FAT4, also known as FAT Atypical Cadherin 4, is a member of the cadherin-associated protein family. It has crucial functions in multiple biological processes, often acting as a tumor suppressor. It is involved in pathways such as Wnt/β-catenin, Hippo, and RET signaling, which are essential for normal development and disease prevention [1,2,4]. Genetic models, like gene knockout (KO) and conditional knockout (CKO) mouse models, have been vital in studying its functions.

In KO mouse models, deletion of Fat4 led to abnormal ureteric budding and excessive RET signaling in kidney development, indicating its role in fine-tuning RET signaling [2]. In human-derived cell lines, CRISPR-Cas9-mediated FAT4-KO in normal hepatic cells disrupted cell-cell adhesion, induced epithelial-mesenchymal transition, and initiated hepatocarcinogenesis through switching of canonical to noncanonical WNT signaling pathways [3]. Stable FAT4 knockdown in endometrial cancer cell lines promoted cell proliferation and invasion via the Hippo pathway [4].

In conclusion, FAT4 is essential for normal development and disease prevention. Model-based research, especially KO/CKO mouse models, has revealed its critical roles in kidney development, osteoblast differentiation, and cancer development, including cervical, lung, liver, and endometrial cancers. These findings provide insights into potential therapeutic targets for related diseases.

References:

1. Wang, Dongying, Wu, Shuying, He, Jiaxing, Wang, Yanhong, Xu, Tianmin. 2023. FAT4 overexpression promotes antitumor immunity by regulating the β-catenin/STT3/PD-L1 axis in cervical cancer. In Journal of experimental & clinical cancer research : CR, 42, 222. doi:10.1186/s13046-023-02758-2. https://pubmed.ncbi.nlm.nih.gov/37658376/

2. Zhang, Hongtao, Bagherie-Lachidan, Mazdak, Badouel, Caroline, Jain, Sanjay, McNeill, Helen. 2019. FAT4 Fine-Tunes Kidney Development by Regulating RET Signaling. In Developmental cell, 48, 780-792.e4. doi:10.1016/j.devcel.2019.02.004. https://pubmed.ncbi.nlm.nih.gov/30853441/

3. Huang, Fung-Yu, Wong, Danny Ka-Ho, Mak, Lung-Yi, Seto, Wai-Kay, Yuen, Man-Fung. 2023. FAT4 loss initiates hepatocarcinogenesis through the switching of canonical to noncanonical WNT signaling pathways. In Hepatology communications, 7, . doi:10.1097/HC9.0000000000000338. https://pubmed.ncbi.nlm.nih.gov/38055646/

4. Che, Xiaoxia, Jian, Fangfang, Jia, Nan, Jiang, Yahui, Feng, Weiwei. 2019. FAT4-USP51 complex regulates the proliferation and invasion of endometrial cancer via Hippo pathway. In American journal of translational research, 11, 2784-2800. doi:. https://pubmed.ncbi.nlm.nih.gov/31217854/