TM4SF5-Mediated Roles in the Development of Fibrotic Phenotypes

Abstract

Transmembrane 4 L six family member 5 (TM4SF5) can form tetraspanin-enriched microdomains (TERMs) on the cell's surface. TERMs contain protein-protein complexes comprised of tetraspanins, growth factor receptors, and integrins. These complexes regulate communication between extracellular and intracellular spaces to control diverse cellular functions. TM4SF5 influences the epithelial-mesenchymal transition (EMT), aberrant multilayer cellular growth, drug resistance, enhanced migration and invasion, circulation through the bloodstream, tumor-initiation property, metastasis, and muscle development in zebrafish. Here, current data on TM4SF5's roles in the development of fibrotic phenotypes are reviewed. TM4SF5 is induced by transforming growth factor β1 (TGFβ1) signaling via a collaboration with epidermal growth factor receptor (EGFR) activation. TM4SF5, by itself or in concert with other receptors, transduces signals intracellularly. In hepatocytes, TM4SF5 expression regulates cell cycle progression, migration, and expression of extracellular matrix components. In CCl4-treated mice, TM4SF5, α-smooth muscle actin (α-SMA), and collagen I expression are observed together along the fibrotic septa regions of the liver. These fibrotic phenotypes are diminished by anti-TM4SF5 reagents, such as a specific small compound [TSAHC, 4′-(p-toluenesulfonylamido)-4-hydroxychalcone] or a chimeric antibody. This review discusses the antifibrotic strategies that target TM4SF5 and its associated protein networks that regulate the intracellular signaling necessary for fibrotic functions of hepatocytes.

TM4SF5 Knockout Protects Mice From Diet-Induced Obesity Partly by Regulating Autophagy in Adipose Tissue

“…Transmembrane 4 L six family member 5 (TM4SF5) is an N-glycosylated plasma membrane protein with four transmembrane domains and is also found in the lysosomal membrane (19). Its regulatory function in actin reorganization, cell adhesion, cell spread, and migration has been reported in relation to the pathogenesis of hepatic diseases, such as fatty liver (19)(20)(21). Importantly, TM4SF5 functions as a lysosomal membrane arginine sensor that promotes mTORC1 activation-mediated cell growth (19).…”

Three Members of Transmembrane-4-Superfamily, TM4SF1, TM4SF4, and TM4SF5, as Emerging Anticancer Molecular Targets against Cancer Phenotypes and Chemoresistance

“…TM4SF proteins are found in almost all multicellular eukaryotes [ 41 , 42 ]. It consists of four transmembrane alpha (α)-helices and two extracellular domains with one shorter (small extracellular domain/loop, SED/SEL or EC1) and one larger (large extracellular domain/loop, LED/LEL or EC) [ 29 , 41 ], with the structure, is shown in Figure 1 . They are differentiated by conserved amino acid sequences, including a CCG motif and other cysteine residues in the EC2 [ 29 , 43 ].…”

“…Generally, six members of TM4SF have been reported with similar topology and sequence homology, including TM4SF1/L6-Ag, TM4SF4/IL-TMP, TM4SF5/L6H, TM4SF18/L6D, TM4SF19/OCTM4, and TM4SF20/TCCE518 [ 27 , 28 , 29 ]. Among them, TM4SF1, TM4SF4, and TM4SF5 are grouped under the transmembrane 4 L6 domain family [ 28 ].…”

TM4SF5-Mediated Regulation of Hepatocyte Transporters during Metabolic Liver Diseases

“…Therefore, TM4SF5 appears to play important roles in the development of chronic liver disease. TM4SF5 is involved in the development of NASH [ 36 ], fibrosis [ 82 , 83 ], and HCC [ 13 , 56 ]. Compared with age-matched wild-type mice, 78-week-old TM4SF5-overexpressing transgenic mice (C57BL/6-TG TM4SF5 ) livers exhibit elevated immune cell infiltration, ballooned hepatocytes, and fibrotic phenotypes [ 36 ].…”