PPIP5K2, or Diphosphoinositol Pentakisphosphate Kinase 2, is an inositol pyrophosphate kinase. It interconverts 5-IP7 and IP8, key members of the inositol pyrophosphate cell-signaling family, and functions at the interface of cell signaling and bioenergetic homeostasis [5]. Genetic models, such as mouse models, are valuable for studying its functions.

In colorectal carcinoma, PPIP5K2 was highly expressed and associated with poor prognosis. Functional studies showed it promoted cell proliferation and migration independently of its kinase activity. S1006 dephosphorylation led to its nuclear translocation, promoting homologous recombination repair by binding and recruiting RPA70 to DNA damage sites [1]. In NSCLC, it facilitated cell proliferation and metastasis via the AKT/mTOR signaling pathway [3]. In familial keratoconus, variants in PPIP5K2 were identified, and gene-trap mouse models showed corneal phenotypes resembling keratoconus [2,4]. Mutations in PPIP5K2 in humans and mouse models were associated with hearing loss, with the p.Arg837His variant affecting enzyme activities and mouse models showing cochlear outer hair cell degeneration [5]. In ovarian cancer, a LncRNA stabilized PPIP5K2, promoting complement C5 secretion and MDSC infiltration in the tumor microenvironment to facilitate metastasis [6].

In conclusion, PPIP5K2 is crucial in multiple disease-related biological processes. Mouse models, including gene-trap and knockout-like models, have been instrumental in revealing its roles in colorectal carcinoma, NSCLC, keratoconus, hearing loss, and ovarian cancer, highlighting its potential as a therapeutic target in these diseases.

References:

1. Cao, Chen-Hui, Ling, Han, Han, Kai, Xie, Dan, Wang, Feng-Wei. 2021. PPIP5K2 promotes colorectal carcinoma pathogenesis through facilitating DNA homologous recombination repair. In Oncogene, 40, 6680-6691. doi:10.1038/s41388-021-02052-5. https://pubmed.ncbi.nlm.nih.gov/34645979/

2. Khaled, Mariam Lofty, Bykhovskaya, Yelena, Gu, Chunfang, Rabinowitz, Yaron S, Liu, Yutao. 2019. PPIP5K2 and PCSK1 are Candidate Genetic Contributors to Familial Keratoconus. In Scientific reports, 9, 19406. doi:10.1038/s41598-019-55866-5. https://pubmed.ncbi.nlm.nih.gov/31852976/

3. Yang, Qi, Cao, Chenhui, Wu, Binghuo, Xu, Chuan, Huang, Xiaoyi. 2024. PPIP5K2 Facilitates Proliferation and Metastasis of Non-Small Lung Cancer (NSCLC) through AKT Signaling Pathway. In Cancers, 16, . doi:10.3390/cancers16030590. https://pubmed.ncbi.nlm.nih.gov/38339341/

4. Akoto, Theresa, Hadvina, Rachel, Jones, Skyler, Smith, Sylvia B, Liu, Yutao. . Identification of Keratoconus-Related Phenotypes in Three Ppip5k2 Mouse Models. In Investigative ophthalmology & visual science, 65, 22. doi:10.1167/iovs.65.6.22. https://pubmed.ncbi.nlm.nih.gov/38869368/

5. Yousaf, Rizwan, Gu, Chunfang, Ahmed, Zubair M, Shears, Stephen B, Riazuddin, Saima. 2018. Mutations in Diphosphoinositol-Pentakisphosphate Kinase PPIP5K2 are associated with hearing loss in human and mouse. In PLoS genetics, 14, e1007297. doi:10.1371/journal.pgen.1007297. https://pubmed.ncbi.nlm.nih.gov/29590114/

6. Li, Yichen, Zhang, Qian, Wu, Mandi, Zhou, Shengtao, He, Ming-Liang. 2022. Suppressing MDSC Infiltration in Tumor Microenvironment Serves as an Option for Treating Ovarian Cancer Metastasis. In International journal of biological sciences, 18, 3697-3713. doi:10.7150/ijbs.70013. https://pubmed.ncbi.nlm.nih.gov/35813475/