HIPK2, or 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 like apoptosis, DNA damage response, and protein transcription [3,5]. HIPK2 is involved in key signaling pathways such as Wnt/β -catenin, TGF -β, Notch, and NF -κB, which are crucial in development, stress response, and disease pathogenesis [1,2,6].

In mouse models, genetic ablation of HIPK2 causes neurological defects, indicating its importance in nervous system development and homeostasis [2]. In the context of myocardial infarction, HIPK2 -/- mice have reduced infarct size and preserved cardiac function post-MI, suggesting that HIPK2 inhibition could be a therapeutic strategy [4]. Also, in pathological cardiac remodeling, pharmacological and genetic inhibition of HIPK2 in mice improved cardiac function and suppressed hypertrophy and fibrosis, with new targets EGR3 and CLEC4D identified [7]. In kidney injury, the caspase-6-mediated removal of the C-terminal region of HIPK2 affected NF-κB transcriptional response, and the expression of the cleaved HIPK2-CT fragment attenuated renal inflammation in mice [6].

In summary, HIPK2 is a multifunctional kinase playing essential roles in various biological processes and disease conditions. Studies using gene knockout (KO) mouse models have revealed its significance in neurological development, cardiac pathologies, and kidney injury. These findings suggest HIPK2 could be a potential therapeutic target for treating related diseases [2,4,6,7].

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. Garufi, Alessia, D'Orazi, Valerio, Pistritto, Giuseppa, Cirone, Mara, D'Orazi, Gabriella. 2023. The Sweet Side of HIPK2. In Cancers, 15, . doi:10.3390/cancers15102678. https://pubmed.ncbi.nlm.nih.gov/37345014/

6. 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/

7. 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/