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evolution
a member of the inositol 1,4,5-trisphosphate 3-kinases family
evolution
inositol(1,4,5)trisphosphate 3-kinases (Itpks) occur in three isoenzyme forms, Itpka/b and c, in human, rat and mouse. They share a catalytic domain relatively well conserved at the C-terminal end and a quite isoenzyme specific regulatory domain at the N-terminal end of the protein
evolution
inositol(1,4,5)trisphosphate 3-kinases (Itpks) occur in three isoenzyme forms, Itpka/b and c, in human, rat and mouse. They share a catalytic domain relatively well conserved at the C-terminal end and a quite isoenzyme specific regulatory domain at the N-terminal end of the protein
evolution
inositol(1,4,5)trisphosphate 3-kinases (Itpks) occur in three isoenzyme forms, Itpka/b and c, in human, rat and mouse. They share a catalytic domain relatively well conserved at the C-terminal end and a quite isoenzyme specific regulatory domain at the N-terminal end of the protein
evolution
enzyme IP3 3-kinase 2 (IP3K2) is a member of the inositol polyphosphate kinase gene family
evolution
inositol 1,4,5-trisphosphate 3-kinase C (ITPKC) is the last identified member of the inositol 1,4,5-trisphosphate 3-kinases family which phosphorylates inositol 1,4,5-trisphosphate into inositol 1,3,4,5-tetrakisphosphate
malfunction
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disruption of InsP3KB leads to impaired T cell and B cell development as well as hyperactivation of neutrophils, in InsP3KB null mice, the bone marrow granulocyte monocyte progenitor (GMP) population is expanded, and GMP cells proliferated significantly faster, neutrophil production in the bone marrow is enhanced, and the peripheral blood neutrophil count is also substantially elevated, neutrophil apoptotic death is enhanced in enzyme knock-out mice, disruption of enzyme promotes myeloid differentiation
malfunction
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enzyme knock-out mice show deficits of synaptic plasticity in perforant path and in hippocampal-dependent memory performances
malfunction
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In transgenic mice that also express soluble hen egg lysozyme, lack of inositol 1,4,5-trisphosphate 3-kinase B converts anergy induction to deletion, mice lacking inositol 1,4,5-trisphosphate 3-kinase B have normal B cell development in the bone marrow, but reduced numbers of all splenic B cell subsets and a shift in the developmental fate toward compartments that are normally selected by strong B cell receptor signals, mature B cells lacking the enzyme fail to proliferate in response to B cell receptor stimulation but show normal responses to the TLR4 ligand LPS or agonistic Abs to CD40. At the immature stage, inositol 1,4,5-trisphosphate 3-kinase B-deficient mice possess a 60% increase in the numbers of immature B cells compared with wild type mice. Examination of splenic B cell populations in inositol 1,4,5-trisphosphate 3-kinase B-deficient/IgHEL tg mice reveals that while the total numbers of B220+ cells are relatively normal, the numbers of follicular mature B cells are increased 2.2fold, while the number of T2 and marginal zone cells are reduced 3- and 3.8fold
malfunction
genetic abrogation of IP3K-A alters amygdala gene expression, particularly in genes involved in key intracellular signaling pathways and genes mediating fear- and anxiety-related behaviors. In agreement with the changes in amygdala gene expression profiles, IP3K-A knockout mice display more robust responses to aversive stimuli and spend less time in the open arms of the elevated plus maze, indicating high levels of innate fear and anxiety. IP3K-A KO mice show decreased excitatory and inhibitory postsynaptic current and reduced c-Fos immunoreactivity in the central nucleus of the amygdala. Overexpression of inositol 1,4,5-trisphosphate 3-kinases isozymes consistently suppresses inositol 1,4,5-trisphosphate-evoked increases in intracellular calcium in response to an agonist, whereas deletion or inactivation of different genes elicits diverse phenotypes depending on cell type. Genetic deletion of IP3K-A produces deficits in long-term potentiation in the dentate gyrus and impairs memory performance. Deletion does not affect spatial learning in the Morris water maze. Phenotypes, overview
malfunction
isozyme Itpka-deficient mice exhibit increased LTP in the CA1 region of the hippocampus
malfunction
ITPKA depletion in mice increases the number of hippocampal spine-synapses while reducing average spine length, depletion of ITPKA reduces the length of dendritic spines of hippocampal pyramidal cells
malfunction
mice deficient for Itpkb have a severe defect in thymocytes differentiation and thus lack peripheral T cells
malfunction
mice genetically-deficient for the B isoform of the inositol 1,4,5-trisphosphate 3-kinase have a severe defect in thymocytes differentiation and thus lack peripheral T cells. Mutant T cells show an increased activated/memory phenotype as well as a decreased proliferative capacity and survival, Itpkb-deficient peripheral T cells have also an increased capacity to secrete cytokines upon stimulation
malfunction
neurite length is significantly decreased in cells overexpressing isozymes Itpka and Itpkb but not Itpkc or IPMK. This result does not depend on the overexpression level of any of the kinases. PC-12 cells overexpressing GFP-tagged kinase-dead mutants Itpka/b have shorter neurites than GFP control cells
malfunction
neurite length is significantly decreased in cells overexpressing isozymes Itpka and Itpkb but not Itpkc or IPMK. This result does not depend on the overexpression level of any of the kinases. PC12 cells overexpressing GFP-tagged kinase-dead mutants Itpka/b have shorter neurites than GFP control cells
malfunction
downregulation of ITPKA in lung adenocarcinoma cancers reduced both, tumor growth and metastasis. Re-expression of wild-type ITPKA completely restores reduced transmigration of ITPKA-depleted cells. Combined inhibition of F-actin bundling and InsP3Kinase activity should inhibit metastasis at early (adhesion, invasion) and late steps (colonization at secondary sites) of metastasis. Inhibition of cellular InsP3Kinase by BIP-4 reduces important steps in the metastatic cascade
malfunction
genetic abrogation of IP3K-A alters amygdala gene expression, particularly in genes involved in key intracellular signaling pathways and genes mediating fear- and anxiety-related behaviors. In agreement with the changes in amygdala gene expression profiles, IP3K-A knockout (KO) mice display more robust responses to aversive stimuli and spent less time in the open arms of the elevated plus maze, indicating high levels of innate fear and anxiety. Decreased excitatory and inhibitory postsynaptic current and reduced c-Fos immunoreactivity are found in the CeA of IP3K-A KO mice
malfunction
IP3K-A knockout mice exhibit deficits in some forms of hippocampus-dependent learning and synaptic plasticity, such as long-term potentiation in the dentate gyrus synapses of the hippocampus. Enzyme overexpressing mutant Tg mice show an increase in both presynaptic release probability of evoked responses, along with bigger synaptic vesicle pools, and miniature excitatory postsynaptic current amplitude, although the spine density or the expression levels of the postsynaptic density-related proteins NR2B, synaptotagmin 1, and PSD-95 are not affected. Hippocampal-dependent learning and memory tasks, including novel object recognition and radial arm maze tasks, are partially impaired in Tg mice. (R,S)-3,5-dihydroxyphenylglycine-induced metabotropic glutamate receptor long-term depression is inhibited in Tg mice and this inhibition is dependent on protein kinase C but not on the IP3 receptor. Long-term potentiation and depression dependent on N-methyl-D-aspartate receptor are marginally affected in Tg mice. The CA1 synapse of Tg mouse have greater evoked synaptic transmission efficacy in mutant mice compared too wild-type
malfunction
ITPKA depletion in mice results in altered synaptic plasticity and thus in impaired learning and memory. Stable knockdown of ITPKA in high expressing tumor cells results in decreased cell growth, colony formation and suppression of xenograft growth in immunosuppressed mice. Stable knockdown of ITPKA suppresses xenograft growth in immunosuppressed mice
malfunction
Itpka-deficient mice exhibit a weak metabolic phenotype, in keeping with functional studies revealing no clear role of ITPKA in metabolic organs. Broad phenotypic screening of itpka-deficient mice, Effects of itpka deficiency on brain function, overview. Among the neurobehavioral tests analyzed, itpka-deficient mice reacted faster to a hot plate, prepulse inhibition is impaired and the accelerating rotarod test shows decreased latency of itpka deficient mice to fall. Analysis of extracerebral functions in control and itpka deficient mice reveals significantly reduced glucose, lactate, and triglyceride plasma concentrations in itpka-deficient mice. Itpka deficiency affects energy metabolism, phenotype. Reduced glucose level is measured in plasma of itpka-deficient mice
malfunction
mutant alleles of wavy (wy), a classic locus of the fruit fly Drosophila melanogaster, map to IP3 3-kinase 2 (IP3K2). Mutations in wy disrupt wing structure in a highly specific pattern. RNAi experiments using GAL4 and GAL80ts. Gradations in the severity of the wy phenotype provide high-resolution readouts of IP3K2 function and of overall IP3 signaling are analyzed. A dominant modifier screen reveals that mutations in IP3R strongly suppress the wy phenotype, suggesting that the wy phenotype results from reduced IP4 levels, and/or excessive IP3R signaling. Potential models for how IP3K2 affects wing morphology and how mutations in IP3R dominantly suppress the wy phenotype, modeling the interactions between wavy and IP3R, overview
malfunction
the expression of microRNA-140, termed miR-140-5p, is highly induced during chemotherapy of osteosarcoma cells accompanied by upregulated autophagy. The increased miR-140-5p expression levels upregulate anticancer drug-induced autophagy in osteosarcoma cells and ameliorate the anticancer drug-induced cell proliferation and viability decrease. miR-140-5p regulates this context-specific autophagy through its target, inositol 1,4,5-trisphosphate kinase 2 (IP3k2). miR-140-5p mediated drug-resistance in osteosarcoma cells occurs by inducing autophagy, and miRNA regulation of autophagy through modulation of IP3 signalling. IP3K2 expression and Ca2+ entry are upregulated in osteosarcoma cells following treatment with chemotherapeutic drugs
malfunction
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ITPKA depletion in mice increases the number of hippocampal spine-synapses while reducing average spine length, depletion of ITPKA reduces the length of dendritic spines of hippocampal pyramidal cells
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malfunction
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genetic abrogation of IP3K-A alters amygdala gene expression, particularly in genes involved in key intracellular signaling pathways and genes mediating fear- and anxiety-related behaviors. In agreement with the changes in amygdala gene expression profiles, IP3K-A knockout (KO) mice display more robust responses to aversive stimuli and spent less time in the open arms of the elevated plus maze, indicating high levels of innate fear and anxiety. Decreased excitatory and inhibitory postsynaptic current and reduced c-Fos immunoreactivity are found in the CeA of IP3K-A KO mice
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malfunction
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genetic abrogation of IP3K-A alters amygdala gene expression, particularly in genes involved in key intracellular signaling pathways and genes mediating fear- and anxiety-related behaviors. In agreement with the changes in amygdala gene expression profiles, IP3K-A knockout mice display more robust responses to aversive stimuli and spend less time in the open arms of the elevated plus maze, indicating high levels of innate fear and anxiety. IP3K-A KO mice show decreased excitatory and inhibitory postsynaptic current and reduced c-Fos immunoreactivity in the central nucleus of the amygdala. Overexpression of inositol 1,4,5-trisphosphate 3-kinases isozymes consistently suppresses inositol 1,4,5-trisphosphate-evoked increases in intracellular calcium in response to an agonist, whereas deletion or inactivation of different genes elicits diverse phenotypes depending on cell type. Genetic deletion of IP3K-A produces deficits in long-term potentiation in the dentate gyrus and impairs memory performance. Deletion does not affect spatial learning in the Morris water maze. Phenotypes, overview
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metabolism
1D-myo-inositol 1,3,4,5-tetrakisphosphate, Ins(1,3,4,5)P4 can interact with a relatively specific Ins(1,3,4,5)P4 binding protein Rasa3, alternatively, Ins(1,3,4,5)P4 can also compete with phosphoinositides to the binding of PH domain containing proteins such as Akt, protein kinase B. In neutrophils and hematopoietic progenitors, elevated levels of Ins(1,3,4,5)P4 inhibit the recruitment of Akt at the plasma membrane, and its activation, acting as a competitor of PtdIns(3,4,5)P3 binding to its PH domain
metabolism
1D-myo-inositol 1,3,4,5-tetrakisphosphate, Ins(1,3,4,5)P4 can interact with a relatively specific Ins(1,3,4,5)P4 binding protein Rasa3, alternatively, Ins(1,3,4,5)P4 can also compete with phosphoinositides to the binding of PH domain containing proteins such as Akt, protein kinase B. In neutrophils and hematopoietic progenitors, elevated levels of Ins(1,3,4,5)P4 inhibit the recruitment of Akt at the plasma membrane, and its activation, acting as a competitor of PtdIns(3,4,5)P3 binding to its PH domain
metabolism
1D-myo-inositol 1,3,4,5-tetrakisphosphate, Ins(1,3,4,5)P4 can interact with a relatively specific Ins(1,3,4,5)P4 binding protein Rasa3, alternatively, Ins(1,3,4,5)P4 can also compete with phosphoinositides to the binding of PH domain containing proteins such as Akt, protein kinase B. In neutrophils and hematopoietic progenitors, elevated levels of Ins(1,3,4,5)P4 inhibit the recruitment of Akt at the plasma membrane, and its activation, acting as a competitor of PtdIns(3,4,5)P3 binding to its PH domain
metabolism
isozyme IP3K-A expression is highly enriched in the central nucleus of the amygdala, which plays a pivotal role in the processing and expression of emotional phenotypes in mammals
metabolism
inositol 1,4,5-trisphosphate (IP3) regulates a host of biological processes from egg activation to cell death. When IP3-specific receptors (IP3Rs) bind to IP3, they release calcium from the ER into the cytoplasm, triggering a variety of cell type- and developmental stage-specific responses. Alternatively, inositol polyphosphate kinases can phosphorylate IP3. This limits IP3R activation by reducing IP3 levels, and also generates new signaling molecules altogether. The divergent pathways draw from the same IP3 pool yet cause very different cellular responses. Controlling the relative rates of IP3R activation vs. phosphorylation of IP3 is essential for proper cell functioning. Modeling the interactions between wavy and IP3R
metabolism
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main mechanisms of platelet calcium signaling implemented in the model. The model includes two main compartments: cytosol and dense tubular system (DTS). Thrombin binding to PAR1 receptor leads to phospholipase C (PLC) activation and inositol-3-phosphate (IP3) release into cytosol. IP3 binding to its receptors (IP3R) in the DTS membrane opens this channels for release of calcium that is normally contained in the DTS because of the SERCA pump action. Cytosolic IP3 is being phosphorylated by inositol triphosphate-kinase (IP3K) into IP4 that might be included in the phosphoinositide turnover. Two feedback loops: a PLC-dependent positive feedback loop and the IP3K-dependent negative loop. System modeling, overview
metabolism
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isozyme IP3K-A expression is highly enriched in the central nucleus of the amygdala, which plays a pivotal role in the processing and expression of emotional phenotypes in mammals
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physiological function
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inositol 1,4,5-trisphosphate 3-kinase B converts inositol 1,4,5-trisphosphate to inositol 1,3,4,5-tetrakisphosphate upon Ag receptor activation and controls the fate and function of lymphocytes
physiological function
inositol-1,4,5-trisphosphate-3-kinase-A is a cell motility-promoting protein that increases the metastatic potential of tumour cells by 2 functional activities: it promotes migration of tumour cells by 2 different mechanisms: growth factor independently, high levels of inositol-1,4,5-trisphosphate-3-kinase-A induce the formation of large cellular protrusions by directly modulating the actin cytoskeleton, the F-actin binding activity of inositol-1,4,5-trisphosphate-3-kinase-A stabilizes and bundles actin filaments and thus increases the levels of cellular F-actin, in growth factor stimulated cells, the catalytically active domain enhances basal inositol-1,4,5-trisphosphate-3-kinase-A induced migration by activating store-operated calcium entry through production of inositol-1,3,4,5-tetrakisphosphate and subsequent inhibition of inositol-phosphate-5-phosphatase
physiological function
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on neural activation, inositol 1,4,5-trisphosphate 3-kinase A binds directly to activated Rac1 and recruits it to the actin cytoskeleton in the postsynaptic area, enzyme is critical for the spatial and temporal regulation of spine actin remodeling, synaptic plasticity, and learning and memory via an activity-dependent Rac scaffolding mechanism, inositol 1,4,5-trisphosphate 3-kinase A catalytic activity regulates calcium levels by modulating the metabolism of 1D-myo-inositol 1,4,5-trisphosphate
physiological function
on neural activation, inositol 1,4,5-trisphosphate 3-kinase A binds directly to activated Rac1 and recruits it to the actin cytoskeleton in the postsynaptic area, enzyme is critical for the spatial and temporal regulation of spine actin remodeling, synaptic plasticity, and learning and memory via an activity-dependent Rac scaffolding mechanism, inositol 1,4,5-trisphosphate 3-kinase A catalytic activity regulates calcium levels by modulating the metabolism of 1D-myo-inositol 1,4,5-trisphosphate
physiological function
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physiological modulator of myelopoiesis, enzyme plays a crucial role in hematopoiesis
physiological function
cell-specific inositol phosphate signalling specifically via inositol 1,4,5-trisphosphate 3-kinase, negatively regulates organismal responses to oxidative stress. The Drosophila malpighian tubule is a key epithelial sensor for organismal oxidative stress responses, precise targeting of either gain-of-function constructs of isoforms IP3K-1 and IP3K-2, or loss-of-function constructs to only one cell type in tubule reversibly modulates survival of stress-challenged adult flies
physiological function
cell-specific inositol phosphate signalling specifically via inositol 1,4,5-trisphosphate 3-kinase, negatively regulates organismal responses to oxidative stress. The Drosophila malpighian tubule is a key epithelial sensor for organismal oxidative stress responses, precise targeting of either gain-of-function constructs of isoforms IP3K-1 and IP3K-2, or loss-of-function constructs to only one cell type in tubule reversibly modulates survival of stress-challenged adult flies. In vivo, targeted isoform IP3K-1 directly increases H2O2 production, pro-apoptotic caspase-9 activity and mitochondrial membrane potential. The mitochondrial calcium load in tubule principal cells is significantly increased by isoform IP3K-1 under oxidative stress conditions, leading to apoptosis
physiological function
isoform inositol 1,4,5-trisphosphate 3-kinase A is ectopically expressed in different human tumor cell lines and during tumor progression in the metastatic tumor model Balb-neuT. High expression of isoform 1,4,5-trisphosphate 3-kinase A increases invasive migration in vitro and metastasis in a xenograft SCID mouse model. 1,4,5-Trisphosphate 3-kinase A promotes migration of tumor cells by two different mechanisms: growth factor independently high levels of enzyme induce the formation of large cellular protrusions by directly modulating the actin cytoskeleton. The F-actin binding activity of 1,4,5-trisphosphate 3-kinase A stabilizes and bundles actin filaments and thus increases the levels of cellular F-actin. In growth factor-stimulated cells, the catalytically active domain enhances basal 1,4,5-trisphosphate 3-kinase A-induced migration by activating store-operated calcium entry through production of inositol 1,3,4,5-tetrakisphosphate and subsequent inhibition of inositol phosphate 5-phosphatase
physiological function
isoform inositol 1,4,5-trisphosphate 3-kinase B is important for the control of Bim protein expression and B cell survival rather than for the control of B cell development from one stage to another. B cell receptor transgenic inositol 1,4,5-trisphosphate 3-kinase B-/- B cells exhibit an anergic phenotype with the notable exception of their enhanced antigen-induced calcium signalling. On a deleting H2-Kb genetic background, inositol 1,4,5-trisphosphate 3-kinase B is not essential for B cell receptor editing or negative selection
physiological function
overexpression of isoform inositol-1,4,5-trisphosphate 3-kinase A increases the number of dendritic protrusions by 71% in immature primary neurons. In mature neurons, the effect of inositol-1,4,5-trisphosphate 3-kinase A overexpression on formation of dendritic spines is weaker and depletion of the enzyme does not alter spine density and synaptic contacts. In synaptosomes of mature neurons, enzyme loss results in decreased duration of Ins(1,4,5)P3 signals and shorter Ins(1,4,5)P3-dependent Ca2+ transients. At synapses of inositol-1,4,5-trisphosphate 3-kinase A deficient neurons the levels of Ins(1,4,5)P3-5-phosphatase and sarcoplasmic/endoplasmic reticulum calcium ATPase pump-2b are increased
physiological function
1D-myo-inositol 1,4,5-trisphosphate is a key point in Ca2+ metabolism that promotes Ca2+ release from intracellular stores and together with 1D-myo-inositol 1,3,4,5-tetrakisphosphate regulates Ca2+ homoeostasis. In addition, 1D-myo-inositol 1,3,4,5-tetrakisphosphate is involved in immune cell development. Ca2+ and calmodulin regulate the activity of inositol(1,4,5)trisphosphate 3-kinases via direct interaction
physiological function
ectopic expression of the neuron-specific inositol-1,4,5-trisphosphate-3-kinase A in lung cancer cells increases their metastatic potential because the protein exhibits two actin regulating activities. The isozyme ITPKA bundles actin filaments and regulates inositol-1,4,5-trisphosphate (InsP3)-mediated calcium signals by phosphorylating InsP3
physiological function
functional role of isozyme Itpkb in peripheral T cells, potential role for Itpkb in autoimmunity
physiological function
in addition to cross-linking actin filaments, ITPKA strongly inhibits Arp2/3-complex induced actin filament branching by displacing the complex from F-actin. n vivo ITPKA negatively regulates formation and/or maintenance of synaptic contacts in the mammalian brain. On the molecular level this effect appears to result from the ITPKA-mediated inhibition of Arp2/3-complex F-actin branching activity. ITPKA does not affect the F-actin bundling activity of drebrin A
physiological function
in natural killer (NK) cells, isozyme Itpkb promotes NK-cell terminal maturation but limits NK-cell effector functions
physiological function
in natural killer (NK) cells, isozyme Itpkb promotes NK-cell terminal maturation but limits NK-cell effector functions. Itpka and Itpkb isoforms inhibit neurite outgrowth in PC12 cells, while isozyme Itpkc does not
physiological function
in natural killer (NK) cells, isozyme Itpkb promotes NK-cell terminal maturation but limits NK-cell effector functions. Itpkb controls hematopoietic stem cell homeostasis and prevents lethal hematopoietic failure in mice
physiological function
isozyme IP3K-A has a profound influence on the basal activities of fear- and anxiety-mediating amygdala circuitry and plays an important role in regulating affective states by modulating metabotropic receptor signaling pathways and neural activity in the amygdala. Inositol 1,4,5-trisphosphate 3-kinases modulate intracellular calcium signaling induced by the activation of G-protein coupled receptors associated with phospholipase C. Isozyme IP3K-A is enriched in dendritic spines of mature neurons and modulates actin dynamics in the hippocampus
physiological function
isozyme Itpka contains an F-actin binding site at the N-terminal part that confers to Itpka the properties of an F-actin bundling protein with two major consequences: it can reorganize the cytoskeletal network, particularly in dendritic spines, and it can provide an opportunity for Ins(1,3,4,5)P4 to act very locally as second messenger. Isozyme Itpka is an F-actin bundling protein regulating dendritic spines structural plasticity and a scaffold protein for synaptic rac signaling, Itpka overexpression induces cytoskeletal reorganization, high expression of Itpka in cancer cells increases invasion and migration in vitro
physiological function
isozyme Itpka contains an F-actin binding site at the N-terminal part that confers to Itpka the properties of an F-actin bundling protein with two major consequences: it can reorganize the cytoskeletal network, particularly in dendritic spines, and it can provide an opportunity for Ins(1,3,4,5)P4 to act very locally as second messenger. Isozyme Itpka is an F-actin bundling protein regulating dendritic spines structural plasticity and a scaffold protein for synaptic rac signaling, Itpka overexpression induces cytoskeletal reorganization, high expression of Itpka in cancer cells increases invasion and migration in vitro
physiological function
isozyme Itpka contains an F-actin binding site at the N-terminal part that confers to Itpka the properties of an F-actin bundling protein with two major consequences: it can reorganize the cytoskeletal network, particularly in dendritic spines, and it can provide an opportunity for Ins(1,3,4,5)P4 to act very locally as second messenger. Isozyme Itpka is an F-actin bundling protein regulating dendritic spines structural plasticity and a scaffold protein for synaptic rac signaling, Itpka overexpression induces cytoskeletal reorganization, high expression of Itpka in cancer cells increases invasion and migration in vitro. Itpka and Itpkb isoforms inhibit neurite outgrowth in PC12 cells, while isozyme Itpkc does not
physiological function
isozyme ITPKA induces formation of complex actin networks, but exibits only one N-terminal actin binding domain, the C-terminus of ITPKA acts as spacer between actin filaments, overview. ITPKA induces the formation of a dense network of branched actin filaments, not of linear filaments. Overexpression of ITPKA induces the formation of lamellipodia-like protrusions which consist of cross-linked actin filaments. 1D-myo-inositol 1,3,4,5-tetrakisphosphate inhibits actin polymerization, but does not show a significant effect on bundling activity of ITPKA, while binding of ITPKA to actin stimulates inositol-1,4,5-trisphosphate 3-kinase-a activity
physiological function
isozyme Itpka inhibits neurite outgrowth through both F-actin binding
physiological function
isozyme Itpkb inhibits neurite outgrowth through both F-actin binding
physiological function
isozyme Itpkc does not influence neurite length and neuron growth or F-actin binding
physiological function
Itpka and Itpkb isoforms inhibit neurite outgrowth in PC12 cells, while isozyme Itpkc does not
physiological function
role for ITPKC either in the development or the function of these specialized cellular structures
physiological function
among the ITPK-isoforms ITPKA is the most specialized one. In cells it is exclusively bound to F-actin resulting in cross-linking of actin filaments. ITPKA has two very distinct functions, regulating both, calcium signaling and actin dynamics. Isoform A of ITPK is an oncogene, it is involved in cancer progression, tumor growth is stimulated by the InsP3Kinase activity of ITPKA and metastasis by its actin bundling activity. ITPKA regulates actin dynamics by binding with its homodimeric N-terminal actin binding domain (ABD) to F-actin
physiological function
among the ITPK-isoforms ITPKA is the most specialized one. In cells it is exclusively bound to F-actin resulting in cross-linking of actin filaments. ITPKA has two very distinct functions, regulating both, calcium signaling and actin dynamics. Isoform A of ITPK is an oncogene, it is involved in cancer progression, tumor growth is stimulated by the InsP3Kinase activity of ITPKA and metastasis by its actin bundling activity. ITPKA regulates actin dynamics by binding with its homodimeric N-terminal actin binding domain (ABD) to F-actin. The bulky C-terminus, which includes the InsP3Kinase-domain, acts as spacer between actin filaments resulting in formation of loose networks of F-actin bundles. Cellular calcium signals are regulated by the InsP3Kinase activity of ITPKA. Calcium is an ubiquitous second messenger that is involved in many signal transduction pathways, including protein kinase C and CAMKII signaling. ITPKA phosphorylates the calcium-mobilizing second messenger Ins(1,4,5)P3 at 3'-position, thereby producing Ins(1,3,4,5)P4. Since the Ins(1,4,5)P3 loop binds Ins(1,4,5)P3 with high affinity, but no other InsP-isomers or phosphatidylinositol phosphates, ITPKA is a highly specialized enzyme. Ins(1,3,4,5)P4 is substantially involved in the control of Ins(1,4,5)P3-mediated calcium release. The (1,4,5)P3 phosphatase INPP5A binds Ins(1,3,4,5)P4 with tenfold higher affinity than Ins(1,4,5)P3, resulting in decreased (1,4,5)P3 dephosphorylation. Therefore, production of Ins (1,3,4,5)P4 increases half-life of Ins(1,4,5)P3, thus Ins(1,4,5)P3-mediated calcium release from the endoplasmic reticulum. Based on this property, in the absence of ITPKA calcium release is shortened and calcium-induced calcium entry abrogated. ITPKA is involved in both, the control of calcium signals and the control of dendritic spine morphology. ITPKA belongs to the invasive signature of p130Cas/ErbB2 transformed breast cancer cells showing that in different tumor entities expression of ITPKA is associated with malignancy of tumor cells. Regulation of ITPKA expression in tumor cells, overview
physiological function
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analysis of the roles of feedbacks through phospholipase C and inositol 1,4,5-trisphosphate 3-kinase (IP3K) by means of a computer model of calcium signal transduction in platelets
physiological function
cells positive for ITPKC in the studied tissues express either a multicilium (tracheal and bronchial epithelia, brain ependymal cells), microvilli forming a brush border (small and large intestine, and kidney proximal tubule cells) or a flagellum (spermatozoa), suggesting a role for ITPKC either in the development or the function of these specialized cellular structures
physiological function
inositol 1,4,5-trisphosphate 3-kinase A (IP3K-A) is enriched in the brain and neurons that regulates intracellular calcium levels via signaling through the inositol trisphosphate receptor. IP3K-A expression is highly enriched in the central nucleus of the amygdala (CeA), which plays a pivotal role in the processing and expression of emotional phenotypes in mammals. IP3K-A has a profound influence on the basal activities of fear- and anxiety-mediating amygdala circuitry. IP3K-A plays an important role in regulating affective states by modulating metabotropic receptor signaling pathways and neural activity in the amygdala
physiological function
inositol 1,4,5-trisphosphate 3-kinase A (IP3K-A) regulates the level of the inositol polyphosphates, inositol trisphosphate (IP3) and inositol tetrakisphosphate to modulate cellular signaling and intracellular calcium homeostasis in the central nervous system. IP3K-A binds to F-actin in an activity-dependent manner and accumulates in dendritic spines, where it is involved in the regulation of synaptic plasticity. Overexpressed IP3K-A plays a role in some forms of hippocampus-dependent learning and memory tasks as well as in synaptic transmission and plasticity by regulating both presynaptic and postsynaptic functions
physiological function
IP3K2 function is required in the wing discs of early pupae for normal wing development. Controlling the relative rates of IP3R activation vs. phosphorylation of IP3 is essential for proper cell functioning. IP3K2 function is required in the developing wing blade during early pupal life
physiological function
isozyme ITPKA is involved in the regulation of nociceptive pathways, sensorimotor gating, and motor learning. Inositol-1,4,5-trisphosphate 3-kinase-A (ITPKA) is the neuronal isoform of ITPKs and exhibits both actin bundling and InsP3 kinase activity. In addition to neurons, ITPKA is ectopically expressed in tumor cells, where its oncogenic activity increases tumor cell malignancy. ITPKA is involved in the regulation of nociceptive pathways, sensorimotor gating and motor learning. ITPKA plays a functional role in calcium signaling of CaCo-2 cells
physiological function
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in addition to cross-linking actin filaments, ITPKA strongly inhibits Arp2/3-complex induced actin filament branching by displacing the complex from F-actin. n vivo ITPKA negatively regulates formation and/or maintenance of synaptic contacts in the mammalian brain. On the molecular level this effect appears to result from the ITPKA-mediated inhibition of Arp2/3-complex F-actin branching activity. ITPKA does not affect the F-actin bundling activity of drebrin A
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physiological function
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inositol 1,4,5-trisphosphate 3-kinase A (IP3K-A) is enriched in the brain and neurons that regulates intracellular calcium levels via signaling through the inositol trisphosphate receptor. IP3K-A expression is highly enriched in the central nucleus of the amygdala (CeA), which plays a pivotal role in the processing and expression of emotional phenotypes in mammals. IP3K-A has a profound influence on the basal activities of fear- and anxiety-mediating amygdala circuitry. IP3K-A plays an important role in regulating affective states by modulating metabotropic receptor signaling pathways and neural activity in the amygdala
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physiological function
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isozyme IP3K-A has a profound influence on the basal activities of fear- and anxiety-mediating amygdala circuitry and plays an important role in regulating affective states by modulating metabotropic receptor signaling pathways and neural activity in the amygdala. Inositol 1,4,5-trisphosphate 3-kinases modulate intracellular calcium signaling induced by the activation of G-protein coupled receptors associated with phospholipase C. Isozyme IP3K-A is enriched in dendritic spines of mature neurons and modulates actin dynamics in the hippocampus
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additional information
an F-actin binding site is located in the N-terminal part of isozyme Itpka. The catalytic activity is located at the C-terminal end, N-terminal deletion mutants are fully active
additional information
an F-actin binding site is located in the N-terminal part of isozyme Itpka. The catalytic activity is located at the C-terminal end, N-terminal deletion mutants are fully active
additional information
an F-actin binding site is located in the N-terminal part of isozyme Itpka. The catalytic activity is located at the C-terminal end, N-terminal deletion mutants are fully active
additional information
an F-actin binding site is located in the N-terminal part of isozyme Itpkb. The catalytic activity is located at the C-terminal end, N-terminal deletion mutants are fully active
additional information
an F-actin binding site is located in the N-terminal part of isozyme Itpkb. The catalytic activity is located at the C-terminal end, N-terminal deletion mutants are fully active
additional information
an F-actin binding site is located in the N-terminal part of isozyme Itpkb. The catalytic activity is located at the C-terminal end, N-terminal deletion mutants are fully active
additional information
isozyme Itpkb contains an F-actin binding site at the N-terminal part
additional information
isozyme Itpkb contains an F-actin binding site at the N-terminal part
additional information
isozyme Itpkb contains an F-actin binding site at the N-terminal part
additional information
isozyme Itpkb contains an F-actin binding site at the N-terminal part
additional information
isozyme Itpkb contains an F-actin binding site at the N-terminal part
additional information
isozyme Itpkb contains an F-actin binding site at the N-terminal part
additional information
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isozyme Itpkb contains an F-actin binding site at the N-terminal part
additional information
isozyme Itpkb contains an F-actin binding site at the N-terminal part
additional information
isozyme Itpkb contains an F-actin binding site at the N-terminal part
additional information
isozyme Itpkb contains an F-actin binding site at the N-terminal part
additional information
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isozyme Itpkb contains an F-actin binding site at the N-terminal part
additional information
ITPKC functional polymorphism associates with Kawasaki disease susceptibility
additional information
ITPKC functional polymorphism associates with Kawasaki disease susceptibility
additional information
ITPKC functional polymorphism associates with Kawasaki disease susceptibility
additional information
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ITPKC functional polymorphism associates with Kawasaki disease susceptibility
additional information
neurite length is significantly decreased in cells overexpressing isozymes Itpka and Itpkb but not Itpkc or IPMK. This result does not depend on the overexpression level of any of the kinases
additional information
neurite length is significantly decreased in cells overexpressing isozymes Itpka and Itpkb but not Itpkc or IPMK. This result does not depend on the overexpression level of any of the kinases
additional information
neurite length is significantly decreased in cells overexpressing isozymes Itpka and Itpkb but not Itpkc or IPMK. This result does not depend on the overexpression level of any of the kinases