Department of Animal Biology, School of Life Sciences, University of Hyderabad, Hyderabad, 500046, India.
Cell Death Dis. 2023 Dec 21;14(12):853. doi: 10.1038/s41419-023-06380-0.
The E3 ubiquitin ligase WWP1 (WW Domain-containing E3 Ubiquitin Protein Ligase 1) is a member of the HECT (Homologous to the E6-associated protein Carboxyl Terminus) E3 ligase family. It is conserved across several species and plays crucial roles in various physiological processes, including development, cell growth and proliferation, apoptosis, and differentiation. It exerts its functions through ubiquitination or protein-protein interaction with PPXY-containing proteins. WWP1 plays a role in several human diseases, including cardiac conditions, neurodevelopmental, age-associated osteogenic disorders, infectious diseases, and cancers. In solid tumors, WWP1 plays a dual role as both an oncogene and a tumor suppressor, whereas in hematological malignancies such as AML, it is identified as a dedicated oncogene. Importantly, WWP1 inhibition using small molecule inhibitors such as Indole-3-Carbinol (I3C) and Bortezomib or siRNAs leads to significant suppression of cancer growth and healing of bone fractures, suggesting that WWP1 might serve as a potential therapeutic target for several diseases. In this review, we discuss the evolutionary perspective, structure, and functions of WWP1 and its multilevel regulation by various regulators. We also examine its emerging roles in cancer progression and its therapeutic potential. Finally, we highlight WWP1's role in normal physiology, contribution to pathological conditions, and therapeutic potential for cancer and other diseases.
E3 泛素连接酶 WWP1（WW 结构域包含 E3 泛素蛋白连接酶 1）是 HECT（与 E6 相关蛋白羧基末端同源）E3 连接酶家族的一员。它在多个物种中保守，在包括发育、细胞生长和增殖、细胞凋亡和分化在内的各种生理过程中发挥着关键作用。它通过泛素化或与含有 PPXY 的蛋白质的蛋白-蛋白相互作用发挥功能。WWP1 在几种人类疾病中发挥作用，包括心脏疾病、神经发育、与年龄相关的成骨疾病、传染病和癌症。在实体肿瘤中，WWP1 作为癌基因和肿瘤抑制因子发挥双重作用，而在血液恶性肿瘤如 AML 中，它被鉴定为专门的癌基因。重要的是，使用小分子抑制剂（如吲哚-3-甲醇（I3C）和硼替佐米）或 siRNA 抑制 WWP1 会导致癌症生长的显著抑制和骨折的愈合，这表明 WWP1 可能成为几种疾病的潜在治疗靶点。在这篇综述中，我们讨论了 WWP1 的进化视角、结构和功能及其受各种调节剂的多层次调控。我们还研究了它在癌症进展中的新兴作用及其治疗潜力。最后，我们强调了 WWP1 在正常生理中的作用、对病理状况的贡献以及在癌症和其他疾病中的治疗潜力。
