{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTM4SF5 is a multifunctional transmembrane glycoprotein frequently overexpressed in malignant tissues—most notably in hepatocellular carcinoma and other epithelial cancers—where its aberrant expression disrupts normal cell–cell contact and promotes the epithelial–mesenchymal transition (EMT). In these settings, TM4SF5 expression correlates with enhanced cytosolic stabilization of p27^Kip1, inactivation of RhoA, and altered cell‐cycle dynamics that accelerate G1/S progression, collectively leading to uncontrolled cell proliferation and tumorigenesis. These observations indicate that TM4SF5 drives key oncogenic signaling cascades that dismantle contact inhibition and promote malignant transformation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its role in promoting tumor growth, TM4SF5 facilitates malignant migration and invasion. By interacting directly with components of the integrin and focal adhesion machinery, TM4SF5 modulates cell adhesion and actin reorganization—effects that are manifested as enhanced angiogenesis, invadopodia formation, and focal adhesion kinase (FAK) activation at the leading edge of migrating cells. Such integrin cross‐talk, evidenced by its ability to modulate integrin α2 functions and to potentiate signaling cascades (c‐Src/STAT3), further enables the acquisition of circulating tumor cell properties and metastasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "10"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTM4SF5 also plays a critical role in reprogramming the tumor microenvironment. Through its dynamic interactions with other tetraspanins such as CD151 and by downregulating tumor‐suppressive partners like CD63, TM4SF5 alters membrane protein complexes (tetraspanin‐enriched microdomains) that influence cell differentiation, adhesion properties, and ultimately the malignant phenotype. Expression analyses in diverse cancers—including esophageal tumors—further support its involvement in modulating context‐dependent cell–cell and cell–matrix interactions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "13"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its impact on cellular architecture and motility, TM4SF5 regulates metabolic signaling pathways. Notably, it functions as a sensor that translocates to lysosomal membranes upon arginine sufficiency—directly binding arginine to promote mTORC1/S6K1 activation—and thereby influences autophagy and lipid catabolism in adipose tissues. Moreover, in hepatocytes, TM4SF5 associates with fatty acid transporters to negatively modulate acute fatty acid uptake, suggesting a role in maintaining energy homeostasis under conditions of metabolic stress."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "14", "end_ref": "16"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, TM4SF5’s central role in tumor progression and metabolic regulation renders it an attractive therapeutic target. Preclinical studies using anti‐TM4SF5 monoclonal antibodies and inhibitory cell‐penetrating peptides have demonstrated suppressed tumor growth, reduced metastatic dissemination, and even reversal of drug resistance in both hepatocellular carcinoma and colon cancer models. By directly disrupting TM4SF5 interactions with effectors such as c‐Src—as well as interfering with its capacity to modulate integrin signaling—these strategies hold promise for developing targeted interventions against TM4SF5‐mediated pathologies."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "22"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sung-Yul Lee, Young Tai Kim, Mi-Sook Lee, et al. 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