{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n ADAM17, also known as TNF‑α converting enzyme (TACE), is a membrane‐bound metalloprotease whose proteolytic activity is central to a wide range of physiological and pathological processes. It mediates the ectodomain shedding of several substrates, including key epidermal growth factor receptor (EGFR) ligands—such as epiregulin, transforming growth factor‑α, amphiregulin, and heparin‑binding EGF‑like growth factor—which in turn regulates EGFR activation, downstream mitogenic signaling, and ultimately tumor cell proliferation and progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " ADAM17 also cleaves cell‑surface receptors and cytokine precursors; for example, it is responsible for the regulated shedding of angiotensin‑converting enzyme‑2 (ACE2) from the cell membrane, a process that can modulate viral entry mechanisms and inflammatory responses"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ", and it processes the membrane‐anchored precursor of TNF‑α, thereby releasing soluble TNF‑α and influencing both local and systemic inflammation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " In the context of cancer, ADAM17 activity has been linked to tumor progression and metastasis; for instance, suppression of ADAM17 by the tumor‐suppressor microRNA‑122 correlates with reduced cell migration, invasion, angiogenesis, and intrahepatic metastasis in hepatocellular carcinoma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " Moreover, ADAM17 contributes to tumor immune escape by facilitating the proteolytic release of immunomodulatory ligands—such as MICA—from the surface of malignant cells, thereby impairing cytotoxic lymphocyte recognition."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": " ADAM17’s role extends to the regulation of inflammatory signaling cascades via the shedding of receptors like the interleukin‑6 receptor, which modulates IL‑6 trans‑signaling and subsequent immune responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Given its broad substrate repertoire and central regulatory functions, ADAM17 is implicated in numerous diseases—including cancer, neurodegeneration, cardiovascular, and inflammatory disorders—and is considered a promising therapeutic target."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": " Moreover, proteins such as iRhom2 regulate ADAM17 maturation and trafficking, adding another layer of control over its enzymatic activity in innate immune responses."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Finally, loss‑of‑function mutations in ADAM17 have been linked to human syndromes featuring neonatal inflammatory skin and bowel lesions, underscoring its essential role in maintaining immune homeostasis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Umut Sahin, Gisela Weskamp, Kristine Kelly, et al. 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