{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTGFBR3, also known as betaglycan, is a multifunctional co‐receptor that critically modulates transforming growth factor–β (TGF‑β) superfamily signaling. It binds a diverse array of ligands—including TGF‑β isoforms and bone morphogenetic proteins—and facilitates ligand presentation as well as receptor internalization via interactions with beta‑arrestin. Its extracellular domain contains distinct binding regions, such as a specific inhibin‐binding epitope, that contribute to its ability to fine‑tune both canonical Smad and non‑Smad signal transduction pathways during development and tissue homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn cancer contexts, TGFBR3 frequently acts as a tumor suppressor by restraining cell migration, invasion, and epithelial-to-mesenchymal transition. Loss or downregulation of TGFBR3 expression—whether through decreased gene expression, altered cytoplasmic domain signaling, or increased ectodomain shedding to generate a soluble antagonist—can lead to enhanced tumor cell motility and metastatic progression. These effects have been documented in several malignancies including pancreatic, prostate, renal, lung, and oral squamous cell carcinomas, where TGFBR3 also contributes to mechanisms such as the induction of cellular dormancy via p38MAPK activation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic and cytogenetic studies further underline the multifaceted roles of TGFBR3 by linking polymorphisms and chromosomal rearrangements to diverse clinical phenotypes. Variants in TGFBR3 have been associated with differences in bone mineral density and optic disc area, while recurrent rearrangements involving the TGFBR3 locus occur in soft tissue tumors such as myxoinflammatory fibroblastic sarcoma and hemosiderotic fibrolipomatous tumor. Moreover, genetic associations have implicated TGFBR3 variants in vascular complications—including priapism—and in modulating susceptibility to bacteremia in disorders like sickle cell anemia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "19"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond cancer and genetic predisposition, TGFBR3 influences several other biological processes. In chondrogenesis, targeting by specific microRNAs can modulate early differentiation, while complex formation with endoglin on chondrocytes helps regulate extracellular matrix dynamics. In lung fibroblasts, glucocorticoid exposure upregulates TGFBR3 expression, thereby altering downstream TGF‑β pathway outputs. Furthermore, altered TGFBR3 levels in placental tissue and in membranous lupus nephritis point to its relevance in reproductive and autoimmune disorders."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Wei Chen, Kellye C Kirkbride, Tam How, et al. 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