Alternative titles; symbols
HGNC Approved Gene Symbol: IP6K1
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38) : 3:49,724,294-49,786,542 (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 IHPK1 (Saiardi et al., 1999).
By screening an immature myeloid cell line for cDNAs with the potential to encode large proteins, Nagase et al. (1996) identified a cDNA encoding IHPK1, which they called KIAA0263, a deduced 462-amino acid protein. Northern blot analysis detected ubiquitous, low-level expression that was highest in testis.
By comparison with rat Ihpk1 and database searching, Saiardi et al. (1999) identified mouse Ihpk1, which is 97% homologous to KIAA0263. Western blot analysis showed expression of a 50-kD protein. Northern blot analysis revealed expression of a 5.0-kb transcript in mouse brain and testis, with much lower levels in heart, liver, kidney, lung, and spleen.
Using confocal microscopy, Saiardi et al. (2001) demonstrated that mouse Ihpk1 is present in both the nucleus and the cytoplasm, whereas IHPK2 (IP6K2; 606992) is almost exclusively nuclear and IHPK3 (IP6K3; 606993) is predominantly cytoplasmic.
Saiardi et al. (1999) showed that cells expressing Ihpk1 displayed a robust InsP6 kinase activity. They proposed that IHPK1 and IHPK2 may act as energy reserves in selected intracellular sites.
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 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.
By radiation hybrid analysis, Nagase et al. (1996) mapped the IHPK1 gene to chromosome 3.
Kamimura et al. (2004) reported a family in which a balanced reciprocal translocation, t(3;9)(p21.31;q33.1), was associated with type II diabetes mellitus (125853). To isolate a candidate gene, they constructed physical maps covering both the 3p and 9q breakpoints of the translocation. The IHPK1 gene was found to be disrupted in the 3p21.31 breakpoint. The authors carried out sequence analysis of all coding regions of IHPK1 in 405 unrelated patients with type II diabetes mellitus and failed to detect any pathogenic changes. Kamimura et al. (2004) concluded that the disruption of IHPK1 or another predisposing gene affected by position effect of the translocation may explain the diabetic phenotype in this family, or alternatively, that the IHPK1 disruption was a chance association.
Bhandari et al. (2008) created mice with a targeted deletion of the Ip6k1 exon encoding the C-terminal catalytic domain. Mutant mice showed marked reduction in the production of inositol pyrophosphates. They were smaller than wildtype mice despite normal food intake, and they showed markedly lower circulating insulin. Male mutant mice were sterile and exhibited defects in spermiogenesis, with few advanced spermatids in the seminiferous tubules and none in the epididymis. Female mutant mice were fertile.
AKT is (see 164730) a serine/threonine kinase that regulates glucose homeostasis via phosphorylation of GSK3-beta (GSK3B; 605004) and protein translation via the MTOR (FRAP1; 601231) pathway. Chakraborty et al. (2010) showed that insulin sensitivity in Ip6k1 -/- mice was due to elevated Akt signaling. Insulin and growth factors induced IP7 formation by Ip6k1 in wildtype mice, and IP7 inhibited activating phosphorylation of Akt by Pdk1 (605213). In the absence of IP7 in Ip6k1 -/- mice, Akt and Mtor signaling were augmented and Gsk3-beta activity was reduced in skeletal muscle, white adipose tissue, and liver. As a result, Ip6k1 -/- mice exhibited sustained insulin sensitivity, resistance to diet-induced weight gain, and increased hepatic fat oxidation.
Bhandari, R., Juluri, K. R., Resnick, A. C., Snyder, S. H. Gene deletion of inositol hexakisphosphate kinase 1 reveals inositol pyrophosphate regulation of insulin secretion, growth, and spermiogenesis. Proc. Nat. Acad. Sci. 105: 2349-2353, 2008. [PubMed: 18268345] [Full Text: https://doi.org/10.1073/pnas.0712227105]
Chakraborty, A., Koldobskiy, M. A., Bello, N. T., Maxwell, M., Potter, J. J., Juluri, K. R., Maag, D., Kim, S., Huang, A. S., Dailey, M. J., Saleh, M., Snowman, A. M., Moran, T. H., Mezey, E., Snyder, S. H. Inositol pyrophosphates inhibit Akt signaling, thereby regulating insulin sensitivity and weight gain. Cell 143: 897-910, 2010. [PubMed: 21145457] [Full Text: https://doi.org/10.1016/j.cell.2010.11.032]
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]
Kamimura, J., Wakui, K., Kadowaki, H., Watanabe, Y., Miyake, K., Harada, N., Sakamoto, M., Kinoshita, A., Yoshiura, K., Ohta, T., Kishino, T., Ishikawa, M., Kasuga, M., Fukushima, Y., Niikawa, N., Matsumoto, N. The IHPK1 gene is disrupted at the 3p21.31 breakpoint of t(3;9) in a family with type 2 diabetes mellitus. J. Hum. Genet. 49: 360-365, 2004. [PubMed: 15221640] [Full Text: https://doi.org/10.1007/s10038-004-0158-z]
Nagase, T., Seki, N., Ishikawa, K., Ohira, M., Kawarabayasi, Y., Ohara, O., Tanaka, A., Kotani, H., Miyajima, N., Nomura, N. Prediction of the coding sequences of unidentified human genes. VI. The coding sequences of 80 new genes (KIAA0201-KIAA0280) deduced by analysis of cDNA clones from cell line KG-1 and brain. DNA Res. 3: 321-329, 1996. Note: Supplement: DNA Res. 3: 341-354, 1996. [PubMed: 9039502] [Full Text: https://doi.org/10.1093/dnares/3.5.321]
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]