ADAM17, also known as tumor necrosis factor-a converting enzyme (TACE), is a cell membrane-bound protease of the ADAM family. It has a crucial role in "ectodomain shedding" of various substrates like cytokines, growth factors, adhesion proteins and their receptors, thus regulating cell adhesion, proliferation, migration, proteolysis and cell signaling transduction pathways [6,7]. It is involved in multiple biological processes and is of great importance in understanding disease mechanisms. Genetic models, such as KO/CKO mouse models, are valuable for studying ADAM17.

ADAM17 has been implicated in numerous disease conditions. In atherosclerosis, it promotes vascular inflammation in endothelial cells, smooth muscle cells, and macrophages, regulating the disease's development [1]. In tumor development, it is involved in immune regulation and the shedding of cell membrane proteins relevant to tumor formation [2]. In colorectal cancer, tumor-derived exosomal ADAM17 enhances vascular permeability, promoting pre-metastatic niche formation and metastasis, and its inhibitors can reduce metastasis in vivo [3]. In liver damage, ADAM17 has a complex role as its substrates are involved in promoting liver injury or contributing to liver regeneration [5]. A variant in ADAM17 in humans causes hair loss, and in knockin mice, it leads to hair follicle stem cell exhaustion and abnormal hair follicles due to enhanced degradation of ADAM17 protein by TRIM47, affecting the Notch signaling pathway [4].

In conclusion, ADAM17 is a key protease regulating multiple biological processes. Model-based research, especially KO/CKO mouse models, has revealed its significant roles in diseases like atherosclerosis, tumors, liver damage, and hair loss-related conditions. Understanding ADAM17 provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Tang, Bai-Yi, Ge, Jin, Wu, Yang, Wen, Juan, Tang, Xiao-Hong. 2022. The Role of ADAM17 in Inflammation-Related Atherosclerosis. In Journal of cardiovascular translational research, 15, 1283-1296. doi:10.1007/s12265-022-10275-4. https://pubmed.ncbi.nlm.nih.gov/35648358/

2. Wang, Kai, Xuan, Zixue, Liu, Xiaoyan, Yang, Chao, Wang, Haiyong. 2022. Immunomodulatory role of metalloproteinase ADAM17 in tumor development. In Frontiers in immunology, 13, 1059376. doi:10.3389/fimmu.2022.1059376. https://pubmed.ncbi.nlm.nih.gov/36466812/

3. Li, Keyu, Xue, Wenhua, Lu, Zhihua, Yang, Yang, Sun, Jinbing. 2024. Tumor-derived exosomal ADAM17 promotes pre-metastatic niche formation by enhancing vascular permeability in colorectal cancer. In Journal of experimental & clinical cancer research : CR, 43, 59. doi:10.1186/s13046-024-02991-3. https://pubmed.ncbi.nlm.nih.gov/38413999/

4. Wang, Xiaoxiao, Pan, Chaolan, Zheng, Luyao, Zhang, Hui, Li, Ming. 2024. ADAM17 variant causes hair loss via ubiquitin ligase TRIM47-mediated degradation. In JCI insight, 9, . doi:10.1172/jci.insight.177588. https://pubmed.ncbi.nlm.nih.gov/38771644/

5. Al-Salihi, Mazin, Bornikoel, Anna, Zhuang, Yuan, Lang, Karl S, Lang, Philipp A. 2021. The role of ADAM17 during liver damage. In Biological chemistry, 402, 1115-1128. doi:10.1515/hsz-2021-0149. https://pubmed.ncbi.nlm.nih.gov/34192832/

6. Lisi, Sabrina, D'Amore, Massimo, Sisto, Margherita. 2014. ADAM17 at the interface between inflammation and autoimmunity. In Immunology letters, 162, 159-69. doi:10.1016/j.imlet.2014.08.008. https://pubmed.ncbi.nlm.nih.gov/25171914/

7. Yang, Guang, Cui, Mengying, Jiang, Weibo, Yang, Yongsheng, Zhang, Xuewen. 2021. Molecular switch in human diseases-disintegrin and metalloproteinases, ADAM17. In Aging, 13, 16859-16872. doi:10.18632/aging.203200. https://pubmed.ncbi.nlm.nih.gov/34182543/