{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nIntegrin‐mediated cell–matrix interactions are central to the dynamic regulation of cell adhesion, spreading, and extracellular matrix (ECM) assembly. In particular, the α5β1 receptor—which binds fibronectin—modulates RhoA activity and governs focal adhesion distribution and cytoskeletal organization. Post‐translational modifications (for example, via GnT‐III) can alter α5 integrin N‐glycosylation, reducing its ligand affinity and thereby suppressing cell–matrix adhesion, while signaling cascades initiated “inside‐out” via kinases such as Akt further promote fibronectin fibrillogenesis and matrix assembly. Moreover, extracellular stimuli (such as chemerin) rapidly induce integrin clustering, thereby enhancing cell adhesion even in the absence of major changes in ligand affinity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "7"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to regulating adhesion and migration, α5β1‐integrin signaling plays essential roles during development and vascular morphogenesis. Its engagement with fibronectin is critical for cardiac outflow tract formation, proper neural migration and cortical lamination, and the maintenance of cerebral vascular integrity. In hypoxic conditions, for example, rapid up‐regulation of fibronectin and associated integrins in the brain contributes to angiogenesis and vessel stabilization. Blockade or genetic ablation of specific integrin subunits in neuronal or endothelial lineages disrupts normal morphogenesis and leads to hemorrhagic complications or congenital heart defects, highlighting the indispensable developmental functions of this receptor."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAberrant integrin signaling and altered α5β1 expression are also strongly implicated in pathological processes. Elevated α5‐integrin levels have been associated with enhanced metastatic potential in melanoma, while dysregulated receptor recycling and clustering can influence viral entry pathways and promote inflammatory signaling cascades in endothelial cells. In chronic disease models, for instance, excessive fibronectin deposition via α5β1 drives inflammation in atherosclerosis and contributes to fibrotic remodeling in organs such as the liver and kidney. These diverse findings underscore how integrin α5β1 functions as a central hub—transducing both mechanical forces and biochemical signals—to mediate cell survival, migration, and tissue remodeling under both physiological and disease‐associated conditions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "13", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Erik H J Danen, Petra Sonneveld, Cord Brakebusch, et al. 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