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Information on EC 2.7.4.21 - inositol-hexakisphosphate 5-kinase and Organism(s) Mus musculus and UniProt Accession Q80V72
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2.7.4.21 inositol-hexakisphosphate 5-kinaseIUBMB Comments
Three mammalian isoforms are known to exist.
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Word Map
- 2.7.4.21
- pyrophosphate
- polyphosphate
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pp-insps
- tetrakisphosphate
- ppip5ks
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bis-diphosphoinositol
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pyrophosphorylation
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5-insp7
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5-diphosphoinositol
- medicine
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ptdins3,4,5p3
The taxonomic range for the selected organisms is: Mus musculus
The enzyme appears in selected viruses and cellular organisms
The enzyme appears in selected viruses and cellular organisms
Reaction Schemes
+
=
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Synonyms
ip6k1, ip6k2, ip6k3, ppip5k1, ppip5k2, insp6k2, inositol hexakisphosphate kinase, inositol hexakisphosphate kinase 1, ihpk2, atvip1, 
more
topSYNONYM 
ORGANISM
UNIPROT
COMMENTARY 
LITERATURE
ATP:1D-myo-inositol-hexakisphosphate phosphotransferase
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diphosphoinositol pentakisphosphate synthetase
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inositol hexakisphosphate kinase
inositol hexakisphosphate kinase 1
inositol hexakisphosphate kinase-1
InsP6 kinase
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InsP6K3
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IP6 kinase
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IP6K
IP6K1
kinase (phosphorylating), inositol hexakisphosphate
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additional information
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IP6K1 belongs to the family of inositol hexakisphosphate kinases
inositol hexakisphosphate kinase
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inositol hexakisphosphate kinase 1
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IP6K
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REACTION TYPE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phospho-group transfer
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PATHWAY SOURCE
PATHWAYS
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SYSTEMATIC NAME
IUBMB Comments
ATP:1D-myo-inositol-hexakisphosphate 5-phosphotransferase
Three mammalian isoforms are known to exist.
CAS REGISTRY NUMBER
COMMENTARY
176898-37-6
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SUBSTRATE
PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
Reversibility
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + 1D-myo-inositol hexakisphosphate
ADP + 1D-myo-inositol 1-diphosphate 2,3,4,5,6-pentakisphosphate
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-
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?
ATP + 1D-myo-inositol hexakisphosphate
ADP + 1D-myo-inositol 5-diphosphate 1,2,3,4,6-pentakisphosphate
ATP + 1D-myo-inositol hexakisphosphate
ADP + 5-diphospho-1D-myo-inositol (1,2,3,4,6)-pentakisphosphate
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-
-
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?
ATP + 1D-myo-inositol hexakisphosphate
ADP + 5-diphospho-1D-myo-inositol 1,2,3,4,6-pentakisphosphate
ATP + 1D-myo-inositol hexakisphosphate
ADP + diphosphoinositol pentakisphosphate + bisdiphosphoinositol tetrakisphosphate
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?
ATP + 1D-myo-inositol hexakisphosphate
ADP + 1D-myo-inositol 5-diphosphate 1,2,3,4,6-pentakisphosphate
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?
ATP + 1D-myo-inositol hexakisphosphate
ADP + 1D-myo-inositol 5-diphosphate 1,2,3,4,6-pentakisphosphate
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?
ATP + 1D-myo-inositol hexakisphosphate
ADP + 5-diphospho-1D-myo-inositol 1,2,3,4,6-pentakisphosphate
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?
ATP + 1D-myo-inositol hexakisphosphate
ADP + 5-diphospho-1D-myo-inositol 1,2,3,4,6-pentakisphosphate
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?
ATP + 1D-myo-inositol hexakisphosphate
ADP + 5-diphospho-1D-myo-inositol 1,2,3,4,6-pentakisphosphate
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?
additional information
?
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the enzyme generates inositol 1,3,4,5-tetrakisphosphate (InsP4) and InsP5
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?
additional information
?
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the enzyme generates inositol 1,3,4,5-tetrakisphosphate (InsP4) and InsP5
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?
additional information
?
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the enzyme generates inositol 1,3,4,5-tetrakisphosphate (InsP4) and InsP5
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?
additional information
?
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IHPK2 binds to tumor necrosis factor receptor-associated factor 2 and interferes with phosphorylation of transforming growth factor beta-activated kinase 1, TAK1, thereby inhibiting NF-kappaB signaling. IHPK2 contains two sites required for TRAF2 binding, Ser347 and Ser359. IHPK2-TRAF2 binding leads to attenuation of TAK1- and NF-kappa B-mediated signaling and is partially responsible for the apoptotic activity of IHPK2. A portion of the death-promoting function of IHPK2 is independent of its kinase activity
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?
additional information
?
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IP6K2 belongs to a family of enzymes generating the inositol pyrophosphate IP7 [diphosphoinositol pentakisphosphate (5-PP-IP5)], it mediates apoptosis, increased IP6K2 activity sensitizes cancer cells to stressors, whereas its depletion blocks cell death
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?
additional information
?
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enzyme IP6K3 physiologically binds to the cytoskeletal proteins adducin and spectrin in mouse cerebellum
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?
additional information
?
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the enzyme generates inositol 1,3,4,5-tetrakisphosphate (InsP4) and InsP5
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?
additional information
?
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the enzyme generates inositol 1,3,4,5-tetrakisphosphate (InsP4) and InsP5
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?
additional information
?
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the enzyme generates inositol 1,3,4,5-tetrakisphosphate (InsP4) and InsP5
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?
NATURAL SUBSTRATE
NATURAL PRODUCT
REACTION DIAGRAM
ORGANISM
UNIPROT
COMMENTARY
(Substrate)
(Substrate)
LITERATURE
(Substrate)
(Substrate)
COMMENTARY
(Product)
(Product)
LITERATURE
(Product)
(Product)
REVERSIBILITY
r=reversible
ir=irreversible
?=not specified
r=reversible
ir=irreversible
?=not specified
ATP + 1D-myo-inositol hexakisphosphate
ADP + 1D-myo-inositol 1-diphosphate 2,3,4,5,6-pentakisphosphate
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-
-
?
ATP + 1D-myo-inositol hexakisphosphate
ADP + 1D-myo-inositol 5-diphosphate 1,2,3,4,6-pentakisphosphate
ATP + 1D-myo-inositol hexakisphosphate
ADP + 1D-myo-inositol 5-diphosphate 1,2,3,4,6-pentakisphosphate
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?
ATP + 1D-myo-inositol hexakisphosphate
ADP + 1D-myo-inositol 5-diphosphate 1,2,3,4,6-pentakisphosphate
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?
additional information
?
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IHPK2 binds to tumor necrosis factor receptor-associated factor 2 and interferes with phosphorylation of transforming growth factor beta-activated kinase 1, TAK1, thereby inhibiting NF-kappaB signaling. IHPK2 contains two sites required for TRAF2 binding, Ser347 and Ser359. IHPK2-TRAF2 binding leads to attenuation of TAK1- and NF-kappa B-mediated signaling and is partially responsible for the apoptotic activity of IHPK2. A portion of the death-promoting function of IHPK2 is independent of its kinase activity
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?
additional information
?
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IP6K2 belongs to a family of enzymes generating the inositol pyrophosphate IP7 [diphosphoinositol pentakisphosphate (5-PP-IP5)], it mediates apoptosis, increased IP6K2 activity sensitizes cancer cells to stressors, whereas its depletion blocks cell death
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?
additional information
?
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enzyme IP6K3 physiologically binds to the cytoskeletal proteins adducin and spectrin in mouse cerebellum
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COFACTOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
METALS and IONS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
Mg2+
INHIBITOR
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
heat shock protein Hsp90
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binding of HSP90 inhibits IP6K2 catalytic activity, IP6K2 binds to HSP90's C terminus. Depletion of HSP90 by RNAi in HEK-293 cells increases IP6K catalytic activity about 2.5fold, specificity of IP6K2-HSP90 interaction, overview. Drugs and selective mutations that abolish HSP90IP6K2 binding elicit activation of IP6K2, leading to cell death. Overexpression of HSP90 markedly and specifically reduces IP6K catalytic activity in HEK-293 cells, overexpression of HSP90 does not influence catalytic activity of IP6K1
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N(2)-(m-(trifluoromethyl)benzyl) N(6)-(p-nitrobenzyl)purine
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selective inhibitor in vitro
N2-(m-(trifluoromethy)lbenzyl)N6-(p-nitrobenzyl)purine
potent and selective inhibitor
N2-(m-(trifluoromethyl) benzyl) N6-(p-nitrobenzyl) purine
TNP, a selective inhibitor, abolishes the basal and Cx43-potentiated Runx2 activity in response to FGF2 treatment relative to DMSO treated controls
additional information
radiation virtually abolishes binding of wild-type IP6K1 to the signalosome
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N2-(3-trifluorobenzyl)-N6-(4-nitrobenzyl)purine
a selective inhibitor, abolishes the basal and Cx43-potentiated Runx2 activity in response to FGF2 treatment relative to DMSO treated controls
N2-(3-trifluorobenzyl)-N6-(4-nitrobenzyl)purine
inhibiting IP6Ks by the compound 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 enhance the activation of Akt in mesenchymal stem cells
N2-(3-trifluorobenzyl)-N6-(4-nitrobenzyl)purine
a selective inhibitor, abolishes the basal and Cx43-potentiated Runx2 activity in response to FGF2 treatment relative to DMSO treated controls
N2-(3-trifluorobenzyl)-N6-(4-nitrobenzyl)purine
inhibiting IP6Ks by the compound 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 enhance the activation of Akt in mesenchymal stem cells
ACTIVATING COMPOUND
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
IMAGE
additional information
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drugs and selective mutations that abolish HSP90IP6K2 binding elicit activation of IP6K2, leading to cell death
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pH OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
TEMPERATURE OPTIMUM
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
ORGANISM
COMMENTARY
LITERATURE
UNIPROT
SEQUENCE DB
SOURCE
SOURCE TISSUE
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
SOURCE
MC3T3 osteoblasts express IP6K1 and IP6K2 mRNA more than 25fold more abundantly than IP6K3
isozyme IP6K3 is highly concentrated in the brain in cerebellar Purkinje cells
immunohistochemic analysis of the enzyme in wild-type and mutant mouse brains, overview
MC-3T3 osteoblasts express IP6K1 and IP6K2 mRNA more than 25fold more abundantly than IP6K3
MC3T3 osteoblasts express IP6K1 and IP6K2 mRNA more than 25fold more abundantly than IP6K3
inositol hexakisphosphate kinase 3 is highly expressed at the leading edge of migrating cells
LOCALIZATION
ORGANISM
UNIPROT
COMMENTARY
GeneOntology No.
LITERATURE
SOURCE
additional information
IP6K1 exhibits dual localization in the cytoplasm and nucleus
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enzyme IP6K1 requires phosphatidic acid binding for nuclear localization and repression of mIno1 transcription. Deletion of the Q2 domain results in decreased nuclear localization in more than 60% of cells
GENERAL INFORMATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
malfunction
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
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
malfunction
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
additional information
the catalytic motif of enzyme IP6K1 lies in the Q3 domain
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
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
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
physiological function
hypoxia increases IP6Ks activity and 5-diphosphoinositol pentakisphosphate production
physiological function
IP6K regulates Runx2 and osteoblast gene expression
physiological function
inositol hexakisphosphate kinase-2 in cerebellar granule cells regulates Purkinje cells and motor coordination via protein 4.1N
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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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
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
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
enzyme deletion reduces cell migration and invasion, conferring protection from aerodigestive tract carcinoma
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. 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
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
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
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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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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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
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-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
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
the enzyme is involved in early cytoskeleton remodeling events during cancer progression and essential for 4-nitroquinoline-1-oxide-induced invasive carcinoma
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
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) 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
UNIPROT
ENTRY NAME
ORGANISM
NO. OF AA
NO. OF TRANSM. HELICES
MOLECULAR WEIGHT[Da]
SOURCE
SEQUENCE
LOCALIZATION PREDICTION
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable).
The reliability class of the localization prediction ranges from 1 (very reliable) to 5 (not reliable). MOLECULAR WEIGHT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
55000
SUBUNIT
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
POSTTRANSLATIONAL MODIFICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
phosphoprotein
the phosphorylation of IP6K1 at a PKC/PKA motif modulates its interaction with PLIN1 and lipolysis. GST-IP6K1 phosphorylation in HEK293 cells is enhanced by forskolin-mediated PKA activation. Endogenous IP6K1 phosphorylation in HEK293 cells is enhanced to a greater extent by PKC activation compared to PKA activation as evidenced by PMA and FSK treatments. No phosphorylation of IP6K1 mutant S118A-S121A in HEK293 cells
PROTEIN VARIANTS
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
K217A
a kinase-dead mutant IP6K3, the catalytically inactive IP6K3 K217A mutant binds spectrin/adducin similarly to the wild-type enzyme
R133A
-
mutation of IP6K2 in its putative HSP90-binding motif, mutation of Arg133 abolishes IP6K2-HSP90 binding
R136A
-
mutation of IP6K2 in its putative HSP90-binding motif, mutation of Arg136 abolishes IP6K2-HSP90 binding
S118A/S121A
site-directed mutagenesis, no phosphorylation of IP6K1 mutant S118A-S121A in HEK293 cells. The mutant does not efficiently bind Myc-PLIN1 in HEK293 cells
S347A/S359A
-
site-directed mutagenesis, the mutant displays 3.5fold greater TAK1 activation following TNF-alpha, the mutant demonstrates a 6-10fold increase in NF-kappaB DNA binding following TNF-alpha compared with wild type IHPK2-expressing cells in which NF-kappa B DNA binding is inhibited
S85A
site-directed mutagenesis, the mutation does not influence its binding to Myc-PLIN1 in HEK293 cells
W131A
-
mutation of IP6K2 in its putative HSP90-binding motif, mutation of Trp131 modestly diminishes IP6K2-HSP90 binding, the catalytically impaired IP6K2-W131A does not induce cell death
additional information
additional information
-
construction of an inactive enzyme mutant, overexpression of wild-type IHPK2 sensitizes ovarian carcinoma cell lines to the growth-suppressive and apoptotic effects of interferon beta, IFN-alpha2, and gamma-irradiation. Expression of a kinase-dead mutant abrogates 50% of the apoptosis induced by IFN-beta
additional information
-
depletion of IP6K2 in HEK-293 cells by RNAi leads to 40-50% reduced cell death, overview. Deletion mapping of IP6K2 to identify HSP90-binding motif, overview. The yeast Saccharomyces cerevisiae possesses constitutive and inducible homologues of HSP90, designated HSC82 and HSP82, respectively. In HSC82 KO yeast, IP6K activity is 2.5fold higher than murine wild-type, in yeast HSP82 null mutant, IP6K catalytic activity is increased but to a lesser extent. Overexpression of HSP90 markedly reduces IP6K catalytic activity in HEK-293 cells
additional information
-
gene deletion of IP6K1 in mice leads to markedly diminished production of inositol diphosphates. Male mutant mice are sterile with defects in spermiogenesis. Mutant mice are smaller than wild-type despite normal food intake. The mutants display markedly lower circulating insulin, phenotype, overview
additional information
construction of IP6K1 knockout MEF cells. Deletion of the Q2 domain results in decreased nuclear localization in more than 60% of cells
additional information
generation of enzyme-deficient Ip6k1-/- mice, phenotype, overview
additional information
IP6K3 knockdown HEK293 cells are generated by lentiviral transduction. Diminished cerebellar synapses in IP6K3 mutants
PURIFICATION (Commentary)
ORGANISM
UNIPROT
LITERATURE
CLONED (Commentary)
ORGANISM
UNIPROT
LITERATURE
gene ip6k2, quantitative real-time PCr enzyme expression analysis
expression of the wild-type enzyme in Saccharomyces cerevisiae mutant strains, overexpression of the GST-tagged or Myc-tagged enzyme in HEK-293, HeLa, and HCT116 cells, expression of wild-type and mutant enzymes in HEK-293 cells
-
gene Ihpk1, located on chromosome 9, has 6 exons, of which exon 1 is exclusively noncoding, the start codon is located in exon 2, and the stop codon is located in exon 6, DNA and amino acid sequence determination and analysis. Expressionin MEF cell lines
-
gene Ip6k1, expression of murine IP6K1 rescues yeast kcs1DELTA inositol auxotrophy. Nuclear recombinant expression of GFP-tagged wild type IP6K1 in IP6K1 knockout cells
gene ip6k1, quantitative real-time PCr enzyme expression analysis
gene IP6K1, recombinant coexpression of GST-tagged wild-type and mutant enzymes with Myc-tagged PLIN1 in HEK-293 cells, recombinant expression of Myc-tagged enzyme
gene IP6K1, recombinant expression of GST-tagged enzyme in Escherichia coli strain BL21(DE3), coexpression of IP6K1 prevents enhancement of ubiquitylation by the expression of DDB1/Cul4A in HEK293 cells. IP6K1 expression of shRNA-resistant mouse IP6K1 in IP6K1 knockdown cells, overexpression of TAP-IP6K1 in HEK-293 cells
gene ip6k3, quantitative real-time PCr enzyme expression analysis
overexpression of wild-type and inactive mutant IHPK2 in ovarian carcinoma cell lines
-
recombinant expression of wild-type and mutant enzymes with a Flag-tag beta-adducin tail and MARCKS domain tagged to it, or tagged with actin-binding domain (1-275 aa), repeat domain (303-525 aa), and PH domain (2197-2307 aa) of beta2-spectrin. Tag cleavage by prescission protease
EXPRESSION
ORGANISM
UNIPROT
LITERATURE
IP6K3 is upregulated by dexamethasone. Ip6k3 expression is elevated under diabetic, fasting, and disuse conditions in mouse skeletal muscles
APPLICATION
ORGANISM
UNIPROT
COMMENTARY
LITERATURE
medicine
medicine
-
selectively blocking HSP90-IP6K2 binding could provide effective and safer modes of chemotherapy to block apoptosis
REF.
AUTHORS
TITLE
JOURNAL
VOL.
PAGES
YEAR
ORGANISM (UNIPROT)
PUBMED ID
SOURCE
Saiardi, A.; Erdjument-Bromage, H.; Snowman, A.M.; Tempst, P.; Snyder, S.H.
Synthesis of diphosphoinositol pentakisphosphate by a newly identified family of higher inositol polyphosphate kinases
Curr. Biol.
9
1323-1326
1999
Homo sapiens (Q9UHH9), Mus musculus (Q6PD10)
Albert, C.; Safrany, S.T.; Bembenek, M.E.; Reddy, K.M.; Reddy, K.K.; Falck, J.R.; Brcker, M.; Shears, S.B.; Mayr, G.W.
Biological variability in the structures of diphosphoinositol polyphosphates in Dictyostelium discoideum and mammalian cells
Biochem. J.
327
553-560
1997
Cricetulus griseus, Homo sapiens, Mus musculus
-
Saiardi, A.; Nagata, E.; Luo, H.R.; Snowman, A.M.; Snyder, S.H.
Identification and characterization of a novel inositol hexakisphosphate kinase
J. Biol. Chem.
276
39179-39185
2001
Mus musculus, Homo sapiens (Q96PC2)
Morrison, B.H.; Bauer, J.A.; Lupica, J.A.; Tang, Z.; Schmidt, H.; DiDonato, J.A.; Lindner, D.J.
Effect of inositol hexakisphosphate kinase 2 on transforming growth factor beta-activated kinase 1 and NF-kappaB activation
J. Biol. Chem.
282
15349-15356
2007
Homo sapiens, Mus musculus
Chakraborty, A.; Koldobskiy, M.A.; Sixt, K.M.; Juluri, K.M.; Mustafa, A.K.; Snowman, A.M.; van Rossum, D.B.; Patterson, R.L.; Snyder, S.H.
HSP90 regulates cell survival via inositol hexakisphosphate kinase-2
Proc. Natl. Acad. Sci. USA
105
1134-1139
2008
Mus musculus
Bhandari, R.; Juluri, K.R.; Resnick, A.C.; Snyder, S.H.
Gene deletion of inositol hexakisphosphate kinase 1 reveals inositol pyrophosphate regulation of insulin secretion, growth, and spermiogenesis
Proc. Natl. Acad. Sci. USA
105
2349-2353
2008
Mus musculus
Jadav, R.S.; Chanduri, M.V.; Sengupta, S.; Bhandari, R.
Inositol pyrophosphate synthesis by inositol hexakisphosphate kinase 1 is required for homologous recombination repair
J. Biol. Chem.
288
3312-3321
2013
Mus musculus
Chakraborty, A.; Latapy, C.; Xu, J.; Snyder, S.H.; Beaulieu, J.M.
Inositol hexakisphosphate kinase-1 regulates behavioral responses via GSK3 signaling pathways
Mol. Psychiatry
19
284-293
2014
Mus musculus
Prasad, A.; Jia, Y.; Chakraborty, A.; Li, Y.; Jain, S.K.; Zhong, J.; Roy, S.G.; Loison, F.; Mondal, S.; Sakai, J.; Blanchard, C.; Snyder, S.H.; Luo, H.R.
Inositol hexakisphosphate kinase 1 regulates neutrophil function in innate immunity by inhibiting phosphatidylinositol-(3,4,5)-trisphosphate signaling
Nat. Immunol.
12
752-760
2011
Homo sapiens, Mus musculus
Zhang, Z.; Liang, D.; Gao, X.; Zhao, C.; Qin, X.; Xu, Y.; Su, T.; Sun, D.; Li, W.; Wang, H.; Liu, B.; Cao, F.
Selective inhibition of inositol hexakisphosphate kinases (IP6Ks) enhances mesenchymal stem cell engraftment and improves therapeutic efficacy for myocardial infarction
Basic Res. Cardiol.
109
417
2014
Mus musculus (Q6PD10), Mus musculus (Q6ZQB6), Mus musculus (Q80V72), Mus musculus C57BL/6a (Q6PD10), Mus musculus C57BL/6a (Q6ZQB6), Mus musculus C57BL/6a (Q80V72)
Chanduri, M.; Rai, A.; Malla, A.B.; Wu, M.; Fiedler, D.; Mallik, R.; Bhandari, R.
Inositol hexakisphosphate kinase 1 (IP6K1) activity is required for cytoplasmic dynein-driven transport
Biochem. J.
473
3031-3047
2016
Dictyostelium discoideum, Homo sapiens (Q92551), Mus musculus (Q6PD10), Mus musculus C57BL/6 (Q6PD10)
Ghosh, S.; Shukla, D.; Suman, K.; Lakshmi, B.J.; Manorama, R.; Kumar, S.; Bhandari, R.
Inositol hexakisphosphate kinase 1 maintains hemostasis in mice by regulating platelet polyphosphate levels
Blood
122
1478-1486
2013
Mus musculus (Q6PD10), Mus musculus C57BL/6 (Q6PD10)
Jadav, R.S.; Kumar, D.; Buwa, N.; Ganguli, S.; Thampatty, S.R.; Balasubramanian, N.; Bhandari, R.
Deletion of inositol hexakisphosphate kinase 1 (IP6K1) reduces cell migration and invasion, conferring protection from aerodigestive tract carcinoma in mice
Cell. Signal.
28
1124-1136
2016
Mus musculus (Q6PD10), Mus musculus
Ghoshal, S.; Tyagi, R.; Zhu, Q.; Chakraborty, A.
Inositol hexakisphosphate kinase-1 interacts with perilipin1 to modulate lipolysis
Int. J. Biochem. Cell Biol.
78
149-155
2016
Mus musculus (Q6PD10)
Yu, W.; Ye, C.; Greenberg, M.L.
Inositol hexakisphosphate kinase 1 (IP6K1) regulates inositol synthesis in mammalian cells
J. Biol. Chem.
291
10437-10444
2016
Mus musculus (Q6PD10)
Niger, C.; Luciotti, M.A.; Buo, A.M.; Hebert, C.; Ma, V.; Stains, J.P.
The regulation of runt-related transcription factor 2 by fibroblast growth factor-2 and connexin43 requires the inositol polyphosphate/protein kinase Cdelta cascade
J. Bone Miner. Res.
28
1468-1477
2013
Mus musculus (Q6PD10), Mus musculus (Q80V72), Mus musculus (Q8BWD2)
Fu, C.; Xu, J.; Li, R.J.; Crawford, J.A.; Khan, A.B.; Ma, T.M.; Cha, J.Y.; Snowman, A.M.; Pletnikov, M.V.; Snyder, S.H.
Inositol hexakisphosphate kinase-3 regulates the morphology and synapse formation of cerebellar Purkinje cells via spectrin/adducin
J. Neurosci.
35
11056-11067
2015
Mus musculus (Q8BWD2)
Rao, F.; Xu, J.; Khan, A.B.; Gadalla, M.M.; Cha, J.Y.; Xu, R.; Tyagi, R.; Dang, Y.; Chakraborty, A.; Snyder, S.H.
Inositol hexakisphosphate kinase-1 mediates assembly/disassembly of the CRL4-signalosome complex to regulate DNA repair and cell death
Proc. Natl. Acad. Sci. USA
111
16005-16010
2014
Mus musculus (Q6PD10)
Rajasekaran, S.S.; Kim, J.; Gaboardi, G.C.; Gromada, J.; Shears, S.B.; Dos Santos, K.T.; Nolasco, E.L.; Ferreira, S.S.; Illies, C.; Koehler, M.; Gu, C.; Ryu, S.H.; Martins, J.O.; Dare, E.; Barker, C.J.; Berggren, P.O.
Inositol hexakisphosphate kinase 1 is a metabolic sensor in pancreatic beta-cells
Cell. Signal.
46
120-128
2018
Mus musculus (Q6PD10), Homo sapiens (Q92551)
Nagpal, L.; Fu, C.; Snyder, S.H.
Inositol hexakisphosphate kinase-2 in cerebellar granule cells regulates Purkinje cells and motor coordination via protein 4.1N
J. Neurosci.
38
7409-7419
2018
Mus musculus (Q80V72)
Kim, M.G.; Zhang, S.; Park, H.; Park, S.J.; Kim, S.; Chung, C.
Inositol hexakisphosphate kinase-1 is a key mediator of prepulse inhibition and short-term fear memory
Mol. Brain
13
72
2020
Mus musculus (Q6PD10), Mus musculus
Fu, C.; Xu, J.; Cheng, W.; Rojas, T.; Chin, A.C.; Snowman, A.M.; Harraz, M.M.; Snyder, S.H.
Neuronal migration is mediated by inositol hexakisphosphate kinase 1 via alpha-actinin and focal adhesion kinase
Proc. Natl. Acad. Sci. USA
114
2036-2041
2017
Mus musculus (Q6PD10)
Rojas, T.; Cheng, W.; Gao, Z.; Liu, X.; Wang, Y.; Malla, A.P.; Chin, A.C.; Romer, L.H.; Snyder, S.H.; Fu, C.
Inositol hexakisphosphate kinase 3 promotes focal adhesion turnover via interactions with dynein intermediate chain 2
Proc. Natl. Acad. Sci. USA
116
3278-3287
2019
Mus musculus (Q8BWD2), Homo sapiens (Q96PC2)
Chin, A.; Gao, Z.; Riley, A.; Furkert, D.; Wittwer, C.; Dutta, A.; Rojas, T.; Semenza, E.; Felder, R.; Pluznick, J.; Jessen, H.; Fiedler, D.; Potter, B.; Snyder, S.; Fu, C.
The inositol pyrophosphate 5-InsP7drives sodium-potassium pump degradation by relieving an autoinhibitory domain of PI3K p85alpha
Sci. Adv.
6
eabb8542
2020
Mus musculus (Q6PD10)
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