{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNECTIN4 is a Ca²⁺‐independent immunoglobulin‐like cell adhesion molecule that plays a central role at epithelial adherens junctions and has been shown to function as an essential receptor for several viruses. In particular, structural and functional studies have demonstrated that its membrane‐distal IgV domain binds measles virus hemagglutinin with high affinity, thereby facilitating viral entry, spread, and noncytopathic lateral transmission across differentiated airway epithelia. The downregulation of NECTIN4 on infected epithelial cells appears to be part of the viral exit mechanism, contributing to efficient virus shedding and enabling systemic viral dissemination."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn a broad spectrum of human cancers—including those of the breast, lung, ovary, bladder, and other epithelial origins—NECTIN4 is aberrantly overexpressed and has emerged as both a robust histological and serological biomarker as well as a promising therapeutic target. Elevated NECTIN4 levels correlate with aggressive tumor features, enhanced cell proliferation, invasion, metastasis, and poor clinical prognosis. Its critical role in oncogenesis has been further exploited therapeutically with antibody–drug conjugates (for example, enfortumab vedotin) that target NECTIN4‐positive tumor cells. These findings underscore the molecule’s utility in precision oncology, where its expression can inform both prognosis and treatment stratification."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "21"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in viral pathogenesis and tumor progression, NECTIN4 is fundamentally involved in cell–cell adhesion, tissue morphogenesis, and the regulation of key intracellular signaling pathways. Mutations in the PVRL4 gene (which encodes NECTIN4) underlie certain forms of ectodermal dysplasia, underscoring its importance in proper adherens junction formation and epithelial integrity. NECTIN4 is subject to regulated proteolytic cleavage by ADAM proteases, a process that modulates the release of its soluble ectodomain and thus influences downstream signaling through pathways such as PI3K/AKT, Rac1, WNT/β‐catenin, and Hippo. In addition, NECTIN4 trans‐interacts with other nectin family members and receptor tyrosine kinases—events that integrate its adhesive functions with the control of cell motility, cancer stem cell maintenance, and even trans‐endocytosis of cytoplasmic components."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "22", "end_ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ryan S Noyce, Daniel G Bondre, Michael N Ha, et al. 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