Alternative titles; symbols
HGNC Approved Gene Symbol: IP6K2
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38) : 3:48,688,003-48,717,221 (from NCBI)
Inositol trisphosphate is a messenger molecule that releases calcium from intracellular stores. Homologs with multiple phosphates, including pyrophosphates, have also been identified. Inositol pyrophosphates are formed by several enzymes, including IHPK2 (Saiardi et al., 1999).
By database screening for homologs of rat Ihpk1 (IP6K1; 606991), Saiardi et al. (1999) obtained a cDNA encoding IHPK2, which had been called PiUS because it stimulates the uptake of inorganic phosphate but lacks transporter features. The deduced 426-amino acid protein is 98% identical to the rabbit protein and 48% identical to mouse Ihpk1. It contains a 25-residue conserved sequence also found in ITPKA (147521), ITPKB (147522), and 2 yeast proteins. Western blot analysis showed expression of a 49-kD protein. Northern blot analysis revealed high-level expression of a 1.9-kb transcript in mouse brain and lung, with lower levels in liver, kidney, and testis.
Using confocal microscopy, Saiardi et al. (2001) demonstrated that mouse Ihpk1 is present in both the nucleus and the cytoplasm, whereas IHPK2 is almost exclusively nuclear and IHPK3 is predominantly cytoplasmic.
Saiardi et al. (1999) showed that cells expressing IHPK2 displayed robust InsP6 kinase activity. They proposed that IHPK1 and IHPK2 may act as energy reserves in selected intracellular sites.
Morrison et al. (2002) showed that IHPK2 expression leads to a reduction of colony-forming cells, while overexpression causes increased radiosensitivity. Exposure to beta-interferon (IFNB; 147640) or radiation induced caspase-8 (CASP8; 601763), but only IFNB induced TRAIL (TNFSF10; 603598), and only radiation induced DR4 (TNFRSF10A; 603611). The apoptotic effects of these treatments could be blocked by a dominant-negative mutant of the TRAIL receptor DR5 (TNFRSF10B; 603612) or by BCL2 (151430). Morrison et al. (2002) concluded that IHPK2 expression enhances sensitivity of some ovarian carcinomas to interferon and radiation treatment. Furthermore, they proposed that IHPK2 functions to enhance the expression of CASP8 through different extrinsic receptor-mediated pathways.
Illies et al. (2007) observed that pancreatic beta cells maintain high basal concentrations of the pyrophosphate diphosphoinositol pentakisphosphate (IP7). Inositol hexakisphosphate kinases (IP6Ks) that can generate IP7 were overexpressed. This overexpression stimulated exocytosis of insulin-containing granules from the readily releasable pool. Exogenously applied IP7 dose-dependently enhanced exocytosis at physiologic concentrations. Illies et al. (2007) determined that IP6K1 (606991) and IP6K2 were present in beta cells. RNA silencing of IP6K1, but not IP6K2, inhibited exocytosis, which suggests that IP6K1 is the critical endogenous kinase. Maintenance of high concentrations of IP7 in the pancreatic beta cell may enhance the immediate exocytotic capacity and consequently allow rapid adjustment of insulin secretion in response to increased demand.
Some heat-shock proteins, such as HSP90 (see HSPCA; 140571), can be antiapoptotic and are the targets of anticancer drugs. Increased IP6K2 activity sensitizes cancer cells to stressors, whereas its depletion blocks cell death. Using mouse tissues and human cell lines, Chakraborty et al. (2008) showed that HSP90 physiologically bound IP6K2 and inhibited its catalytic activity. Drugs and selective mutations that abolished HSP90-IP6K2 binding elicited activation of IP6K2, leading to cell death. Chakraborty et al. (2008) concluded that the prosurvival actions of HSP90 reflect inhibition of IP6K2 signaling.
Morrison et al. (2002) stated that the IHPK2 gene maps to chromosome 3p21, a region highly susceptible to aberrant rearrangements and deletions in human cancers.
Morrison et al. (2009) found that mice with targeted deletion of the Ihpk2 gene showed normal development, growth, and fertility. However, chronic exposure to a carcinogen in drinking water resulted in a 4-fold increased incidence of invasive squamous cell carcinoma in the oral cavity and esophagus compared to wildtype mice. Paradoxically, Ihpk2-knockout mice displayed relative resistance to ionizing radiation and showed enhanced survival following total body irradiation. Fibroblasts derived from Ihpk2-knockout mice showed resistance to antiproliferative effects of beta-interferon and increased colony forming units following ionizing radiation; this phenomenon was associated with accelerated DNA repair. Wildtype Ihpk2, but not the enzymatically inactive variant, was able to reverse the knockout phenotype, suggesting that the enzymatic activity contributes to radiosensitivity. Tissues from Ihpk2-knockout mice showed relative overexpression of putative oncogenes, Ttf1 (NKX2-1; 600635) and Twistnb (Polr1f; 608312), as well as downregulation of 2 putative tumor suppressor genes Dusp16 (607175) and Ext2 (608210).
Chakraborty, A., Koldobskiy, M. A., Sixt, K. M., Juluri, K. R., 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. Nat. Acad. Sci. 105: 1134-1139, 2008. [PubMed: 18195352] [Full Text: https://doi.org/10.1073/pnas.0711168105]
Illies, C., Gromada, J., Fiume, R., Leibiger, B., Yu, J., Juhl, K., Yang, S.-N., Barma, D. K., Falck, J. R., Saiardi, A., Barker, C. J., Berggren, P.-O. Requirement of inositol pyrophosphates for full exocytotic capacity in pancreatic beta cells. Science 318: 1299-1302, 2007. [PubMed: 18033884] [Full Text: https://doi.org/10.1126/science.1146824]
Morrison, B. H., Bauer, J. A., Hu, J., Grane, R. W., Ozdemir, A. M., Chawla-Sarkar, M., Gong, B., Almasan, A., Kalvakolanu, D. V., Lindner, D. J. Inositol hexakisphosphate kinase 2 sensitizes ovarian carcinoma cells to multiple cancer therapeutics. Oncogene 21: 1882-1889, 2002. [PubMed: 11896621] [Full Text: https://doi.org/10.1038/sj.onc.1205265]
Morrison, B. H., Haney, R., Lamarre, E., Drazba, J., Presetwich, G. D., Lindner, D. J. Gene deletion of inositol hexakisphosphate kinase 2 predisposes to aerodigestive tract carcinoma. Oncogene 28: 2383-2392, 2009. [PubMed: 19430495] [Full Text: https://doi.org/10.1038/onc.2009.113]
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. [PubMed: 10574768] [Full Text: https://doi.org/10.1016/s0960-9822(00)80055-x]
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. [PubMed: 11502751] [Full Text: https://doi.org/10.1074/jbc.M106842200]