WWP1, also known as WW Domain-containing E3 Ubiquitin Protein Ligase 1, is a member of the HECT E3 ligase family. It exerts functions through ubiquitination or protein-protein interaction with PPXY-containing proteins. WWP1 is involved in multiple physiological processes such as development, cell growth, apoptosis, and differentiation, and is thus of great biological importance. Genetic models, like KO/CKO mouse models, are valuable for studying its functions [1,4].

In KO mouse models, WWP1 knockout protected the heart from transverse aortic constriction (TAC)-induced hypertrophy, suggesting its role in pressure overload-induced cardiac remodeling. The mechanism involves WWP1 promoting K27-linked polyubiquitination of DVL2, exacerbating cardiac hypertrophy via the DVL2/CaMKII/HDAC4/MEF2C pathway [2]. In cancer, genetic ablation or pharmacological inhibition of WWP1 triggered PTEN reactivation, unleashing its tumor-suppressive activity, indicating WWP1's role in MYC-driven tumorigenesis [3].

In conclusion, WWP1 is crucial in various physiological processes. Model-based research, especially using WWP1 KO/CKO mouse models, has revealed its significant roles in cardiac hypertrophy and cancer. These findings provide potential therapeutic targets for treating cardiac diseases and malignancies [1,2,3].

References:

1. Behera, Abhayananda, Reddy, Aramati Bindu Madhava. 2023. WWP1 E3 ligase at the crossroads of health and disease. In Cell death & disease, 14, 853. doi:10.1038/s41419-023-06380-0. https://pubmed.ncbi.nlm.nih.gov/38129384/

2. Zhao, Dingsheng, Zhong, Guohui, Li, Jianwei, Li, Yingxian, Ling, Shukuan. 2021. Targeting E3 Ubiquitin Ligase WWP1 Prevents Cardiac Hypertrophy Through Destabilizing DVL2 via Inhibition of K27-Linked Ubiquitination. In Circulation, 144, 694-711. doi:10.1161/CIRCULATIONAHA.121.054827. https://pubmed.ncbi.nlm.nih.gov/34139860/

3. Lee, Yu-Ru, Chen, Ming, Lee, Jonathan D, Wei, Wenyi, Pandolfi, Pier Paolo. . Reactivation of PTEN tumor suppressor for cancer treatment through inhibition of a MYC-WWP1 inhibitory pathway. In Science (New York, N.Y.), 364, . doi:10.1126/science.aau0159. https://pubmed.ncbi.nlm.nih.gov/31097636/

4. Zhi, Xu, Chen, Ceshi. 2011. WWP1: a versatile ubiquitin E3 ligase in signaling and diseases. In Cellular and molecular life sciences : CMLS, 69, 1425-34. doi:10.1007/s00018-011-0871-7. https://pubmed.ncbi.nlm.nih.gov/22051607/