Itpkb-KO Mouse

Inositol 1,4,5-trisphosphate 3-kinase B (ITPKB) is an important lipid kinase that inactivates inositol 1,4,5-trisphosphate (IP3), a secondary messenger that stimulates calcium release from the endoplasmic reticulum (ER). ITPKB plays a critical role in regulating calcium mobilization, the subcellular localization of PH domain-containing target proteins, and the production of higher inositol phosphates. Studies in gene-deficient mice have shown that ITPKB is essential for the survival of naive mature B cells and the control of proapoptotic Bim protein expression, rather than for the control of B cell transition from one developmental stage to another. It is also suggested that ITPKB is an important component in the control of B cell anergy [6].

ITPKB has been implicated in various diseases, including glioblastoma, Parkinson's disease, and ovarian cancer. In glioblastoma, ITPKB has been found to be upregulated in recurrent tumors and associated with poor survival in glioma patients. Mechanistically, the decreased phosphorylation of the E3 ligase Trim25 at the S100 position in recurrent glioblastoma samples accounted for the weakened ITPKB ubiquitination, which in turn elevated ITPKB stability and impaired reactive oxygen species (ROS) production. Depletion of ITPKB or the use of an ITPKB inhibitor effectively overcame temozolomide (TMZ) chemoresistance in a glioma xenograft mouse model [1].

Several studies have also shown an association between ITPKB and Parkinson's disease. A recent meta-analysis of Parkinson's disease (PD) genome-wide association studies identified 17 novel risk loci in the European population. Among these, two loci, ITPKB and ZNF184, were significantly associated with PD in East Asian samples. Additionally, a case-control study in Taiwan found that the dominant models of ITPKB rs4653767, IL1R2 rs34043159, and COQ7 rs11343 were associated with PD. Furthermore, ITPKB has been shown to protect against α-synuclein aggregation by regulating ER-to-mitochondria calcium release. ITPKB activity or expression level has been found to impact PD phenotypes in cellular and animal models [2,4,5,8,9].

In ovarian cancer, ITPKB has been identified as a critical vulnerability in cisplatin-resistant cells. CAMK2G, a calcium/calmodulin-dependent protein kinase II gamma, directly senses ROS, both basal and cisplatin-induced, to control the phosphorylation of ITPKB at serine 174, which directly regulates ITPKB activity to modulate cisplatin-induced ROS stress. Pharmacologic inhibition of CAMK2G significantly sensitizes ovarian cancer cells to cisplatin treatment in vitro and in vivo. Clinically, upregulation of CAMK2G activity and ITPKB pS174 correlates with cisplatin resistance in human ovarian cancers [3].

In addition to its role in cancer and neurodegenerative diseases, ITPKB deficiency has been associated with severe combined immunodeficiency, a condition characterized by a lack of immune function [7].

Overall, ITPKB is an important gene involved in various physiological processes and diseases. Its role in calcium mobilization, cell survival, and immune function makes it a potential therapeutic target for several diseases, including glioblastoma, Parkinson's disease, and ovarian cancer. Further research is needed to fully understand the mechanisms by which ITPKB functions and to develop targeted therapies for diseases associated with ITPKB dysregulation.

References:

1. Yan, Yuanliang, Zhou, Shangjun, Chen, Xi, Li, Zhi, Sun, Lunquan. 2024. Suppression of ITPKB degradation by Trim25 confers TMZ resistance in glioblastoma through ROS homeostasis. In Signal transduction and targeted therapy, 9, 58. doi:10.1038/s41392-024-01763-x. https://pubmed.ncbi.nlm.nih.gov/38438346/

2. Chew, Elaine Guo Yan, Tan, Louis C S, Au, Wing-Lok, Foo, Jia Nee, Tan, Eng-King. 2019. ITPKB and ZNF184 are associated with Parkinson's disease risk in East Asians. In Neurobiology of aging, 86, 201.e15-201.e17. doi:10.1016/j.neurobiolaging.2019.01.026. https://pubmed.ncbi.nlm.nih.gov/30814023/

3. Li, Jie, Zheng, Cuimiao, Wang, Mingshuo, Yao, Shuzhong, Pan, Chaoyun. 2022. ROS-regulated phosphorylation of ITPKB by CAMK2G drives cisplatin resistance in ovarian cancer. In Oncogene, 41, 1114-1128. doi:10.1038/s41388-021-02149-x. https://pubmed.ncbi.nlm.nih.gov/35039634/

4. Fang, Hwa-Shin, Wang, Chun-Chieh, Chao, Chih-Ying, Su, Shih-Chi, Wu, Yih-Ru. 2021. Association of ITPKB, IL1R2 and COQ7 with Parkinson's disease in Taiwan. In Journal of the Formosan Medical Association = Taiwan yi zhi, 121, 679-686. doi:10.1016/j.jfma.2021.06.016. https://pubmed.ncbi.nlm.nih.gov/34244037/

5. Apicco, Daniel J, Shlevkov, Evgeny, Nezich, Catherine L, Runz, Heiko, Hirst, Warren D. . The Parkinson's disease-associated gene ITPKB protects against α-synuclein aggregation by regulating ER-to-mitochondria calcium release. In Proceedings of the National Academy of Sciences of the United States of America, 118, . doi:10.1073/pnas.2006476118. https://pubmed.ncbi.nlm.nih.gov/33443159/

6. Schurmans, Stéphane, Pouillon, Valérie, Maréchal, Yoann. 2010. Regulation of B cell survival, development and function by inositol 1,4,5-trisphosphate 3-kinase B (Itpkb). In Advances in enzyme regulation, 51, 66-73. doi:10.1016/j.advenzreg.2010.08.001. https://pubmed.ncbi.nlm.nih.gov/21035494/

7. Almutairi, Abduarahman, Wallace, Jacqueline G, Jaber, Faris, Sobh, Ali, Geha, Raif S. 2020. Severe combined immunodeficiency caused by inositol-trisphosphate 3-kinase B (ITPKB) deficiency. In The Journal of allergy and clinical immunology, 145, 1696-1699.e6. doi:10.1016/j.jaci.2020.01.014. https://pubmed.ncbi.nlm.nih.gov/31987846/

8. Di Leva, Francesca, Filosi, Michele, Oyston, Lisa, Hicks, Andrew A, Corti, Corrado. 2023. Increased Levels of the Parkinson's Disease-Associated Gene ITPKB Correlate with Higher Expression Levels of α-Synuclein, Independent of Mutation Status. In International journal of molecular sciences, 24, . doi:10.3390/ijms24031984. https://pubmed.ncbi.nlm.nih.gov/36768321/

9. Gao, Ting, Zheng, Ran, Ruan, Yang, Pu, Jiali, Zhang, Baorong. 2020. Association of ZNF184, IL1R2, LRRK2, ITPKB, and PARK16 with sporadic Parkinson's disease in Eastern China. In Neuroscience letters, 735, 135261. doi:10.1016/j.neulet.2020.135261. https://pubmed.ncbi.nlm.nih.gov/32682840/