“…Indeed, we have reported by mutation study and molecular modeling that TSAHC binding to TM4SF5 occurs at a region of the long extracellular loop (W124 to E129 of LEL) caused induced fit changes, leading to inhibitions of protein–protein interaction, l -arginine binding, and its downstream signaling activity [ 26 ]. TSAHC is quite specific for TM4SF5 at 0.3–5 μM, since TM4SF5-negative hepatocytes were not responsive to its treatment [ 25 , 33 , 34 ]. Fig.…”
Section: Discussionmentioning
confidence: 99%
“…TM4SF5 expression in hepatocytes promotes phosphorylations of FAK [ 37 ], c-SRC [ 20 ], STAT3 [ 21 , 38 ], and mTOR/S6K1 [ 26 ]. TM4SF5 also binds EGFR [ 39 ], integrin α5 [ 38 , 39 ], CD133 [ 34 ], CD151 [ 40 ], CD44 [ 41 ], and mTOR [ 26 ] membrane receptors or proteins. Interaction of TM4SF5 with integrin α5 induces VEGF secretion for hepatic angiogenesis via enhanced proliferation and migration of endothelial cells [ 38 ].…”
Aberrant extracellular matrix and immune cell alterations within the tumor microenvironment promote the pathological progression of liver carcinogenesis. Although transmembrane 4 L six family member 5 (TM4SF5) is involved in liver fibrosis and cancer, its mechanism avoiding immune surveillance during carcinogenesis remains unknown. We investigated how TM4SF5-mediated signaling caused immune evasion using in vitro primary cells and in vivo liver tissues from genetic or chemically induced mouse models. TM4SF5-transgenic and diethylnitrosamine (DEN)-induced liver cancer mouse models exhibited fibrotic and cancerous livers, respectively, with enhanced TM4SF5, pY705STAT3, collagen I, and laminin γ2 levels. These TM4SF5-mediated effects were abolished by TM4SF5 inhibitor, 4′-(p-toluenesulfonylamido)-4-hydroxychalcone (TSAHC). TM4SF5-dependent tumorigenesis involved natural killer (NK) cell exhaustion-like phenotypes including the reduction of NK cell number or function, which were blocked with TSAHC treatment. TM4SF5 expression in cancer cells downregulated stimulatory ligands and receptors for NK cell cytotoxicity, including SLAMF6, SLAMF7, MICA/B, and others. TM4SF5 suppression or inhibition reduced STAT3 signaling activity and recovered the receptor levels and NK cell surveillance, leading to reduced fibrotic and cancerous phenotypes, and longer survival. Altogether, these findings suggest that TM4SF5-mediated STAT3 activity for extracellular matrix modulation is involved in the progression of liver disease to HCC and that TM4SF5 appears to suppress NK cells during liver carcinogenesis.
“…Indeed, we have reported by mutation study and molecular modeling that TSAHC binding to TM4SF5 occurs at a region of the long extracellular loop (W124 to E129 of LEL) caused induced fit changes, leading to inhibitions of protein–protein interaction, l -arginine binding, and its downstream signaling activity [ 26 ]. TSAHC is quite specific for TM4SF5 at 0.3–5 μM, since TM4SF5-negative hepatocytes were not responsive to its treatment [ 25 , 33 , 34 ]. Fig.…”
Section: Discussionmentioning
confidence: 99%
“…TM4SF5 expression in hepatocytes promotes phosphorylations of FAK [ 37 ], c-SRC [ 20 ], STAT3 [ 21 , 38 ], and mTOR/S6K1 [ 26 ]. TM4SF5 also binds EGFR [ 39 ], integrin α5 [ 38 , 39 ], CD133 [ 34 ], CD151 [ 40 ], CD44 [ 41 ], and mTOR [ 26 ] membrane receptors or proteins. Interaction of TM4SF5 with integrin α5 induces VEGF secretion for hepatic angiogenesis via enhanced proliferation and migration of endothelial cells [ 38 ].…”
Aberrant extracellular matrix and immune cell alterations within the tumor microenvironment promote the pathological progression of liver carcinogenesis. Although transmembrane 4 L six family member 5 (TM4SF5) is involved in liver fibrosis and cancer, its mechanism avoiding immune surveillance during carcinogenesis remains unknown. We investigated how TM4SF5-mediated signaling caused immune evasion using in vitro primary cells and in vivo liver tissues from genetic or chemically induced mouse models. TM4SF5-transgenic and diethylnitrosamine (DEN)-induced liver cancer mouse models exhibited fibrotic and cancerous livers, respectively, with enhanced TM4SF5, pY705STAT3, collagen I, and laminin γ2 levels. These TM4SF5-mediated effects were abolished by TM4SF5 inhibitor, 4′-(p-toluenesulfonylamido)-4-hydroxychalcone (TSAHC). TM4SF5-dependent tumorigenesis involved natural killer (NK) cell exhaustion-like phenotypes including the reduction of NK cell number or function, which were blocked with TSAHC treatment. TM4SF5 expression in cancer cells downregulated stimulatory ligands and receptors for NK cell cytotoxicity, including SLAMF6, SLAMF7, MICA/B, and others. TM4SF5 suppression or inhibition reduced STAT3 signaling activity and recovered the receptor levels and NK cell surveillance, leading to reduced fibrotic and cancerous phenotypes, and longer survival. Altogether, these findings suggest that TM4SF5-mediated STAT3 activity for extracellular matrix modulation is involved in the progression of liver disease to HCC and that TM4SF5 appears to suppress NK cells during liver carcinogenesis.
“…Tetraspanins including TM4SF5 form protein‐protein complexes on cell membranes and can thereby regulate the trafficking or stability of their binding protein partners 27,28 . T 5 ERMs are, thus, formed at the PMs via massive protein‐protein interactions; TM4SF5 binds CD44, 29 CD133, 25 CD151, 5 integrin α5, and EGF receptor 3,4 . In addition, similar to another tetraspanin CD63, TM4SF5 can traffic between endosomal membranes and the PM 5 and translocalize to the lysosome during mTORC1 activation upon amino acid or L‐arginine repletion 6 .…”
Section: Discussionmentioning
confidence: 99%
“…TM4SF5‐null SNU449 or SNU761 and endogenously TM4SF5‐expressing Huh7 or HepG2 cells 25 were obtained from the Korean Cell Bank (Seoul National University, Korea), and maintained in RPMI‐1640 or DMEM (HyClone) with 10% FBS (GenDEPOT, Barker, TX) at 37°C and 5% CO 2 . SNU449 cells stably expressing control or HA‐tagged TM4SF5 expression plasmids were established via retrovirus infection previously described 9 .…”
Transmembrane 4 L six family member 5 (TM4SF5) translocates intracellularly and promotes cell migration, but how subcellular TM4SF5 traffic is regulated to guide cellular migration is unknown. We investigated the influences of the extracellular environment and intracellular signaling on the TM4SF5 traffic with regard to migration directionality. Cell adhesion to fibronectin (FN) but not poly‐l‐lysine enhanced the traffic velocity and straightness of the TM4SF5WT (but not palmitoylation‐deficient mutant TM4SF5Pal−) toward the leading edges, depending on tubulin acetylation. Acetylated‐microtubules in SLAC2B‐positive cells reached mostly the juxtanuclear regions, but reached‐out toward the leading edges upon SLAC2B suppression. TM4SF5 expression caused SLAC2B not to be localized at the leading edges. TM4SF5 colocalization with HDAC6 depended on paxillin expression. The trimeric complex consisting of TM4SF5, HDAC6, and SLAC2B might, thus, be enriched at the perinuclear cytosols toward the leading edges. More TM4SF5WT translocation to the leading edges was possible when acetylated‐microtubules reached the frontal edges following HDAC6 inhibition by paxillin presumably at new cell‐FN adhesions, leading to persistent cell migration. Collectively, this study revealed that cell‐FN adhesion and microtubule acetylation could control intracellular traffic of TM4SF5 vesicles to the leading edges via coordinated actions of paxillin, SLAC2B, and HDAC6, leading to TM4SF5‐dependent cell migration.
“…TM4SF5 expression results in acquired cancer stem cell properties via a physical association with CD44 17 . TM4SF5 expression is promoted by, and subsequently interacts with, CD133, a cancer cell marker 29 . In addition to CD44 and CD133, TM4SF5 interacts with the EGF receptor and integrin α5 for directional migration 13 .…”
Reactive oxygen species (ROS) regulate cell fate, although signaling molecules that regulate ROS hormesis remain unclear. Here we show that transmembrane 4 L six family member 5 (TM4SF5) in lung epithelial cells induced the alternatively spliced CD44v8-10 variant via an inverse ZEB2/epithelial splicing regulatory proteins (ESRPs) linkage. TM4SF5 formed complexes with the cystine/glutamate antiporter system via TM4SF5- and CD44v8-10-dependent CD98hc plasma-membrane enrichment. Dynamic TM4SF5 binding to CD98hc required CD44v8-10 under ROS-generating inflammatory conditions. TM4SF5 and CD44v8-10 upregulated cystine/glutamate antiporter activity and intracellular glutathione levels, leading to ROS modulation for cell survival. Tm4sf5-null mice exhibited attenuated bleomycin-induced pulmonary fibrosis with lower CD44v8-10 and ESRPs levels than wild-type mice. Primary mouse alveolar epithelial cells (AECs) revealed type II AECs (AECII), but not type I, to adapt the TM4SF5-mediated characteristics, suggesting TM4SF5-mediated AECII survival following AECI injury during idiopathic pulmonary fibrosis (IPF). Thus, the TM4SF5-mediated CD44v8-10 splice variant could be targeted against IPF.
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