Inositol-1,4,5-trisphosphate 3-kinase-A (ITPKA) is frequently over-expressed and functions as an oncogene in several tumor types

Abstract

At present targeted tumor therapy is based on inhibition of proteins or protein mutants that are up-regulated in tumor but not in corresponding normal cells. The actin bundling Inositol-trisphosphate 3-kinase A (ITPKA) belongs to such molecular targets. ITPKA is expressed in a broad range of tumor types but shows limited expression in normal cells. In lung and breast cancer expression of ITPKA is stimulated by gene body methylation which increases with increasing malignancy of these tumors but is not detectable in the corresponding normal tissues. Since ITPKA gene body methylation occurs early in tumor development, it could serve as biomarker for early detection of lung cancer. Detailed mechanistic studies revealed that down-regulation of ITPKA in lung adenocarcinoma cancers reduced both, tumor growth and metastasis. It is assumed that tumor growth is stimulated by the InsP3Kinase activity of ITPKA and metastasis by its actin bundling activity. A selective inhibitor against the InsP3Kinase activity of ITPKA has been identified but compounds inhibiting the actin bundling activity are not available yet. Since no curative therapy option for metastatic lung or breast tumors exist, therapies that block activities of ITPKA may offer new options for patients with these tumors. Thus, efforts should be made to develop clinical drugs that selectively target InsP3Kinase activity as well as actin bundling activity of ITPKA.

Mouse Ataxin-2 Expansion Downregulates CamKII and Other Calcium Signaling Factors, Impairing Granule—Purkinje Neuron Synaptic Strength

“…Upon extracellular activation of receptor tyrosine kinases (RTKs) or ionotropic glutamate receptors (e.g., GluAs) or metabotropic glutamate receptors (mGluRs), the phospholipase C (PLC) isoforms are activated at the intracellular plasma membrane leaflet and catalyze the cleavage of PIP 2 (phosphatidylinositol-4,5-bisphosphate) into IP 3 (inositol 1,4,5-trisphosphate), as well as DAG (diacylglycerol) [ 63 , 64 ]. IP 3 may directly bind and activate IP3R leading to Ca 2+ flux from ER to cytosol; alternatively, it can be phosphorylated by ITPKA or de-phosphorylated by INPP5A for recycling [ 65 ]. On the other hand, DAG signals either directly to plasma membrane Ca 2+ channel TRPC3 or indirectly via activating protein kinase C (PKC) [ 63 ].…”

Inhibition of Inositol Polyphosphate Kinases by Quercetin and Related Flavonoids: A Structure–Activity Analysis

“…One such compound, 2-[3,5-Dimethyl-1-(4- nitrophenyl)-1H-pyrazol-4-yl]-5,8-dinitro-1H-benzo[de]isoquin-oline-1,3(2H)-dione (BIP-4), inhibits IP3Ks (Fig. 1) 9, 17 . However, the target specificity profile of BIP-4 is unknown, while its polar nitro groups impede cellular uptake and are potentially toxic in vivo 9, 17 .…”

Excavating thyroid carcinoma risk metabolic genes associated with biological clock by bioinformatics analysis: A study based on TCGA and GEO data

“…In the paper, one hundred and forty-one with the normal controls. The levels of ITPKA that are important in cellular signaling [48] . FBP2 as gluconeogenesis regulatory enzyme which catalyzes the hydrolysis of fructose 1,6-bisphosphate to fructose 6-phosphate and inorganic phosphate [49] .…”