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.
Highlights
Membrane proteins and receptors can be enriched at unique and specific regions on a cell’s surface
When cells are replated onto inert materials of poly-L-lysines or when cells precoated with anti-integrin β1 antibodies are replated onto fibronectin, Transmembrane 4 L six family member 5 (TM4SF5)-mediated focal adhesion kinase (FAK) phosphorylation is higher than when cells are kept in suspension
TM4SF5 has been investigated for its roles in diverse cellular functions by mostly us and others
Summary
Membrane proteins and receptors can be enriched at unique and specific regions on a cell’s surface. Specific strategies targeting membrane proteins could result in promising antifibrotic reagents that maybe clinically valuable Because it is a member of the transmembrane 4 L six family similar to the tetraspanins (TM4SFs), TM4SF5’s role in the development of fibrotic phenotypes is discussed in this review. The differential association and localization of TM4SF5 with EGFR and/or integrin α5 fine-tune signaling activities that regulate dynamic cellular and biochemical processes in the leading edge of migratory cells The dynamics of these coordinated protein associations within T5ERMs, which occur proximal to or distal from the leading membrane edges, depend on cellular cholesterol levels and the PTMs of TM4SF5. This information can be used to develop approaches to manipulate cellular migration processes
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