{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSmoothened (SMO) is a seven‐transmembrane receptor that serves as the central signal transducer of the Hedgehog (Hh) pathway, a fundamental regulator of embryogenesis, tissue patterning, and cellular homeostasis. Under basal conditions, inhibition by the receptor Patched keeps SMO inactive; however, when Hh ligands bind to Patched, this repression is relieved, allowing SMO to undergo conformational changes and accumulate—often in the primary cilium—to trigger downstream transcription via the GLI family. Recent high‐resolution structural studies have defined SMO’s unusual architecture, composed of a transmembrane helical bundle and a cysteine‐rich extracellular domain, with multiple ligand‐binding sites that accommodate diverse small molecules and sterols (which include cholesterol and oxysterols). In addition, SMO activity is finely regulated by phosphorylation, ubiquitination/deubiquitination cycles, and dynamic interactions with regulatory proteins such as GRK2 and USP8, all of which influence its subcellular trafficking and ability to couple to heterotrimeric Gi proteins."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAberrant SMO activation is a hallmark of diverse malignancies. Activating mutations in SMO have been identified in aggressive tumors such as medulloblastoma, basal cell carcinoma, meningioma, and ameloblastoma, and can render the receptor resistant to clinically applied antagonists (for example, vismodegib and related agents). In several instances, mutations that alter conserved residues within the ligand‐binding pocket of SMO preserve its intrinsic signaling activity while diminishing drug binding. The oncogenic potential of SMO is further underscored by its ability to suppress tumor‐suppressor functions—for instance, by enhancing Mdm2‐mediated degradation of p53—and by its transcriptional upregulation in hypoxic conditions or in cross-talk with pathways such as RAS–MAPK and BRAF. Moreover, in cancers ranging from hepatocellular carcinoma to chronic myelogenous leukemia and glioma, both genetic and epigenetic dysregulation of SMO (including diminished microRNA control) appear to promote cellular proliferation, survival and the maintenance of cancer stem cell properties. Together, these data emphasize SMO’s critical role in tumorigenesis and drug resistance while highlighting its attractiveness as a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "31"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its canonical role in Hh signal transduction, SMO engages in nontraditional pathways that impact diverse physiological processes. For example, a cilium‐dependent SMO–Ca²⁺–AMPK axis has been shown to induce rapid, Warburg-like metabolic reprogramming and drive insulin-independent glucose uptake in muscle and brown adipose tissue. Furthermore, SMO signaling can modulate cytoskeletal dynamics through Gi protein coupling, thereby influencing cell migration and morphogenesis, and it contributes to pathological tissue remodeling such as hepatic fibrosis by regulating epithelial–mesenchymal transitions. 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