{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n FRAT1 (Frequently Rearranged in Advanced T‐cell Lymphomas 1) is a key positive regulator of the canonical Wnt/β‐catenin pathway that functions at multiple levels. Through direct interactions with Dishevelled‐1 and casein kinase Iε, FRAT1 cooperates to enhance Wnt signaling by promoting the stabilization and nuclear translocation of β‐catenin while diminishing its phosphorylation by glycogen synthase kinase‑3 (GSK‑3)."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In addition, FRAT1 disrupts the assembly of the destruction complex—preventing GSK‑3β from associating with Axin–APC–CK1—which further reduces β‐catenin phosphorylation, thereby promoting β‐catenin accumulation and activation of TCF/LEF‑dependent gene transcription."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}, {"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " In several cancers, including colorectal, esophageal, lung, glioma/astrocytoma, and pancreatic ductal adenocarcinoma, overexpression of FRAT1 has been found to correlate with increased nuclear β‐catenin and upregulation of oncogenic targets such as c‑Myc, thereby driving tumor cell proliferation, invasion, and metastasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "9"}]}, {"type": "t", "text": " Furthermore, in chondrosarcomas, the co‐expression of FRAT1 with other Wnt pathway components has been associated with higher histological grades, metastatic potential, and poor survival, supporting its utility as both a diagnostic marker and therapeutic target."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " In addition, regulatory inputs from noncoding RNAs—such as microRNAs like miR‑490‑3p and long noncoding RNAs including SNHG1—modulate FRAT1 expression and, consequently, Wnt/β‑catenin activity in tumor cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Finally, post‐translational modifications such as protein kinase A–mediated phosphorylation of FRAT1 add further layers of control over its capacity to inhibit GSK‑3β, thereby fine‑tuning Wnt signaling output."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Collectively, these findings underscore FRAT1’s multifaceted role as a modulator of Wnt/β‑catenin signaling—with critical implications for tumorigenesis and cancer progression—and highlight its potential as a molecular target for therapeutic intervention (1–12).\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Shin-ichiro Hino, Tatsuo Michiue, Makoto Asashima, et al. 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