Ubiquitin Ligase WWP2
WWP2 (WW domain containing E3 ubiquitin-protein ligase 2) is an enzyme that contains 4 tandem WW (double-tryptophan) domains, named after the presence of two conserved tryptophans (W). WWP2 is a member of the Nedd4 superfamily, a small group within the E3 ubiquitin ligase enzymes and is involved in post-translational modifications.[1][2]
WWP2 is dysregulated in various of tumors, and it promotes carcinogenesis mainly through PTEN/Akt signaling pathway. WWP2 also participates in anti-cancer agents' sensitivity, indicating WWP2 may be a novel target for cancer treatment.[3] WWP2 can cause the ubiquitin-dependent degradation of specific tumor suppressor proteins (such as Oct4[4] and PTEN [229]) in many cancers [230].
The tubulointerstitial expression of WWP2 was associated with fibrotic progression in CKD patients and in murine kidney disease models. WWP2 deficiency promoted myofibroblast proliferation and halts pro-fibrotic activation, reducing the severity of kidney fibrosis in vivo. In renal myofibroblasts, WWP2 deficiency increased fatty acid oxidation and activated the pentose phosphate pathway, boosting mitochondrial respiration at the expense of glycolysis. WWP2 suppressed the transcription of PGC-1α, a metabolic mediator of fibrotic response, and pharmacological inhibition of PGC-1α partially abrogated the protective effects of WWP2 deficiency on myofibroblasts.[5]
References
- ↑ Chen, W., Jiang, X., & Luo, Z. (2014). WWP2: a multifunctional ubiquitin ligase gene. Pathology & Oncology Research, 20, 799-803. PMID: 25216927 DOI: 10.1007/s12253-014-9838-y
- ↑ You, S., Xu, J., Guo, Y., Guo, X., Zhang, Y., Zhang, N., ... & Sun, Y. (2024). E3 ubiquitin ligase WWP2 as a promising therapeutic target for diverse human diseases. Molecular Aspects of Medicine, 96, 101257. PMID: 38430667 DOI: 10.1016/j.mam.2024.101257
- ↑ Zhang, R., Zhang, J., Luo, W. et al. (2019). WWP2 Is One Promising Novel Oncogene. Pathol. Oncol. Res. 25, 443–446 PMID: 30415470 DOI: 10.1007/s12253-018-0506-5
- ↑ Liao, B., & Jin, Y. (2010). Wwp2 mediates Oct4 ubiquitination and its own auto-ubiquitination in a dosage-dependent manner. Cell research, 20(3), 332-344.
- ↑ Chen, H., You, R., Guo, J., Zhou, W., Chew, G., Devapragash, N., ... & Petretto, E. (2024). WWP2 Regulates Kidney Fibrosis and the Metabolic Reprogramming of Profibrotic Myofibroblasts. Journal of the American Society of Nephrology, 10-1681. PMID: 38502123 DOI: 10.1681/ASN.0000000000000328
