History and progression of Fat cadherins in health and disease

Abstract

Intercellular adhesions are vital hubs for signaling pathways during multicellular development and animal morphogenesis. In eukaryotes, under aberrant intracellular conditions, cadherins are abnormally regulated, which can result in cellular pathologies such as carcinoma, kidney disease, and autoimmune diseases. As a member of the Ca²⁺-dependent adhesion super-family, Fat proteins were first described in the 1920s as an inheritable lethal mutant phenotype 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 growth control through specific protein-protein interactions of its cytoplasmic tail. FAT2 and FAT3 are relatively less studied and are thought to participate in the development of human cancer through a pathway similar to that of the Ena/VASP proteins. In contrast, FAT4 has been widely studied in the context of biological functions and tumor mechanisms and has been shown to regulate the planar cell polarity pathway, the Hippo signaling pathway, the canonical Wnt signaling cascade, and the expression of YAP1. Overall, Fat cadherins may be useful as emerging disease biomarkers and as novel therapeutic targets.

Keywords: CpG island; FAT1; FAT2; FAT3; FAT4; Fat cadherins; Hippo pathway; WNT signaling.

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.

Figure 2

FAT4 participates in tumor transformation through the Hippo–Wnt signaling pathway by inducing YAP–TAZ activation. Notes: Src-mediated tumorigenesis also results from Src activation to repress FAT4 gene expression via MEK/ERK or cofilin1. In addition, FAT4 interacts with well-known anti-oncogenes through indirect interactions, such as p53 and p21. Mutations in p53 and APC are major drivers of tumor development. FAT4 is a novel SMG. Solid and dashed lines indicate interactions that appear to be direct and indirect, respectively. Oval represents the cell nucleus.

Figure 3

CpG islands in the human Fat4 promoter region and previously reported somatic mutation in cancer. Notes: The CpG islands span ~2.7 kb and are located in the promoter region and the first exon of the Fat4 gene. The locus of FAT4 amino acid substitutions is caused by genomic deletion and somatic mutation in common tumors.