{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTransforming growth factor‐α (TGFA) acts as a potent ligand for the epidermal growth factor receptor (EGFR) that regulates normal epithelial physiology. In cholangiocytes, for example, bile acids trigger EGFR phosphorylation and cell growth via a TGFA‐dependent mechanism."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Similarly, in human keratinocytes, TGFA not only enhances cell migration but also up‐regulates toll‐like receptors (TLR5 and TLR9), thus bolstering local host defense during wound healing."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": " Moreover, studies comparing serum and plasma effects on keratinocyte motility have demonstrated that TGFA accounts for most of the migration‐promoting activity found in serum, with its neutralization or depletion significantly inhibiting keratinocyte movement."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer, aberrant TGFA signaling is frequently implicated in tumor progression and metastasis. TGFA has been shown to transactivate receptors that up‐regulate growth‐promoting pathways in endocrine and breast cancer cells, thereby contributing to cell survival and resistance to therapy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " In osteosarcoma models, elevated TGFA levels increase cell migration through activation of the PI3K/Akt and NF‑κB cascades, while genetic studies have linked specific TGFA variants with an increased risk of nonsyndromic oral clefts."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "10"}]}, {"type": "t", "text": " In addition, ectopic expression of TGFA contributes to the acquisition of growth factor independence and enhanced tumorigenicity in colon carcinoma cell models"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": ", and overexpression in the pancreas has been linked to the development of ductal neoplasms."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": " Furthermore, TGFA secreted by stromal fibroblasts is capable of promoting peritoneal metastasis of ovarian cancer through EGFR activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nTGFA signaling is also an important contributor to fibrotic and degenerative diseases. Overexpression of TGFA in lung tissue leads to progressive pulmonary fibrosis and vascular remodeling, with downstream signal transduction involving mTOR pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " In the kidney, ADAM17‐mediated shedding of TGFA correlates with the development of fibrotic lesions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": " Moreover, in joint tissues altered TGFA signaling is associated with cartilage degradation in osteoarthritis, and genetic association studies have linked TGFA variants with changes in cartilage thickness."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": " In airway epithelia, TGFA released in response to pathogens or inflammatory stimuli drives mucin overproduction, a process further amplified by secondary EGFR reactivation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": " Additionally, effects on epithelial ion transport have been observed whereby TGFA release modulates chloride secretion in intestinal cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe bioavailability and activity of TGFA are subject to tight regulatory control. Proteolytic shedding of TGFA from the plasma membrane by ADAM17 is modulated by Src‐kinase activity and mitochondrial reactive oxygen species"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": ", while its proper basolateral delivery in polarized cells is mediated by cargo recognition proteins such as Naked2."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": " New layers of regulatory control are emerging, including modulation of TGFA expression by non‐coding RNAs—for instance, a circRNA that sponges miR‑140‑3p in the setting of diabetic retinopathy has been shown to regulate TGFA levels."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nFinally, TGFA functions can be context dependent. 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