{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ESRP2 is a pivotal epithelial‐specific RNA‐binding protein that orchestrates a broad alternative splicing program to establish and maintain epithelial cell identity. Functioning in concert with its paralog ESRP1, ESRP2 regulates mutually exclusive exon selection in key transcripts such as fibroblast growth factor receptor 2 (FGFR2), CD44, p120‐catenin, and hMena, thereby promoting the expression of epithelial isoforms and suppressing mesenchymal splice variants."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Its expression is tightly modulated during epithelial–mesenchymal transition (EMT): signaling pathways such as TGF‐β induce factors (e.g., δEF1/SIP1) that repress ESRP2 transcription, shifting the splicing balance towards mesenchymal isoforms that favor cell migration, invasion, and tumor progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In developmental contexts, ESRP2 is equally critical; for example, its postnatal induction drives a neonatal‐to‐adult splicing switch in hepatocytes, thereby supporting terminal differentiation and proper organ maturation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " Moreover, alterations in ESRP2 expression have been implicated in diverse pathologies. In orofacial clefting, aberrant ESRP2 function contributes to defects in epithelial adhesion, while in various carcinomas—including colorectal, head and neck, and renal cancers—loss or dysregulation of ESRP2 is associated with enhanced EMT features, increased cellular motility, and poorer clinical outcomes, indicating a tumor‐suppressive role through maintenance of epithelial splicing patterns."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "9"}]}, {"type": "t", "text": " Recent reviews also highlight the dual roles of ESRP2 in both suppressing malignant progression and, in certain contexts, promoting epithelial cell survival under stress, which underscores its fine-tuned regulation in development and disease."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " In hepatocellular carcinoma and other settings, decreased ESRP2 levels correlate with widespread splicing dysregulation and perturbed cellular homeostasis, emphasizing its function as a master regulator that integrates transcriptional, epigenetic, and signal-dependent inputs to control alternative splicing."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Finally, recent mechanistic studies in laryngeal cancer further implicate ESRP2 as an effector within regulatory pathways—including those modulated by MYCT1—that influence EMT and metastatic behavior."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Collectively, these studies establish ESRP2 as a central coordinator of an epithelial-specific splicing network that is essential for tissue morphogenesis, cellular differentiation, and the suppression of malignant phenotypes.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Claude C Warzecha, Trey K Sato, Behnam Nabet, et al. 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