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Literature summary for 2.7.1.127 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

Application Comment Organism
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
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)

Cloned (Comment) Organism
gene Itpka Homo sapiens
gene Itpka Mus musculus

Protein Variants

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

Inhibitors

Inhibitors Comment Organism Structure
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

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

Metals/Ions

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

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
ATP + 1D-myo-inositol 1,4,5-trisphosphate Homo sapiens
-
ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
-
?
ATP + 1D-myo-inositol 1,4,5-trisphosphate Mus musculus
-
ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
-
?
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

Organism UniProt Comment Textmining
Homo sapiens P23677
-
-
Mus musculus Q8R071
-
-

Source Tissue

Source Tissue Comment Organism Textmining
brain high expression level in pyramidal neurons of the CA1 region and the dentate gyrus of the hippocampus Homo sapiens
-
breast cancer cell
-
Homo sapiens
-
carcinoma cell
-
Homo sapiens
-
carcinoma cell
-
Mus musculus
-
colonic cancer cell
-
Homo sapiens
-
hippocampus
-
Homo sapiens
-
liver cancer cell
-
Homo sapiens
-
lung cancer cell
-
Homo sapiens
-
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
-
NCI-H1299 cell high expression Homo sapiens
-
neuron pyramidal, in neurons, ITPKA is concentrated at postsynaptic densities (PSD) of hippocampal dendritic spines Homo sapiens
-
pancreatic cancer cell
-
Homo sapiens
-
prostate gland cancer cell
-
Homo sapiens
-
skin cancer cell
-
Homo sapiens
-
small cell lung cancer cell
-
Homo sapiens
-
testicular cancer cell
-
Homo sapiens
-
thyroid cancer cell
-
Homo sapiens
-
uterine cancer cell
-
Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
ATP + 1D-myo-inositol 1,4,5-trisphosphate
-
Homo sapiens ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
-
?
ATP + 1D-myo-inositol 1,4,5-trisphosphate
-
Mus musculus ADP + 1D-myo-inositol 1,3,4,5-tetrakisphosphate
-
?
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

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

Cofactor

Cofactor Comment Organism Structure
ATP
-
Homo sapiens
ATP
-
Mus musculus

IC50 Value

IC50 Value IC50 Value Maximum Comment Organism Inhibitor Structure
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

Organism Comment Expression
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

General Information Comment Organism
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
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
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
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