{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPTPN2 (also known as TC‐PTP) has emerged as an important susceptibility factor in a range of immune‐mediated disorders. Large‐scale genetic studies have identified variants at the PTPN2 locus in patients with Crohn’s disease, ulcerative colitis, Addison’s disease, rheumatoid arthritis, juvenile idiopathic arthritis, and type 1 diabetes, underscoring its critical role in immune homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, PTPN2 functions as a critical negative regulator of cytokine signalling. Its nuclear isoform (TC45) dephosphorylates key signal transducers such as STAT1 and STAT3, thereby attenuating interferon‐, interleukin‑6–, and interleukin‑2–mediated responses. Such dephosphorylation events help define the amplitude and duration of these pathways and thereby prevent aberrant inflammatory signalling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to modulating immune signals, PTPN2 regulates receptor tyrosine kinase pathways. It dephosphorylates substrates such as the insulin receptor, the Met receptor, and VEGFR2, which contributes to the downregulation of insulin‐induced signalling, control of cellular growth factor responses, and moderation of oncogenic events. These actions not only impact metabolic homeostasis but also establish a tumor suppressor role for PTPN2 in malignancies like T-cell acute lymphoblastic leukemia, breast cancer, and lung adenocarcinoma."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "23"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond cytokine and receptor signalling, PTPN2 regulates diverse cellular processes that are critical for tissue integrity and homeostasis. In pancreatic β-cells, it modulates apoptosis in response to proinflammatory cytokines, while in intestinal epithelial cells it participates in the control of autophagy and maintenance of barrier function. PTPN2 also directly influences innate antiviral responses by dephosphorylating the adaptor MITA/STING, triggers changes in endothelial tight junction stability, and its expression is modulated by microRNAs to control proliferation and migration. These multifaceted roles highlight the therapeutic potential of targeting PTPN2 in inflammatory diseases, autoimmunity, metabolic disorders, and cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "24", "end_ref": "37"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Miles Parkes, Jeffrey C Barrett, Natalie J Prescott, et al. 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