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Literature summary extracted from

  • Windhorst, S.; Song, K.; Gazdar, A.F.
    Inositol-1,4,5-trisphosphate 3-kinase-A (ITPKA) is frequently over-expressed and functions as an oncogene in several tumor types (2017), Biochem. Pharmacol., 137, 1-9 .
    View publication on PubMedView publication on EuropePMC

Application

EC Number Application Comment Organism
2.7.1.127 diagnostics in lung and breast cancer expression of ITPKA is stimulated by gene body methylation, ITPKA gene body methylation occurs early in tumor development. ITPKA enzyme expression may serve as biomarker for early detection of lung cancer Homo sapiens
2.7.1.127 medicine the actin bundling enzyme inositol-trisphosphate 3-kinase A (ITPKA) is a target in tumor therapy, because it is upregulated in tumor but not in corresponding normal cells. Downregulation of ITPKA in lung adenocarcinoma cancers reduced both, tumor growth and metastasis Homo sapiens

Cloned(Commentary)

EC Number Cloned (Comment) Organism
2.7.1.127 gene Itpka Homo sapiens
2.7.1.127 gene Itpka Mus musculus

Protein Variants

EC Number Protein Variants Comment Organism
2.7.1.127 additional information generation of ITPKA knock-out mice that exhibit increased synaptic plasticity and slight impairments of learning and memory Mus musculus

Inhibitors

EC Number Inhibitors Comment Organism Structure
2.7.1.127 2-[3,5-dimethyl-1-(4-nitrophenyl)-1H-pyrazol-4-yl]-5,8-dinitro-1H-benzo[de]isoquinoline-1,3(2H)-dione BIP-4, BIP-4 is competitive to Ins(1,4,5)P3 and shows high selectivity for the Ins(1,4,5)P3 binding pocket, BIP-4 does not block the actin bundling activity of ITPKA Homo sapiens

Localization

EC Number Localization Comment Organism GeneOntology No. Textmining
2.7.1.127 actin filament
-
 Homo sapiens 5884
-
2.7.1.127 actin filament
-
 Mus musculus 5884
-

Metals/Ions

EC Number Metals/Ions Comment Organism Structure
2.7.1.127 Mg2+ required Homo sapiens
2.7.1.127 Mg2+ required Mus musculus

Natural Substrates/ Products (Substrates)

EC Number Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
2.7.1.127 ATP + 1D-myo-inositol 1,4,5-trisphosphate Homo sapiens
-
 ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
-
 ?
2.7.1.127 ATP + 1D-myo-inositol 1,4,5-trisphosphate Mus musculus
-
 ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
-
 ?
2.7.1.127 additional information Homo sapiens ITPKA is a bifunctional protein; it phosphorylates Ins(1,4,5)P3 by its kinase activity and cross-links F-actin by its F-actin bundling activity ?
-
-

Organism

EC Number Organism UniProt Comment Textmining
2.7.1.127 Homo sapiens P23677
-
-
2.7.1.127 Mus musculus Q8R071
-
-

Source Tissue

EC Number Source Tissue Comment Organism Textmining
2.7.1.127 brain high expression level in pyramidal neurons of the CA1 region and the dentate gyrus of the hippocampus Homo sapiens
-
2.7.1.127 breast cancer cell
-
 Homo sapiens
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2.7.1.127 carcinoma cell
-
 Homo sapiens
-
2.7.1.127 carcinoma cell
-
 Mus musculus
-
2.7.1.127 colonic cancer cell
-
 Homo sapiens
-
2.7.1.127 hippocampus
-
 Homo sapiens
-
2.7.1.127 liver cancer cell
-
 Homo sapiens
-
2.7.1.127 lung cancer cell
-
 Homo sapiens
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2.7.1.127 additional information ITPKA is expressed in a broad range of tumor types but shows limited expression in normal cells. ITPKA enzyme expression analysis, overview Homo sapiens
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2.7.1.127 NCI-H1299 cell high expression Homo sapiens
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2.7.1.127 neuron pyramidal, in neurons, ITPKA is concentrated at postsynaptic densities (PSD) of hippocampal dendritic spines Homo sapiens
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2.7.1.127 pancreatic cancer cell
-
 Homo sapiens
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2.7.1.127 prostate gland cancer cell
-
 Homo sapiens
-
2.7.1.127 skin cancer cell
-
 Homo sapiens
-
2.7.1.127 small cell lung cancer cell
-
 Homo sapiens
-
2.7.1.127 testicular cancer cell
-
 Homo sapiens
-
2.7.1.127 thyroid cancer cell
-
 Homo sapiens
-
2.7.1.127 uterine cancer cell
-
 Homo sapiens
-

Substrates and Products (Substrate)

EC Number Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
2.7.1.127 ATP + 1D-myo-inositol 1,4,5-trisphosphate
-
 Homo sapiens ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
-
 ?
2.7.1.127 ATP + 1D-myo-inositol 1,4,5-trisphosphate
-
 Mus musculus ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
-
 ?
2.7.1.127 additional information ITPKA is a bifunctional protein; it phosphorylates Ins(1,4,5)P3 by its kinase activity and cross-links F-actin by its F-actin bundling activity Homo sapiens ?
-
-

Synonyms

EC Number Synonyms Comment Organism
2.7.1.127 inositol-1,4,5-trisphosphate 3-kinase-A
-
 Homo sapiens
2.7.1.127 inositol-1,4,5-trisphosphate 3-kinase-A
-
 Mus musculus
2.7.1.127 InsP3Kinase
-
 Homo sapiens
2.7.1.127 InsP3Kinase
-
 Mus musculus
2.7.1.127 ITPKA
-
 Homo sapiens
2.7.1.127 ITPKA
-
 Mus musculus

Cofactor

EC Number Cofactor Comment Organism Structure
2.7.1.127 ATP
-
 Homo sapiens
2.7.1.127 ATP
-
 Mus musculus

IC50 Value

EC Number IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
2.7.1.127 0.000157
-
 pH and temperature not specified in the publication Homo sapiens 2-[3,5-dimethyl-1-(4-nitrophenyl)-1H-pyrazol-4-yl]-5,8-dinitro-1H-benzo[de]isoquinoline-1,3(2H)-dione

Expression

EC Number Organism Comment Expression
2.7.1.127 Homo sapiens in lung and breast cancer expression of ITPKA is stimulated by gene body methylation, ITPKA gene body methylation occurs early in tumor development up

General Information

EC Number General Information Comment Organism
2.7.1.127 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 Homo sapiens
2.7.1.127 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 Mus musculus
2.7.1.127 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 Mus musculus
2.7.1.127 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 Homo sapiens