{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent high‐resolution structural and biophysical studies have revealed that neurotensin receptor 1 (NTSR1), a class‐A G protein–coupled receptor, adopts multiple conformational states that underpin its versatile signal transduction. Crystallographic and cryo–electron microscopy analyses have shown both canonical and non–canonical complexes with heterotrimeric G proteins, while detailed mapping of the receptor’s binding crevice and key transmembrane residues—further modulated by post–translational modifications (such as arginylation and palmitoylation) and direct cholesterol interactions—clarify how NTSR1’s membrane localization and its biased engagement of G proteins versus β–arrestins are dictated."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNTSR1 is now recognized as a key driver of oncogenic processes in a broad spectrum of human malignancies. In lung, colorectal, breast, prostate, pancreatic, ovarian, hepatocellular, and glioblastoma tumors, overexpression of NTSR1 and its ligand neurotensin establishes autocrine/paracrine loops that trigger mitogenic cascades—including MAP kinase, NF–κB, and EGFR/HER–mediated pathways—and promote cellular proliferation, migration, invasion, and epithelial–to–mesenchymal transition. Moreover, aberrant NTSR1 expression and epigenetic modifications (such as promoter methylation alterations) correlate with aggressive disease features and poorer clinical outcomes, thereby underscoring its value both as a prognostic biomarker and as a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "40"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its autonomous signaling, NTSR1 engages in receptor–receptor interactions that modulate its cellular output. Formation of heteromers between NTSR1 and other G protein–coupled receptors—notably the dopamine D2 and kappa opioid receptors—alters the receptor’s canonical signaling profile via allosteric cross–talk, thereby influencing diverse cellular responses in both neural and tumor tissues."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "41", "end_ref": "44"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nVariations in NTSR1 function—whether through genetic polymorphisms, altered receptor trafficking, or the development of ligands with preferential signaling biases—carry important clinical implications. Selective NTSR1 antagonists, β–arrestin–biased agonists, and imaging agents show promise in preclinical models by enhancing chemotherapeutic responses and reducing tumor growth, while emerging evidence also links NTSR1 genetic variation to neurocognitive traits such as working memory. Collectively, these findings support the targeting of NTSR1 as part of precision medicine strategies in both oncology and neuropsychiatric disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "45", "end_ref": "48"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Mireille Toy-Miou-Leong, Catherine Llorens Cortes, Alain Beaudet, et al. 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