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History and Progression of Fat Cadherins in Health and Disease

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Journal name: OncoTargets and Therapy Article Designation: Review Year: 2016 Volume: 9 OncoTargets and Therapy Dovepress Running head verso: Zhang et al Running head recto: History and progression of Fat cadherins open access to scientific and medical research DOI: http://dx.doi.org/10.2147/OTT.S111176 Open Access Full Text Article REVIEW History and progression of Fat cadherins in health and disease Xiaofeng Zhang1,2,* Abstract: Intercellular adhesions are vital hubs for signaling pathways during multicellular Jinghua Liu3,* development and animal morphogenesis. In eukaryotes, under aberrant intracellular conditions, Xiao Liang1,2 cadherins are abnormally regulated, which can result in cellular pathologies such as carcinoma, Jiang Chen1,2 kidney disease, and autoimmune diseases. As a member of the Ca2+-dependent adhesion super- Junjie Hong1,2 family, Fat proteins were first described in the 1920s as an inheritable lethal mutant phenotype Libo Li1 in Drosophila, consisting of four member proteins, FAT1, FAT2, FAT3, and FAT4, all of which are highly conserved in structure. Functionally, FAT1 was found to regulate cell migration and Qiang He3 growth control through specific protein–protein interactions of its cytoplasmic tail. FAT2 and Xiujun Cai1,2 FAT3 are relatively less studied and are thought to participate in the development of human 1Department of General Surgery, cancer through a pathway similar to that of the Ena/VASP proteins. In contrast, FAT4 has 2Key Laboratory of Surgery of Zhejiang Province, Sir Run Run been widely studied in the context of biological functions and tumor mechanisms and has been For personal use only. Shaw Hospital, Zhejiang University, shown to regulate the planar cell polarity pathway, the Hippo signaling pathway, the canonical 3 Hangzhou, Zhejiang, Department of Wnt signaling cascade, and the expression of YAP1. Overall, Fat cadherins may be useful as Hepatobiliary Surgery, Linyi People’s Hospital, Linyi, Shandong, People’s emerging disease biomarkers and as novel therapeutic targets. Republic of China Keywords: Fat cadherins, FAT1, FAT2, FAT3, FAT4, CpG island, Hippo pathway, WNT *These authors contribute equally signaling to this work Introduction Cell–cell adhesions are important for the development of multicellular organisms and the process of animal morphogenesis. In eukaryotes, aberrant intracellular environ- ments can induce pathologic regulation of cadherins, leading to cellular pathologies such as carcinoma, kidney disease, and autoimmune diseases.1 OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 137.108.70.14 on 22-Jan-2020 As a member of the Ca2+-dependent adhesion superfamily, the cadherin family is divided into several subfamilies: classical cadherins, desmosomal cadherins, protocad- herins, Flamingo/Celsr, Dachsous (DS), and Fat cadherins. Each cadherin subfamily exhibits slightly divergent functions. For instance, classical cadherins function as links Correspondence: Xiujun Cai Department of General Surgery, Sir Run to the actin cytoskeleton, desmosomal cadherins are specific to the desmosome, proto- Run Shaw Hospital, Zhejiang University, cadherins are associated with stereocilia and somite epithelialization, and Flamingo/ Hangzhou 310016, Zhejiang, People’s 2 Republic of China Celsr and DS regulate the planar cell polarity (PCP) pathway. Tel/fax +86 571 8600 6605 Fat was first described in the 1920s in Drosophila as an inheritable lethal Email [email protected] mutant phenotype.2 Vertebrate Fat cadherin proteins are highly homologous with Qiang He Drosophila Fat proteins. Four members comprise this gene family: Fat1, Fat2, Fat3, Department of Hepatobiliary Surgery, and Fat4.1,3 Sequence analysis of the four vertebrate Fat cadherins, and in particular Linyi People’s Hospital, 27 East Jiefang Road, Linyi 276000, Shandong, People’s Fat4, shows that they are orthologous to Drosophila Fat. The Fat family is also Republic of China well conserved in structure and function, especially in human beings. In the past Tel/fax +86 539 807 8508 Email [email protected] two decades, the Fat family was demonstrated to be a tumor suppressor.1 In reality, submit your manuscript | www.dovepress.com OncoTargets and Therapy 2016:9 7337–7343 7337 Dovepress © 2016 Zhang et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you http://dx.doi.org/10.2147/OTT.S111176 hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Powered by TCPDF (www.tcpdf.org) 1 / 1 Zhang et al Dovepress owing to the extremely large size of mRNA transcripts and were found to interact with atrophin, a transcriptional co- encoded proteins, understanding the roles of Fat proteins repressor that also contributes to the function of Fat proteins has been challenging, and thus, the roles remain unknown. in the PCP pathway.8 While both Fat-Hippo and Fat-PCP signaling cascades have previously been shown to result in malformations, Fat1 tumorigenesis, and cancer metastasis, additional roles Structure and function remain to be elucidated.3–6 However, with the accumula- Fat1 is located on chromosome 4q34–35 and consists of tion of experimental data, technological advancements, 27 exons. It is the first Fat family member to be identified and and broader knowledge of disease mechanisms, the Fat the most frequently studied Fat protein. Fat1 was cloned in cadherin family is considered as an “emerging giant” of 1995 from a human T-leukemia cell line and has since been the cadherin superfamily. shown to be closely related to human diseases.1 Fat cadherins are single transmembrane receptors, distin- FAT1 interacts with related cadherins and Ena/VASP guished by 32–34 extracellular cadherin repeats of alternating proteins to regulate cell migration and actins dynamics. laminin G-like and EGF-like motifs. FAT1 and FAT4 contain Further studies have shown that FAT1 also binds to Ena/ 34 cadherin repeats, while FAT2 and FAT3 contain 32 and VASP proteins and regulates actin dynamics at both the 33 repeats, respectively. There are unique arrangements and cell–cell contact and ruffling edges.2,9 Furthermore, a TCF/ quantities of EGF-like and laminin G-like motifs that are LEF-binding site was discovered in the Fat1 promoter, specific for each member. Usually, the type of protein–protein 1,100 bp upstream of its transcriptional start site.6 interaction in the cytoplasmic domain of Fat cadherins differs Additionally, because the cytoplasmic region contains from that in its functional domains (Figure 1). various domains, FAT1 can interact directly with the Hippo– Furthermore, because of similarities in the structure of Wnt signaling cascade via the atrophin protein, HOMER-1 Fat proteins with other characterized proteins, Fat proteins to HOMER-3 protein, which competes with Ena for bind- may also act in similar signaling pathways.1–3 In a previous ing to FAT1 and β-cadherin.10–12 Finally, FAT1 was shown For personal use only. study on the common mutations in Fat genes of patients, non- to undergo alternative splicing in cancer cells undergoing synonymous somatic missense mutations did not influence epithelial-to-mesenchymal transition, where its cytoplasmic their level of protein expression.7 Additionally, Fat proteins tail was cleaved by the γ-secretase enzyme complex.13–15 &HOO +LSSR:QWVLJQDO PLJUDWLRQ SDWKZD\ $WURSKLQ 6FULEEOH OncoTargets and Therapy downloaded from https://www.dovepress.com/ by 137.108.70.14 on 22-Jan-2020 <$3±7$= '6 3RODUL]HGFHOO GLYLVLRQ )UL]]OHG βFDWHQLQ (QD9$63 &HOOJURZWK 3&3 &HOOJURZWK $FWLQ &HOO DQGPLJUDWLRQ SRO\PHUL]DWLRQ PRYHPHQW Figure 1 Structure and function of the Fat cadherin family in human beings. Notes: The general molecular structure of Fat cadherins is illustrated in the schematic form based on the human sequence. All members have a predicted molecular weight in excess of 500 kDa. Their extracellular domain interacts with DS, and their cytoplasmic domain is related to proteins such as β-catenin, atrophin, and scribble. Abbreviation: DS, Dachsous. 7338 submit your manuscript | www.dovepress.com OncoTargets and Therapy 2016:9 Dovepress Powered by TCPDF (www.tcpdf.org) 1 / 1 Dovepress History and progression of Fat cadherins Pathogenicity mechanism and signaling pathways cell carcinoma cells diminished the migration and number Analysis of adult human tissues shows Fat1 to be expressed in of filopodia.15 A Basic Local Alignment Search Tool search the development organs and at low levels in adult epithelia.16 of the human Fat2 coding sequence suggests that Fat2 Paradoxically, although it is a tumor suppressor, Fat1 was mRNA is expressed in gastric cancer, pancreatic cancer, downregulated in invasive breast cancer. On the contrary, ovarian cancer, and esophageal cancer. Furthermore, Fat2 Fat1 was upregulated in patients with leukemia and preB- expression was detected in hematological tissue, especially acute lymphoblastic leukemia.17,18 Thus, FAT1 may function in patients with 5q-syndrome. Mutations in Fat2 can also as a tumor suppressor and an oncogenic protein.19 Further- result in the
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  • Characterization of a Dchs1 Mutant Mouse Reveals Requirements For

    Characterization of a Dchs1 Mutant Mouse Reveals Requirements For

    RESEARCH ARTICLE 947 Development 138, 947-957 (2011) doi:10.1242/dev.057166 © 2011. Published by The Company of Biologists Ltd Characterization of a Dchs1 mutant mouse reveals requirements for Dchs1-Fat4 signaling during mammalian development Yaopan Mao1, Joanna Mulvaney2, Sana Zakaria2, Tian Yu2,3, Katherine Malanga Morgan1, Steve Allen4, M. Albert Basson2,3, Philippa Francis-West2,*,† and Kenneth D. Irvine1,*,† SUMMARY The Drosophila Dachsous and Fat proteins function as ligand and receptor, respectively, for an intercellular signaling pathway that regulates Hippo signaling and planar cell polarity. Although gene-targeted mutations in two mammalian Fat genes have been described, whether mammals have a Fat signaling pathway equivalent to that in Drosophila, and what its biological functions might be, have remained unclear. Here, we describe a gene-targeted mutation in a murine Dachsous homolog, Dchs1. Analysis of the phenotypes of Dchs1 mutant mice and comparisons with Fat4 mutant mice identify requirements for these genes in multiple organs, including the ear, kidney, skeleton, intestine, heart and lung. Dchs1 and Fat4 single mutants and Dchs1 Fat4 double mutants have similar phenotypes throughout the body. In some cases, these phenotypes suggest that Dchs1-Fat4 signaling influences planar cell polarity. In addition to the appearance of cysts in newborn kidneys, we also identify and characterize a requirement for Dchs1 and Fat4 in growth, branching and cell survival during early kidney development. Dchs1 and Fat4 are predominantly expressed in mesenchymal cells in multiple organs, and mutation of either gene increases protein staining for the other. Our analysis implies that Dchs1 and Fat4 function as a ligand-receptor pair during murine development, and identifies novel requirements for Dchs1-Fat4 signaling in multiple organs.