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Role of FAT1 in Health and Disease (Review)

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Role of FAT1 in Health and Disease (Review) ONCOLOGY LETTERS 21: 398, 2021 Role of FAT1 in health and disease (Review) ZIZHEN PENG, YANYU GONG and XIAOQIU LIANG Hunan Province Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer Research Institute, Hengyang School of Medicine, University of South China, Hengyang, Hunan 421001, P.R. China Received September 23, 2020; Accepted February 25, 2021 DOI: 10.3892/ol.2021.12659 Abstract. FAT atypical cadherin 1 (FAT1), which encodes a 1. Introduction protocadherin, is one of the most frequently mutated genes in human cancer. Over the past 20 years, the role of FAT1 in Intercellular adhesion is the structural basis for the growth tissue growth and in the development of diseases has been and development of multicellular organisms. The abnormal extensively studied. There is definitive evidence that FAT1 expression of proteins involved in the process of intercel‑ serves a substantial role in the maintenance of organs and lular adhesion can cause various complications, such as development, and its expression appears to be tissue‑specific. kidney, cardiovascular and autoimmune diseases, as well FAT1 activates a variety of signaling pathways through as cancer (1‑3). Cadherins are essential for cell adhesion. In protein‑protein interactions, including the Wnt/β‑catenin, vertebrates, it is generally accepted that there are six main Hippo and MAPK/ERK signaling pathways, which affect subfamilies of cadherins: Classical cadherins, desmosomal cell proliferation, migration and invasion. Abnormal FAT1 cadherins, protocadherins, Flamingo/Celsr, Dachsous and expression may lead to the development of tumors and may FAT atypical cadherins (FAT) (4). affect prognosis. Therefore, FAT1 may have potential in tumor In the 1920s, FAT was discovered in Drosophila due to therapy. The structural and functional changes mediated by a lethal mutation (5). Drosophila has two FAT cadherin FAT1, its tissue distribution and changes in FAT1 expression members, Ft and Ft2, which are considered tumor suppres‑ in human diseases are described in the present review, which sors (6). Most functional mutations of the Ft gene result in an provides further insight for understanding the role of FAT1 in ‘epithelial overgrowth phenotype’ in Drosophila larvae, which development and disease. can affect the wings, legs, eye antennae, glands and genital imaging disc (6,7). The overgrowth phenotype observed following Ft inactivation is hypothesized to be partly associated Contents with the fact that Ft can affect the localization and expression levels of the Hippo signaling pathway transcription factors, 1. Introduction Yorkie (Yki), Warts (Wts) and Expanded (8‑10). In addition, 2. Signaling pathways and mechanisms in the eyes of FAT mutant Drosophila, the omentum exhibits 3. FAT1 in development reversed dorsal‑ventral polarity (11). This is hypothesized to 4. FAT1 in hereditary diseases be caused by the effect of Ft on planar cell polarity (PCP) (11). 5. FAT1 in cancer The other FAT cadherin member in Drosophila, Ft2, is 6. Therapeutic targeting of FAT1 necessary for morphogenesis and maintenance of tubular 7. Conclusions and perspectives structures of ectodermal origin (7,12). Deletion of Ft2 results in abnormal development of renal tubular structures, such as loss of the trachea, gastric glands and salivary glands (12). The established functional roles of Ft and Ft2 in Drosophila primarily include regulation of morphogenesis, growth control and PCP (8,11,12), providing a platform for the study of FAT cadherins in vertebrates. From Drosophila to vertebrates, the FAT cadherin family Correspondence to: Professor Xiaoqiu Liang, Hunan Province has expanded from two members to four, but their structure Key Laboratory of Tumor Cellular and Molecular Pathology, Cancer and function remain conserved across species (13). The FAT Research Institute, Hengyang School of Medicine, University of South China, 28 Changsheng West Street, Hengyang, Hunan 421001, cadherin family in vertebrates consists of FAT1‑4 (5), all of P. R. Ch i na which have unique arrangements and number of laminin G E‑mail: [email protected] motifs and EGF‑like motifs, which bestows upon them unique functions. FAT1 and FAT4 contain 34 extracellular cadherin Key words: FAT atypical cadherin 1, FAT cadherins, Wnt signaling repeats, whereas FAT2 contains 32 repeats and FAT3 contains pathway, Hippo signaling pathway, cancer 33 repeats (Fig. 1) (14). As FAT mRNA transcripts and coding proteins are large, understanding the function of FAT proteins is challenging. At present, the majority of research on FAT 2 PENG et al: ROLE OF FAT1 IN HEALTH AND DISEASE proteins have focused on FAT1, as FAT1 was the first member where FAT1 expression was knocked out, the amount of Vasp to be identified in humans, and the effects of FAT1 mutations in protein that accumulated at the front of cells was significantly tumors, such as acute lymphoblastic leukemia (ALL) (15) and decreased, the cells did not become polarized and the migra‑ hepatocellular carcinoma (HCC) (16), are more prominent (7). tory ability of cells was decreased. In in vitro wound healing The human FAT1 gene was cloned from a human T‑cell assays, FAT1‑knockout NRK‑52E cells (rat kidney epithelioid ALL (T‑ALL) cell line in 1995 (15). The gene is located on cells) exhibited abnormal lamella dynamics at the wound edge, chromosome 4q34‑35 and consists of 27 exons in humans (15). which included an absence of lamella or abnormal lamella lipid It is a type I transmembrane protein, consisting of an extracel‑ membranes, decreased lamella size and abnormally structured lular region, transmembrane region and cytoplasmic tail (17). lamellae, all of which resulted in delayed wound closure (31). It has been reported that FAT1 is involved in numerous These results indicate that FAT1 is necessary for physiological processes, such as cell adhesion, proliferation and migration via lamellipodial dynamics, and FAT1‑knockout disrupts normal protein‑protein interactions of its cytoplasmic tail (7). Existing lamellipodial dynamics to a certain extent (29,30). This may evidence has shown that FAT1 can bind to the actin‑regulatory provide an explanation for the weakened cell migration in protein Enabled (Ena)/vasodilator‑stimulated phosphopro‑ FAT1‑deficient cells. tein (Vasp) and β‑catenin to regulate cell proliferation and migration, and that it serves a role in the Wnt/β‑catenin, FAT1 and the Wnt/β ‑catenin signaling pathway. The role of Hippo and MAPK/ERK signaling pathways, as well affecting the Wnt/β‑catenin signaling pathway in human development epithelial‑mesenchymal transition (EMT) (18‑22). At present, and maintaining adult tissue homeostasis is well‑established. knowledge regarding the exact downstream signaling Abnormalities in the Wnt signaling pathway are closely pathways mediated by FAT1 remains incomplete, but an associated with the occurrence of numerous diseases, such as increasing body of knowledge is indicating that changes in osteoporosis, Alzheimer's disease and pigmented diseases (32). FAT1 expression are associated with several diseases, such as Abnormal activation of the Wnt/β‑catenin signaling pathway facioscapulohumeral muscular dystrophy (FSHD) (23), bipolar is widely considered to be a promoter of tumorigenesis and disorder (BPAD) (24) and ALL (15). In the present review, the cancer cell proliferation in several types of cancer (33), such as latest progress in understanding the role of FAT1 is discussed, HCC (34) and colon cancer (35). The Wnt/β‑catenin signaling with the aim of promoting interest in FAT1 as a biomarker and pathway primarily consists of three steps: Wnt signal trans‑ a potential therapeutic target for the management of several duction at the membrane, stable regulation of β‑catenin in the diseases. cytoplasm and activation of Wnt target genes in the nucleus. FAT1 protein may affect Wnt signaling via modulation of the 2. Signaling pathways and mechanisms latter two steps (36‑38). Just as classical cadherin can bind to β‑catenin and FAT1 and Ena/Vasp. Ena/Vasp is an important regulator regulate its transcriptional activity, FAT1 can also bind to of actin dynamics. The Ena/Vasp protein family regulates β‑catenin and limit its translocation to the nucleus (39). This the assembly of the actin cytoskeleton by antagonizing the links FAT1 to the typical Wnt signaling pathway. A study by dissociation of capping proteins and promoting actin filament Hou et al (36) confirmed this interaction by demonstrating branching connections, which serve a vital role in morphogen‑ increased FAT1 expression following carotid artery injury esis, axon guidance, cell migration and other processes (25‑28). in rats. The rat FAT1 cytoplasmic tail was shown to bind The role of FAT1 in the pathways necessary to determine the to β‑catenin, preventing its translocation to the nucleus and polarity of cells in the tissue plane has been demonstrated thus preventing transcription of its target genes, including the in Drosophila (29). The FAT1 cytoplasmic domain contains known transcriptional target cyclin D1, which is a target of an EVH1 binding motif (4433DFPPPPEE). EVH1 binding the typical Wnt signaling pathway (36). In addition, the results motifs are predicted to interact with members of the Ena/Vasp of FAT1‑knockout revealed that increased FAT1 expression protein family that contain EVH1 domains (30). Thus, FAT1 limited cyclin D1 expression in mouse vascular smooth muscle may serve a role in regulating cell migration by participating cells (VSMCs) (40). Cyclin D1 is a
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