absence of diphosphorylation in the IC(1-70)fragment suggests that the Ser-Pro cluster (residues 71-111) is required to facilitate pyrophosphorylation on Ser51. The site of diphosphorylation in mouse IC-2C is well conserved in human and rat, suggesting that the effect of IP7 on dynein is likely to be conserved in these species
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malfunction
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cells lacking isoform IP6K1 arrest after genotoxic stress, and markers associated with DNA repair are recruited to DNAdamage sites indicating that homologous recombination repair is initiated in these cells. However, repair does not proceed to completion. Enzyme loss increases chromosomal damage susceptibility
malfunction
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deletion of isoform IP6K2 prevents the apoptotic actions of interferon beta and gamma-irradiation and cisplatin in different cancer cell lines
malfunction
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gene disruption of isoform IP6K2 in colorectal cancer cells selectively impairs p53-mediated apoptosis, instead favoring cell-cycle arrest
malfunction
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glycogen synthase kinase 3 activity is inhibited in the brains of IP6K1-deleted mice. Enzyme deletion disrupts social behavior
malfunction
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isoform InsP6K1 disruption augments phosphatidylinositol-(3,4,5)-trisphosphate signaling and enhances superoxide production in neutrophils
malfunction
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isoform InsP6K1 disruption augments phosphatidylinositol-(3,4,5)-trisphosphate signaling and enhances superoxide production in neutrophils
malfunction
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isoform IP6K2 depletion inhibits Hh target gene expression. Inhibiting enzyme activity results in altered Hedgehog signal transduction. Isoform IP6K2 knockdown alters craniofacial and somite structures and inhibits the development and migration of neural crest cells
malfunction
analysis of the impact of siRNA-mediated knockdown of the two more abundant IP6Ks on Runx2 transcriptional activity. Knockdown of IP6K1 inhibits the FGF2-induced Runx2 activity, both basally and in response to Cx43 overexpression, more potently than knockdown of IP6K2. Knockdown of expression and/or inhibition of function of phospholipase Cgamma1, inositol polyphosphate multikinase, which generates inositol 1,3,4,5-tetrakisphosphate (InsP4) and InsP5, and inositol hexakisphosphate kinase 1/2, which generates inositol pyrophosphates, prevented the ability of Cx43 to potentiate FGF2 induced signaling through Runx2. Overexpression of phospholipase Cgamma1 and inositol hexakisphosphate kinase 1/2 enhances FGF2 activation of Runx2 and the effect of Cx43 overexpression on this response. Enzyme inhibition by TNP abolishes the basal and Cx43-potentiated Runx2 activity in response to FGF2 treatment relative to DMSO treated controls
malfunction
analysis of the impact of siRNA-mediated knockdown of the two more abundant IP6Ks on Runx2 transcriptional activity. Knockdown of IP6K1 inhibits the FGF2-induced Runx2 activity, both basally and in response to Cx43 overexpression, more potently than knockdown of IP6K2Knockdown of expression and/or inhibition of function of phospholipase Cgamma1, inositol polyphosphate multikinase, which generates inositol 1,3,4,5-tetrakisphosphate (InsP4) and InsP5, and inositol hexakisphosphate kinase 1/2, which generates inositol pyrophosphates, prevented the ability of Cx43 to potentiate FGF2 induced signaling through Runx2. Overexpression of phospholipase Cgamma1 and inositol hexakisphosphate kinase 1/2 enhances FGF2 activation of Runx2 and the effect of Cx43 overexpression on this response. Enzyme inhibition by TNP abolishes the basal and Cx43-potentiated Runx2 activity in response to FGF2 treatment relative to DMSO treated controls
malfunction
deletion of inositol hexakisphosphate kinase-1 (IP6K1) protects mice from high fat diet induced obesity and insulin resistance in mice. IP6K1-KO mice are lean due to enhanced energy expenditure. IP6K1-KO mice display enhanced basal lipolysis. IP6K1 modulates lipolysis via its interaction with the lipolytic regulator protein perilipin1 (PLIN1)
malfunction
deletion of KCS1, which blocks synthesis of inositol diphosphates on the 5-hydroxyl of the inositol ring, causes inositol auxotrophy and decreased intracellular inositol and phosphatidylinositol levels. These defects are caused by a profound decrease in transcription of INO1, which encodes myo-inositol-3-phosphate synthase. Expression of genes that function in glycolysis, transcription, and protein processing is not affected in kcs1DELTA. Deletion of OPI1, the INO1 transcription repressor, does not fully rescue INO1 expression in kcs1DELTA. Decreased inositol biosynthesis in kcs1DELTA is due to downregulation of INO1 transcription, but decreased inositol biosynthesis in kcs1DELTA is not because of perturbation of the UASINO regulatory complex Opi1-Ino2-Ino4, overview
malfunction
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endosomes derived from slime mold lacking inositol diphosphates display reduced dynein-directed microtubule transport. Intermediate chain recruitment to membranes is reduced in cells lacking IP6K1
malfunction
enzyme deletion reduces cell migration and invasion, conferring protection from aerodigestive tract carcinoma
malfunction
expressing either catalytically inactive or substrate specificity-altered variants of AtIPK2beta cannot rescue the male gametophyte and embryogenesis defects of the atipk2alpha/atipk2beta double mutant. The mutation of AtIPK2alpha and AtIPK2beta results in severely reduced transmission of male gametophyte as a result of abnormal pollen development and defective pollen tube guidance. Overexpression or reduction of the expression of AtIPK2alpha and AtIPK2beta reveal their roles in auxiliary shoot branching, abiotic stress responses and root growth. Phenotype, detailed overview
malfunction
iInositol synthesis is up-regulated in IP6K1 knockout MEF cells. Ip6k1 ablation leads to profound changes in DNA methylation and expression of Isyna1 (designated mIno1), which encodes the rate-limiting enzyme inositol-3-phosphate synthase. Expression of Q3DELTA, which lacks both the HOPA domain and the catalytic motif, leads to increased mIno1 mRNA levels in IP6K1-KO cells. In the mIno1 promoter region, most of the CpG sites exhibit a similar, but slightly decreased, pattern of methylation in IP6K1 knockout cells compared with wild-type cells. The CpG sites between the first and second ATGs exhibit markedly less methylation in IP6K1 knockout cells. Deletion of the Q4 domain of the enzyme results in increased mIno1 expression
malfunction
IP6K3 knock-out cerebella manifest abnormalities in Purkinje cell structure and synapse number, and the mutant mice display deficits in motor learning and coordination. Diminished cerebellar synapses in IP6K3 mutants
malfunction
knockdown of expression and/or inhibition of function of phospholipase Cgamma1, inositol polyphosphate multikinase, which generates inositol 1,3,4,5-tetrakisphosphate (InsP4) and InsP5, and inositol hexakisphosphate kinase 1/2, which generates inositol pyrophosphates, prevented the ability of Cx43 to potentiate FGF2 induced signaling through Runx2. Overexpression of phospholipase Cgamma1 and inositol hexakisphosphate kinase 1/2 enhances FGF2 activation of Runx2 and the effect of Cx43 overexpression on this response. Enzyme inhibition by TNP abolishes the basal and Cx43-potentiated Runx2 activity in response to FGF2 treatment relative to DMSO treated controls
malfunction
mammalian cells lacking IP6K1 display defects in dynein-dependent trafficking pathways, including endosomal sorting, vesicle movement, and Golgi maintenance. Expression of catalytically active but not inactive IP6K1 reverses the defects. Intermediate chain recruitment to membranes is reduced in cells lacking IP6K1
malfunction
mammalian cells lacking IP6K1 display defects in dynein-dependent trafficking pathways, including endosomal sorting, vesicle movement, and Golgi maintenance. Expression of catalytically active but not inactive IP6K1 reverses the defects. Intermediate chain recruitment to membranes is reduced in cells lacking IP6K1. Decreased Tfn distribution in the ERC in Ip6k1-/- MEFs might be due to a delay in Tfn trafficking from endosomes. Tfn is held back in early endosomes in cells lacking IP6K1
malfunction
selective inhibition of inositol hexakisphosphate kinase enhances mesenchymal stem cell engraftment and improves therapeutic efficacy for myocardial infarction. IP6K inhibition may increase Akt activation in mesenchymal stem cells, resulting in enhanced cardiac protective effect after transplantation. Inhibiting IP6Ks by N2-(3-trifluorobenzyl)-N6-(4-nitrobenzyl)purine decreases 5-diphosphoinositol pentakisphosphate synthesis and increases phosphorylation of Akt at T308 and S473 in mesenchymal stem cells, indicating the downregulation of 5-diphosphoinositol pentakisphosphate expression by IP6K inhibition enhances the activation of Akt in mesenchymal stem cells. IP6K inhibition by N2-(3-trifluorobenzyl)-N6-(4-nitrobenzyl)purine is also associated with decreased apoptosis
malfunction
significant reduction in platelet polyP levels in enzyme-deficient Ip6k1-/- mice, along with slower platelet aggregation and lengthened plasma clotting time. Incorporation of polyP into fibrin clots is reduced in Ip6k1-/- mice, thereby altering clot ultrastructure, which is rescued on the addition of exogenous polyP. In vivo assays reveal longer tail bleeding time and resistance to thromboembolism in Ip6k1-/- mice. No alteration in P-selectin surface expression in Ip6k1-/- platelets implies that IP6K1 does not influence platelet alpha-granule content or its thrombin-stimulated release No difference in the extent of fibrinogen binding to activated wild-type or Ip6k1-/- platelets, and no difference in serotonin content. Knockout Ip6k1-/- mice show altered clot homogeneity and architecture and a significant increase in the number of fibers per unit length in Ip6k1-/- derived clots compared to wild-type. Hemostasis defects in Ip6k1-/- mice, overview
malfunction
the UV-induced CRL4-mediated CDT1 degradation is substantially more rapid in IP6K1-deleted murine embryonic fibroblasts, MEFs, indicating enhanced CRL4 activity in the absence of IP6K1. CRL4-CSN binding is stimulated more by kinase-dead than wild-type IP6K1. IP6K1 knockdown greatly diminishes CRL4-CSN binding, an effect rescued by expressing shRNA-resistant mouse IP6K1 in IP6K1 knockdown cells. IP6K1 depletion augments Cul4A neddylation. The binding of substrate receptor DDB2 to Cul4A is diminished upon IP6K1 depletion
malfunction
deletion of inositol hexakisphosphate kinase 1 ( IP6K1) alters probability of presynaptic vesicle release and short-term facilitation of glutamatergic synapses in mouse hippocampus. IP6K1-knockout mice exhibit decreased prepulse inhibition with no defects in Y-maze and elevated plus maze tests. IP6K1 knockout leads to impaired shortterm memory formation in a contextual fear memory retrieval test with no effect on long-term memory. Both hippocampal long-term potentiation and long-term depression in IP6K1-knockout mice are similar to those in the wild-type control
malfunction
deletion of inositol hexakisphosphate kinase 3 (IP6K3) causes defects in cell motility and neuronal dendritic growth, eventually leading to brain malformations
malfunction
deletion of inositol hexakisphosphate kinase 3 (IP6K3) causes defects in cell motility and neuronal dendritic growth, eventually leading to brain malformations
malfunction
deletion of IP6K2 in male/female mice elicits substantial defects in synaptic influences of granule cells upon Purkinje cells as well as notable impairment of locomotor function. The disruption of IP6K2- 4.1N interactions impairs cell viability
malfunction
IP6K1 deletion leads to brain malformation and abnormalities of neuronal migration. IP6K1 deletion disrupts intracellular localization and function of alpha-actinin. The IP6K1 deleted cells display substantial decreases of stress fiber formation and impaired cell migration and spreading. Focal adhesion kinase phosphorylation is substantially decreased in IP6K1 deleted cells
malfunction
IP6K1/2-knockout cells have nondetectable levels of the IP6-derived 5-diphosphoinositol pentakisphosphate and bisdiphosphoinositol tetrakisphosphate and also exhibit reduced synthesis of the 5-diphosphoinositol pentakisphosphate-derived diphosphoinositol tetrakisphosphate. Knockout cells contain increased amounts of ATP, and elevated levels of free intracellular phosphate. Phosphate import and export of phosphate are decreased in the knockout cells
malfunction
Ip6k3-/- mice demonstrate lower blood glucose, reduced circulating insulin, deceased fat mass, lower body weight, increased plasma lactate, enhanced glucose tolerance, lower glucose during an insulin tolerance test, and reduced muscle Pdk4 expression under normal diet conditions. Ip6k3 deletion extends animal lifespan with concomitant reduced phosphorylation of S6 ribosomal protein in the heart. In contrast, Ip6k3-/- mice show unchanged skeletal muscle mass and no resistance to the effects of high fat diet
malfunction
RNAi mediated knock down of the IP6K1 isoform inhibits both glucose-mediated increase in diphosphoinositol pentakisphosphate and first phase insulin secretion
malfunction
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mammalian cells lacking IP6K1 display defects in dynein-dependent trafficking pathways, including endosomal sorting, vesicle movement, and Golgi maintenance. Expression of catalytically active but not inactive IP6K1 reverses the defects. Intermediate chain recruitment to membranes is reduced in cells lacking IP6K1. Decreased Tfn distribution in the ERC in Ip6k1-/- MEFs might be due to a delay in Tfn trafficking from endosomes. Tfn is held back in early endosomes in cells lacking IP6K1
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malfunction
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significant reduction in platelet polyP levels in enzyme-deficient Ip6k1-/- mice, along with slower platelet aggregation and lengthened plasma clotting time. Incorporation of polyP into fibrin clots is reduced in Ip6k1-/- mice, thereby altering clot ultrastructure, which is rescued on the addition of exogenous polyP. In vivo assays reveal longer tail bleeding time and resistance to thromboembolism in Ip6k1-/- mice. No alteration in P-selectin surface expression in Ip6k1-/- platelets implies that IP6K1 does not influence platelet alpha-granule content or its thrombin-stimulated release No difference in the extent of fibrinogen binding to activated wild-type or Ip6k1-/- platelets, and no difference in serotonin content. Knockout Ip6k1-/- mice show altered clot homogeneity and architecture and a significant increase in the number of fibers per unit length in Ip6k1-/- derived clots compared to wild-type. Hemostasis defects in Ip6k1-/- mice, overview
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malfunction
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selective inhibition of inositol hexakisphosphate kinase enhances mesenchymal stem cell engraftment and improves therapeutic efficacy for myocardial infarction. IP6K inhibition may increase Akt activation in mesenchymal stem cells, resulting in enhanced cardiac protective effect after transplantation. Inhibiting IP6Ks by N2-(3-trifluorobenzyl)-N6-(4-nitrobenzyl)purine decreases 5-diphosphoinositol pentakisphosphate synthesis and increases phosphorylation of Akt at T308 and S473 in mesenchymal stem cells, indicating the downregulation of 5-diphosphoinositol pentakisphosphate expression by IP6K inhibition enhances the activation of Akt in mesenchymal stem cells. IP6K inhibition by N2-(3-trifluorobenzyl)-N6-(4-nitrobenzyl)purine is also associated with decreased apoptosis
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metabolism
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isoform inositol hexakisphosphate kinase-2 acts as an effector of the vertebrate Hedgehog pathway. IP6K2 activity is required at the level or downstream of Smoothened but upstream of the transcription activator Gli1
metabolism
the enzyme is involved in the phospholipase Cgamma1/inositol polyphosphate/protein kinase C delta (PKCd) cascade which contributes to the Cx43-dependent transcriptional response of MC3T3 osteoblasts to FGF2. FGF2-signaling involves the inositol polyphosphate cascade, including inositol hexakisphosphate kinase (IP6K). FGF2 is an important regulator of skeletal tissue with complex action, acting at several stages of differentiation to differentially affect osteoblast function. Molecular mechanisms by which inositol diphosphates impact signaling in osteoblastic cells, overview
physiological function
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inositol hexakisphosphate kinase 1 regulates neutrophil function in innate immunity by inhibiting phosphatidylinositol-(3,4,5)-trisphosphate signaling. The enzyme does not regulate neutrophil trafficking and survival
physiological function
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inositol hexakisphosphate kinase 1 regulates neutrophil function in innate immunity by inhibiting phosphatidylinositol-(3,4,5)-trisphosphate signaling. The enzyme does not regulate neutrophil trafficking and survival
physiological function
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inositol hexakisphosphate kinase induces cell death in Huntington disease. The enzyme mediates apoptotic cell death via its translocation from the nucleus to the cytoplasm. Overexpression of the enzyme leads to the depletion of Akt phosphorylation and the induction of cell death
physiological function
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IP6K1 binds and stimulates (4fold) glycogen synthase kinase 3 alpha and beta isoforms enzymatic activity in vitro in a catalytically independent mechanism (physiological activator)
physiological function
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isoform IP6K2 is required for p53-mediated apoptosis and modulates the outcome of the p53 response. IP6K2 acts by binding directly to p53 and decreasing expression of proarrest gene targets such as the cyclin-dependent kinase inhibitor p21
physiological function
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isoform IP6K2 plays a specific role in regulating cell death. Isoform IP6K2 overexpression, that causes 10 to 20fold increase in IP7 level, enhances cell death
physiological function
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isoform P6K2 activity is required for normal development of craniofacial structures, somites, and neural crest cells
physiological function
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loss of inositol pyrophosphate synthesis by inositol hexakisphosphate kinase 1 impairs homologous recombination in mammalian cells, leading to increased cell death
physiological function
generated predominantly by inositol hexakisphosphate kinases (IP6Ks), inositol pyrophosphates can modulate protein function by posttranslational serine diphosphorylation. Ser51 in the dynein intermediate chain is a target for diphosphorylation by IP7, and this modification promotes the interaction of the intermediate chain N-terminus with the p150Glued subunit of dynactin. Involvement of IP6Ks in dynein function, inositol pyrophosphate-mediated diphosphorylation may act as a regulatory signal to enhance dynein-driven transport. Endosomal sorting of Tfn in fibroblasts requires IP6K1 activity, the enzyme activity also is required to maintain Golgi morphology. IP6K1 activity regulates Tfn trafficking, overview
physiological function
generated predominantly by inositol hexakisphosphate kinases (IP6Ks), inositol pyrophosphates can modulate protein function by posttranslational serine diphosphorylation. Ser51 in the dynein intermediate chain is a target for diphosphorylation by IP7, and this modification promotes the interaction of the intermediate chain N-terminus with the p150Glued subunit of dynactin. Involvement of IP6Ks in dynein function, inositol pyrophosphate-mediated diphosphorylation may act as a regulatory signal to enhance dynein-driven transport. IP6K1 activity regulates Tfn trafficking, overview
physiological function
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generated predominantly by inositol hexakisphosphate kinases (IP6Ks), inositol pyrophosphates can modulate protein function by posttranslational serine diphosphorylation. Ser51 in the dynein intermediate chain is a target for diphosphorylation by IP7, and this modification promotes the interaction of the intermediate chain N-terminus with the p150Glued subunit of dynactin. Involvement of IP6Ks in dynein function, inositol pyrophosphate-mediated diphosphorylation may act as a regulatory signal to enhance dynein-driven transport. Phagosomal motility requires IP6K1. IP6K1 activity regulates Tfn trafficking, overview
physiological function
hypoxia increases IP6Ks activity and 5-diphosphoinositol pentakisphosphate production
physiological function
inositol hexakisphosphate kinase 1 maintains hemostasis in mice by regulating platelet polyphosphate levels. Role for IP6K1 in regulation of mammalian hemostasis via its control of platelet polyP levels
physiological function
inositol hexakisphosphate kinase type 2 (InsP6K2), which converts inositol hexakisphosphate (InsP6) to InsP7, mediates cell death in mammalian cells. Cell death is augmented in the presence of cytoplasmic TDP-43 aggregations and activated InsP6K2, while cells with only cytoplasmic TDP-43 aggregation survive because Akt activity increases. Enzyme InsP6K2 causes neuronal cell death in patients suffering frontotemporal lobar degeneration with ubiquitinated inclusions (FTLD-U) or amyotrophic lateral sclerosis (ALS). InsP6K2 and cytoplasmic TDP-43 induce depletion of Akt phosphorylation and decrease casein kinase 2
physiological function
inositol hexakisphosphate kinase-3 regulates the morphology and synapse formation of cerebellar Purkinje cells via spectrin/adducin, isozyme IP6K3 is a major determinant of cytoskeletal disposition and function of cerebellar Purkinje cells. Spectrin/adducin binding is substantially increased by IP6K3, independent of the enzyme's kinase activity, catalytically inactive IP6K3 K217A mutant binds spectrin/adducin similarly to the wild-type enzyme
physiological function
inositol hexakisphosphate kinases (IP6Ks) primarily generate the signaling molecule, inositol diphosphate, 5-IP7. Phosphorylation of IP6K1 at a PKC/PKA motif modulates its interaction with PLIN1 and lipolysis. Enzyme IP6K1 is a regulator of PLIN1 mediated lipolysis. The PKA/PKC phosphorylation motif in IP6K1 regulates its interaction with PLIN1 and lipolysis
physiological function
inositol pyrophosphates containing seven (IP7) or more phosphate groups on a myo-inositol ring are synthesized from inositol hexakisphosphate (IP6) primarily by a family of IP6 kinases. Inositol hexakisphosphate kinase-1 mediates assembly/disassembly of the CRL4-signalosome complex. Under basal conditions, IP6K1 forms a ternary complexwith CSN and CRL4 in which IP6K1 and CRL4 are inactive. UV dissociates IP6K1 to generate IP7, which then dissociates CSN-CRL4 to activate CRL4. IP6K1 is a CRL4 subunit that transduces UV signals to mediate disassembly of the CRL4-CSN complex, thereby regulating nucleotide excision repair and cell death. IP6K1 directly binds to DDB1 and inhibits CRL4. IP6K1 inhibits CRL4 substrate, e.g. c-Jun, ubiquitylation and degradation. CDT1 ubiquitylation is markedly enhanced by overexpressing DDB1/Cul4A, an effect abolished in the presence of IP6K1. CRL4-CSN binding is stimulated more by kinase-dead than wild-type IP6K1
physiological function
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InsP6 (inositol hexakisphosphate), the most abundant inositol phosphate in metazoa, is pyrophosphorylated to InsP7 [5PP-InsP5 (diphosphoinositol pentakisphosphate)] by cytosolic and nuclear IP6Ks (InsP6 kinases) and to 1PP-InsP5 by another InsP6/InsP7 kinase family. IP6Ks are also nuclear and cytosolic InsP6- (and InsP5-)dephosphorylating enzymes whose activity is sensitively driven by a decrease in the cellular ATP/ADP ratio, thus suggesting a role for IP6Ks as cellular adenylate energy sensors
physiological function
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InsP6 (inositol hexakisphosphate), the most abundant inositol phosphate in metazoa, is pyrophosphorylated to InsP7 [5PP-InsP5 (diphosphoinositol pentakisphosphate)] by cytosolic and nuclear IP6Ks (InsP6 kinases) and to 1PP-InsP5 by another InsP6/InsP7 kinase family. IP6Ks are also nuclear and cytosolic InsP6- (and InsP5-)dephosphorylating enzymes whose activity is sensitively driven by a decrease in the cellular ATP/ADP ratio, thus suggesting a role for IP6Ks as cellular adenylate energy sensors
physiological function
IP6K regulates Runx2 and osteoblast gene expression
physiological function
IP6K regulates Runx2 and osteoblast gene expression. The nuclear translocation and association of PKCdelta with Runx2 is dependent upon IP6K1
physiological function
IP6K1, an inositol hexakisphosphate kinase that catalyzes the synthesis of inositol diphosphate, regulates inositol synthesis in mammalian cells. Enzyme IP6K1 may negatively regulate mIno1 transcription by increasing the methylation of mIno1 DNA. The catalytic function of IP6K1 is necessary for repression of mIno1 transcription
physiological function
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isozymes AtVip1 and AtVip2 are differentially expressed in plant tissues, suggesting nonredundant or non-overlapping functions in plants. Both AtVip1 and AtVip2 encode proteins capable of restoring InsP7 synthesis in Saccharomyces cerevisiae mutants, AtVip1 and AtVip2 can function as bonafide InsP6 kinases. The plant paralogues of the yeast Vip genes can catalyze the synthesis of InsP7 and correct the phenotypic consequences of a yeast vip1 null mutation
physiological function
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isozymes AtVip1 and AtVip2 are differentially expressed in plant tissues, suggesting nonredundant or non-overlapping functions in plants. Both AtVip1 and AtVip2 encode proteins capable of restoring InsP7 synthesis in yeast mutants, thus AtVip1 and AtVip2 can function as bonafide InsP6 kinases. The plant paralogues of the Saccharomyces cerevisiae Vip genes can catalyze the synthesis of InsP7 and correct the phenotypic consequences of a yeast vip1 null mutation
physiological function
modulation of Kcs1 controls INO1 transcription by regulating synthesis of inositol diphosphates, model of regulation of INO1 transcription by Kcs1 and inositol diphosphates, overview. bZIP and inositol pyrophosphate kinase (DINS) domains of enzyme Kcs1 are required for INO1 transcription. The Kcs1 protein, but not transcription, is regulated in response to inositol
physiological function
the enzyme is a key component for inositol polyphosphate turnover. The kinase activity of AtIPK2 is required for pollen development, pollen tube guidance and embryogenesis, requirement of inositol polyphosphate signaling in plant sexual reproduction. Isozymes AtIPK2alpha and AtIPK2beta act redundantly during pollen development, pollen tube guidance and embryogenesis
physiological function
the enzyme is involved in early cytoskeleton remodeling events during cancer progression and essential for 4-nitroquinoline-1-oxide-induced invasive carcinoma
physiological function
1D-myo-inositol 5-diphosphate 1,2,3,4,6-pentakisphosphate kinase activity is dominant when PPIP5K1 is expressed in intact cells. 1D-myo-inositol 1,5-bis(diphosphate) 2,3,4,6-tetrakisphosphate phosphatase activity prevails when the enzyme is isolated from its cellular environment. Exogenous expression of PPIP5K1 in Drosophila melanogaster S3 cells elevates levels of 1D-myo-inositol 5-diphosphate 1,2,3,4,6-pentakisphosphate and 1D-myo-inositol 1,5-bis(diphosphate) 2,3,4,6-tetrakisphosphate
physiological function
inositol hexakisphosphate kinase (IP6K1) and IP6K2 together control inositol pyrophosphate metabolism and thereby physiologically regulate phosphate export and other aspects of mammalian cellular phosphate homeostasis
physiological function
inositol hexakisphosphate kinase 1 is a metabolic sensor in pancreatic beta-cells
physiological function
inositol hexakisphosphate kinase 3 promotes focal adhesion turnover via interactions with dynein intermediate chain 2
physiological function
inositol hexakisphosphate kinase 3 promotes focal adhesion turnover via interactions with dynein intermediate chain 2
physiological function
inositol hexakisphosphate kinase-2 in cerebellar granule cells regulates Purkinje cells and motor coordination via protein 4.1N
physiological function
islets from patients with T2D (a multifactorial, polygenetic disease) show impaired ATP generation in response to nutrients, in association with mitochondrial dysfunction. The regulation of IP6K1 activity is likely to be a vulnerable point in early disease development
physiological function
levels of both 1D-myo-inositol 1,5-bis(diphosphate) 2,3,4,6-tetrakisphosphate and ATP decrease upon phosphate starvation and subsequently recover during phosphate replenishment
physiological function
physiological roles of the enzyme (IP6K1) and the associated inositol pyrophosphate metabolism in regulating sensorimotor gating as well as short-term memory
physiological function
product 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate promotes physiological endocytosis and downstream degradation of Na+/K+-ATPase-alpha1. Deletion of IP6K1 elicits a twofold enrichment of Na+/K+-ATPase-alpha1 in plasma membranes of multiple tissues and cell types. 5-diphosphoinositol 1,2,3,4,6-pentakisphosphate binds the RhoGAP domain of phosphatidylinositol 3-kinase (PI3K) p85alpha to disinhibit its interaction with Na+/K+-ATPase-alpha1. This recruits adaptor protein 2 (AP2) and triggers the clathrin-mediated endocytosis of Na+/K+-ATPase-alpha1
physiological function
the enzyme (IP6K1) integrates glucose metabolism and insulin exocytosis
physiological function
the enzyme (IP6K1) integrates glucose metabolism and insulin exocytosis
physiological function
the enzyme (IP6K1) physiologically regulates neuronal migration by binding to alpha-actinin and influencing phosphorylation of both focal adhesion kinase and alpha-actinin through its product 5-diphosphoinositol pentakisphosphate
physiological function
the enzyme is important in numerous areas of cell physiology such as DNA repair and glucose homeostasis. It is implicated in the pathology of diabetes and other human diseases
physiological function
the enzyme promotes cell death of anterior horn cells in the spinal cord of patients with amyotrophic lateral sclerosis
physiological function
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isozymes AtVip1 and AtVip2 are differentially expressed in plant tissues, suggesting nonredundant or non-overlapping functions in plants. Both AtVip1 and AtVip2 encode proteins capable of restoring InsP7 synthesis in Saccharomyces cerevisiae mutants, AtVip1 and AtVip2 can function as bonafide InsP6 kinases. The plant paralogues of the yeast Vip genes can catalyze the synthesis of InsP7 and correct the phenotypic consequences of a yeast vip1 null mutation
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physiological function
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isozymes AtVip1 and AtVip2 are differentially expressed in plant tissues, suggesting nonredundant or non-overlapping functions in plants. Both AtVip1 and AtVip2 encode proteins capable of restoring InsP7 synthesis in yeast mutants, thus AtVip1 and AtVip2 can function as bonafide InsP6 kinases. The plant paralogues of the Saccharomyces cerevisiae Vip genes can catalyze the synthesis of InsP7 and correct the phenotypic consequences of a yeast vip1 null mutation
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physiological function
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generated predominantly by inositol hexakisphosphate kinases (IP6Ks), inositol pyrophosphates can modulate protein function by posttranslational serine diphosphorylation. Ser51 in the dynein intermediate chain is a target for diphosphorylation by IP7, and this modification promotes the interaction of the intermediate chain N-terminus with the p150Glued subunit of dynactin. Involvement of IP6Ks in dynein function, inositol pyrophosphate-mediated diphosphorylation may act as a regulatory signal to enhance dynein-driven transport. Endosomal sorting of Tfn in fibroblasts requires IP6K1 activity, the enzyme activity also is required to maintain Golgi morphology. IP6K1 activity regulates Tfn trafficking, overview
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physiological function
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inositol hexakisphosphate kinase 1 maintains hemostasis in mice by regulating platelet polyphosphate levels. Role for IP6K1 in regulation of mammalian hemostasis via its control of platelet polyP levels
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physiological function
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hypoxia increases IP6Ks activity and 5-diphosphoinositol pentakisphosphate production
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additional information
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a small amount of InsP7 and InsP8 is accumulated in seeds of higher plants. Residue D292 of AtVIP1 is critical for activity of the kinase domain. The kinase domains alone does not show InsP7 synthesis activity to same levels as the intact AtVIP1
additional information
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a small amount of InsP7 and InsP8 is accumulated in seeds of higher plants. The kinase domains alone does not show InsP7 synthesis activity to same levels as the intact AtVIP2
additional information
enzyme InsP6K2 is translocated from the nucleus to the cytosol during apoptosis
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enzyme InsP6K2 is translocated from the nucleus to the cytosol during apoptosis
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lentiviral RNAi-based depletion of MINPP1 at falling cellular ATP/ADP ratios has no significant impact on Ins(2,3,4,5,6)P5 production
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lentiviral RNAi-based depletion of MINPP1 at falling cellular ATP/ADP ratios has no significant impact on Ins(2,3,4,5,6)P5 production
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structural analysis of the IP6K from Entamoeba histolytica
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structural analysis of the IP6K from Entamoeba histolytica
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the catalytic motif of enzyme IP6K1 lies in the Q3 domain
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a homogenous coupled bioluminescence assay is developed for measuring inositol hexakisphosphate kinase 1 activity in a 384-well format
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a homogenous coupled bioluminescence assay is developed for measuring inositol hexakisphosphate kinase 1 activity in a 384-well format
additional information
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a small amount of InsP7 and InsP8 is accumulated in seeds of higher plants. Residue D292 of AtVIP1 is critical for activity of the kinase domain. The kinase domains alone does not show InsP7 synthesis activity to same levels as the intact AtVIP1
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additional information
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a small amount of InsP7 and InsP8 is accumulated in seeds of higher plants. The kinase domains alone does not show InsP7 synthesis activity to same levels as the intact AtVIP2
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