TM4SF5 is a transmembrane glycoprotein of the transmembrane 4 L six family, a branch of the tetraspanin family and highly expressed in many types of cancers. TM4SF5 induces epithelial-mesenchymal transition (EMT) by morphological changes resulting from inactivation of RhoA mediated by stabilized cytosolic p27kip1. TM4SF5-mediated EMT can lead to loss of contact inhibition and enhanced migration/invasion, presumably depending on cross-talks between TM4SF5 and integrins. An anti-TM4SF5 agent appears to target the second extracellular domain of TM4SF5, which is important for cross-talk with integrins, leading to a blockade of TM4SF5-mediated multilayer growth and migration/invasion. In addition, TM4SF5 engages in cross-talk with integrin alpha5 to induce and secrete VEGF, which in turn causes activation of angiogenesis in endothelial cells. Therefore, TM4SF5 plays a central regulatory role in a wide variety of physiological processes through cross-talk with integrins. This review presents current knowledge from in vitro and in vivo observations of the roles of TM4SF5-integrin cooperation in hepatocellular carcinogenesis and discusses important areas for future investigation.
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Three Members of Transmembrane-4-Superfamily, TM4SF1, TM4SF4, and TM4SF5, as Emerging Anticancer Molecular Targets against Cancer Phenotypes and Chemoresistance.
Pharmaceuticals (Basel)
January 2023
Department of Biomedical Science and Therapeutics, Faculty of Medicine and Health Science, Universiti Malaysia Sabah, Kota Kinabalu 88400, Malaysia.
There are six members of the transmembrane 4 superfamily (TM4SF) that have similar topology and sequence homology. Physiologically, they regulate tissue differentiation, signal transduction pathways, cellular activation, proliferation, motility, adhesion, and angiogenesis. Accumulating evidence has demonstrated, among six TM4SF members, the regulatory roles of transmembrane 4 L6 domain family members, particularly TM4SF1, TM4SF4, and TM4SF5, in cancer angiogenesis, progression, and chemoresistance.
View Article and Find Full Text PDFAmino acid transporters as tetraspanin TM4SF5 binding partners.
Exp Mol Med
January 2020
Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul, 08826, Republic of Korea.
Transmembrane 4 L6 family member 5 (TM4SF5) is a tetraspanin that has four transmembrane domains and can be N-glycosylated and palmitoylated. These posttranslational modifications of TM4SF5 enable homophilic or heterophilic binding to diverse membrane proteins and receptors, including growth factor receptors, integrins, and tetraspanins. As a member of the tetraspanin family, TM4SF5 promotes protein-protein complexes for the spatiotemporal regulation of the expression, stability, binding, and signaling activity of its binding partners.
View Article and Find Full Text PDFTM4SF5-Mediated Roles in the Development of Fibrotic Phenotypes.
Mediators Inflamm
March 2018
Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Tumor Microenvironment Global Core Research Center, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
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.
View Article and Find Full Text PDFDynamic and coordinated single-molecular interactions at TM4SF5-enriched microdomains guide invasive behaviors in 2- and 3-dimensional environments.
FASEB J
April 2017
Department of Pharmacy, Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul, South Korea;
Membrane proteins sense extracellular cues and transduce intracellular signaling to coordinate directionality and speed during cellular migration. They are often localized to specific regions, as with lipid rafts or tetraspanin-enriched microdomains; however, the dynamic interactions of tetraspanins with diverse receptors within tetraspanin-enriched microdomains on cellular surfaces remain largely unexplored. Here, we investigated effects of tetraspan(in) TM4SF5 (transmembrane 4 L6 family member 5)-enriched microdomains (TERMs) on the directionality of cell migration.
View Article and Find Full Text PDFTransmembrane 4 L Six Family Member 5 (TM4SF5)-Mediated Epithelial-Mesenchymal Transition in Liver Diseases.
Int Rev Cell Mol Biol
April 2016
Department of Pharmacy, Research Institute of Pharmaceutical Sciences, Tumor Microenvironment Global Core Research Center, Medicinal Bioconvergence Research Center, College of Pharmacy, Seoul National University, Seoul, Korea. Electronic address:
The membrane protein TM4SF5, a member of the transmembrane 4L six family, forms a tetraspanin-enriched microdomain (TEM) on the cell surface, where many different membrane proteins and receptors form a massive protein-protein complex to regulate cellular functions including transdifferentiation, migration, and invasion. We recently reported that TM4SF5 causes epithelial-mesenchymal transition (EMT), eventually contributing to aberrant multilayer cellular growth, drug resistance, enhanced migration, invasion, its circulation in the blood, tumor initiation for successful metastasis, and muscle development in zebrafish. In this review, I summarize the information on the role of TM4SF5 in EMT-related functions at TM4SF5-enriched microdomain (T5EM) on cell surface, where proteins such as TM4SF5, CD151, CD44, integrins, and epidermal growth factor receptor (EGFR) can form numerous protein complexes.
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