Smurf1, short for SMAD specific E3 ubiquitin protein ligase 1, is a HECT-type E3 ubiquitin ligase. It plays crucial roles in multiple biological pathways such as the bone morphogenetic protein pathway, non-canonical Wnt pathway, and mitogen-activated protein kinase pathway [6]. It is involved in cell growth, morphogenesis, migration, polarity, and autophagy, and is related to physiological manifestations like age-dependent bone formation deficiency and tumor cell invasion [6]. Genetic models, like knockout mice, are valuable for studying its functions.

In cancer, Smurf1 overexpression is linked to poor prognosis in cancers such as glioblastoma, colon cancer, and clear cell renal cell carcinoma. It acts as a tumor promoter by ubiquitinating and degrading tumor-suppressing proteins [1]. In KRAS-mutated colorectal cancer, Smurf1-mediated PDK1 neddylation is essential for PI3K-Akt signaling and tumorigenesis, and Smurf1 deficiency reduces tumorigenesis in a genetic mouse model [3]. In hepatocellular carcinoma, Smurf1-mediated ubiquitination of UVRAG promotes autophagosome maturation and inhibits cancer growth [2]. In lupus nephritis, Smurf1 upregulation activates the cGAS/STING/IFN-1 signal axis by ubiquitinating YY1, accelerating the disease progression, and Smurf1 knockdown inhibits LN progression in vivo [5]. In dry age-related macular degeneration, inhibiting Smurf1 alleviates acute retina injury [7]. In ameloblasts, Smurf1 regulates polarization through ubiquitination-mediated degradation of RhoA, and local knockdown in rat lower incisor ameloblasts leads to polarity loss and enamel matrix secretion disorder [4]. In glioblastoma, ER stress induces Smurf1 degradation, and knockdown of Smurf1 upregulates UPR pathway signaling, leading to cell apoptosis, while overexpression activates the NRF2 antioxidant pathway to protect cell survival [8].

In summary, Smurf1 is a multifunctional E3 ubiquitin ligase involved in various biological processes and disease conditions. Gene knockout models, especially in mice, have been instrumental in revealing its roles in cancer, kidney diseases, retinal degeneration, tooth development, and glioblastoma, providing potential therapeutic targets for these diseases.

References:

1. Xia, Qin, Li, Yang, Han, Da, Dong, Lei. 2020. SMURF1, a promoter of tumor cell progression? In Cancer gene therapy, 28, 551-565. doi:10.1038/s41417-020-00255-8. https://pubmed.ncbi.nlm.nih.gov/33204002/

2. Feng, Xing, Jia, Yanyan, Zhang, Yuyu, Qiu, Xingfeng, Zhang, Zhiyong. 2019. Ubiquitination of UVRAG by SMURF1 promotes autophagosome maturation and inhibits hepatocellular carcinoma growth. In Autophagy, 15, 1130-1149. doi:10.1080/15548627.2019.1570063. https://pubmed.ncbi.nlm.nih.gov/30686098/

3. Peng, Zhiqiang, Fang, Wei, Wu, Bo, Cui, Chun-Ping, Zhang, Lingqiang. 2024. Targeting Smurf1 to block PDK1-Akt signaling in KRAS-mutated colorectal cancer. In Nature chemical biology, 21, 59-70. doi:10.1038/s41589-024-01683-5. https://pubmed.ncbi.nlm.nih.gov/39039255/

4. Niu, Haoman, Bi, Fei, Zhao, Wenjun, Guo, Weihua, Chen, Yu. 2022. Smurf1 regulates ameloblast polarization by ubiquitination-mediated degradation of RhoA. In Cell proliferation, 56, e13387. doi:10.1111/cpr.13387. https://pubmed.ncbi.nlm.nih.gov/36579844/

5. Li, Xiaoyan, Tao, Sisi, Xu, Zhiquan, Xiang, Wei, He, Xiaojie. 2023. SMURF1 activates the cGAS/STING/IFN-1 signal axis by mediating YY1 ubiquitination to accelerate the progression of lupus nephritis. In Autoimmunity, 56, 2281235. doi:10.1080/08916934.2023.2281235. https://pubmed.ncbi.nlm.nih.gov/37994046/

6. Cao, Yu, Zhang, Lingqiang. 2012. A Smurf1 tale: function and regulation of an ubiquitin ligase in multiple cellular networks. In Cellular and molecular life sciences : CMLS, 70, 2305-17. doi:10.1007/s00018-012-1170-7. https://pubmed.ncbi.nlm.nih.gov/23007848/

7. Li, Duo, Wei, Ting-Ting, Cai, Jiping, Yao, Yong, Zhu, Lingpeng. 2023. Smurf1: A possible therapeutic target in dry age-related macular degeneration. In Experimental eye research, 233, 109549. doi:10.1016/j.exer.2023.109549. https://pubmed.ncbi.nlm.nih.gov/37348673/

8. Dong, Lei, Xu, Mengchuan, Li, Yang, Zhou, Liying, Xia, Qin. 2023. SMURF1 attenuates endoplasmic reticulum stress by promoting the degradation of KEAP1 to activate NRF2 antioxidant pathway. In Cell death & disease, 14, 361. doi:10.1038/s41419-023-05873-2. https://pubmed.ncbi.nlm.nih.gov/37316499/