{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTGFB3 is a dimeric cytokine of the transforming growth factor‐β superfamily whose structural basis for receptor binding has been deciphered at high resolution. Crystallographic studies have revealed that TGFB3 interacts with its type II and type I receptor extracellular domains via unique ligand–receptor interfaces and specialized extensions that secure the formation of a heterotetrameric signaling complex. Mutagenesis experiments pinpoint key residues—such as arginine 25 and arginine 94—that are critical for high‐affinity receptor engagement and subsequent Smad activation, thus establishing the molecular underpinnings for its diverse biological actions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn various cellular contexts, TGFB3 serves as a pivotal mediator of dynamic cellular transitions and migratory responses. Its transcription can be induced by EMT‐drivers such as the Snail family, and once expressed, TGFB3 propagates autocrine and paracrine signals that promote epithelial-to-mesenchymal transition (EMT) and cytoskeletal reorganization—features that are essential during embryogenesis and are often subverted in cancer progression. Furthermore, TGFB3 contributes to the modulation of inflammation, as evidenced by its ability to stimulate proinflammatory cytokine gene expression in reproductive epithelial cells as well as its production by regulatory T cells that suppress B-cell responses. Under certain conditions, TGFB3 also participates in endothelial-to-mesenchymal transition, either directly or via inducing secondary TGFB2 secretion, thereby influencing cell migratory behaviors and wound-healing responses."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond these signaling roles, TGFB3 is central to multiple developmental and tissue-specific processes. Genetic association studies have linked TGFB3 with craniofacial morphogenesis and non-syndromic clefting disorders, while hypoxia-driven upregulation of TGFB3 in placental trophoblasts contributes to proper differentiation—a process whose dysregulation may be implicated in disorders such as preeclampsia. TGFB3 also synergizes with factors like BMP-2 to enhance chondrogenic differentiation of mesenchymal stem cells and to drive cartilage hypertrophy, and it is capable of promoting the formation of tendon-like tissue in vitro. In addition, by modulating the expression of extracellular matrix components (for example, versican variants in uterine leiomyoma cells and POSTN in cancer-associated fibroblasts), TGFB3 exerts profound effects on tissue remodeling and the tumor microenvironment. 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