HIPK2, short for Homeodomain-interacting protein kinase 2, is an evolutionary conserved serine/threonine kinase. It phosphorylates and regulates numerous transcriptional regulators and chromatin modifiers, modulating multiple cellular processes and signaling pathways such as Wnt/β -catenin, TGF -β, Notch, NF -κB, and p53 pathways. HIPK2 is crucial in processes like stress response, embryonic development, and in pathological conditions including cancer, fibrosis, and neurological disorders [1,2,3].

In cancer, HIPK2 was traditionally considered a tumor suppressor due to its p53 -dependent pro -apoptotic activity and downregulation in many tumor types. However, its role can be oncogenic depending on the cellular context [3]. In fibrosis, HIPK2 regulates pro -fibrotic pathways and is a promising therapeutic target [1]. In the nervous system, its genetic ablation in mice causes neurological defects, highlighting its role in neuronal development, survival, and homeostasis [2]. In the heart, HIPK2 inhibition protects against myocardial infarction and pathological cardiac remodeling. HIPK2 -/- mice have reduced infarct size after acute MI and preserved cardiac function in remodeling [4,6]. In the kidney, caspase -6 -mediated removal of the C -terminal region of HIPK2 leads to hyperactive p65 NF -κB transcriptional response, while the expression of the cleaved HIPK2 -CT fragment can restrain NF -κB transcriptional activity. Inducing HIPK2 -CT overexpression in kidney tubular cells attenuates renal inflammation in mouse models [5].

In summary, HIPK2 is a multifunctional kinase with key roles in various biological processes and diseases. Studies using gene knockout (KO) and conditional knockout (CKO) mouse models have revealed its functions in cancer, fibrosis, neurological, cardiac, and kidney diseases, providing valuable insights for potential therapeutic strategies in these disease areas.

References:

1. Garufi, Alessia, Pistritto, Giuseppa, D'Orazi, Gabriella. 2023. HIPK2 as a Novel Regulator of Fibrosis. In Cancers, 15, . doi:10.3390/cancers15041059. https://pubmed.ncbi.nlm.nih.gov/36831402/

2. Sardina, F, Conte, A, Paladino, S, Pierantoni, G M, Rinaldo, C. 2023. HIPK2 in the physiology of nervous system and its implications in neurological disorders. In Biochimica et biophysica acta. Molecular cell research, 1870, 119465. doi:10.1016/j.bbamcr.2023.119465. https://pubmed.ncbi.nlm.nih.gov/36935052/

3. Conte, Andrea, Valente, Valeria, Paladino, Simona, Pierantoni, Giovanna Maria. 2022. HIPK2 in cancer biology and therapy: Recent findings and future perspectives. In Cellular signalling, 101, 110491. doi:10.1016/j.cellsig.2022.110491. https://pubmed.ncbi.nlm.nih.gov/36241057/

4. Zhou, Qiulian, Deng, Jiali, Yao, Jianhua, Sluijter, Joost Pg, Xiao, Junjie. 2021. Exercise downregulates HIPK2 and HIPK2 inhibition protects against myocardial infarction. In EBioMedicine, 74, 103713. doi:10.1016/j.ebiom.2021.103713. https://pubmed.ncbi.nlm.nih.gov/34837851/

5. Feng, Ye, Li, Zhengzhe, Wang, Heather, Lee, Kyung, He, John Cijiang. 2024. HIPK2 C-terminal domain inhibits NF-κB signaling and renal inflammation in kidney injury. In JCI insight, 9, . doi:10.1172/jci.insight.175153. https://pubmed.ncbi.nlm.nih.gov/38512421/

6. Zhou, Qiulian, Meng, Danni, Li, Feng, Sluijter, Joost P G, Xiao, Junjie. 2022. Inhibition of HIPK2 protects stress-induced pathological cardiac remodeling. In EBioMedicine, 85, 104274. doi:10.1016/j.ebiom.2022.104274. https://pubmed.ncbi.nlm.nih.gov/36182775/