{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRecent genetic studies have implicated NOTCH2 in diverse human disorders. Genome‐wide association studies have uncovered common variants in the NOTCH2 locus that modestly influence type 2 diabetes risk and progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": " In parallel, analyses of patients with congenital disorders have revealed that heterozygous truncating mutations in NOTCH2 are a cause of syndromic conditions. For example, in Alagille syndrome—especially in cases lacking JAG1 mutations—alterations in NOTCH2 contribute to multisystem phenotypes with notable renal involvement"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": ", while exome‐sequencing in Hajdu–Cheney syndrome has identified clustered C‐terminal truncations that lead to enhanced NOTCH2 signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBiochemical and structural studies have provided insight into the molecular regulation of NOTCH2. The crystal structure of its negative regulatory region (NRR) shows an autoinhibited conformation that buries the metalloprotease cleavage site, indicating that substantial conformational changes are required for its activation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " In addition, post‐translational modifications such as hydroxylation—mediated by factor inhibiting HIF—affect conserved ankyrin repeats in NOTCH receptors, thereby modulating interactions with downstream effectors."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the arena of oncogenesis, NOTCH2 signaling exerts context‐dependent effects. In pancreatic cancer cells, up‐regulation of NOTCH2 and its ligand Jagged‑1 is linked to the acquisition of an epithelial–mesenchymal transition phenotype and chemoresistance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": " Genome‐wide association studies in breast cancer have identified susceptibility signals near the NOTCH2 locus, and functional investigations have shown that while NOTCH1 appears to promote tumor aggressiveness, high levels of NOTCH2 correlate with improved differentiation and patient survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": " In cutaneous squamous cell carcinoma, frequent loss‐of‐function mutations in NOTCH2 support a tumor‑suppressor role"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}]}, {"type": "t", "text": ", whereas in splenic marginal zone lymphoma recurrent mutations that truncate the C‑terminal PEST domain result in prolonged NOTCH2 signaling and contribute to lymphomagenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": " In glioblastoma, NOTCH2 drives the transcription of tenascin‑C—a pro‑invasive extracellular matrix protein—with mutant forms failing to activate this target, thereby potentially modulating tumor invasiveness."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": " Similarly, in osteosarcoma, competing endogenous RNA networks modulate NOTCH2 expression to affect cell proliferation and invasion"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": ", and in liver cancer stem cells, activated NOTCH2 signaling sustains self‑renewal and correlates with tumor severity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": " In breast cancer models, enforced activation of NOTCH2 promotes apoptosis and suppresses tumor growth."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": " Investigations in bladder cancer have revealed seemingly contradictory roles—with some studies documenting loss‐of‐function mutations supporting a tumor‑suppressive role"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": "and others proposing an oncogenic function amenable to targeted inhibition."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": " In colon cancer cells, niclosamide treatment that down‐regulates NOTCH2 associates with reduced cell proliferation and migration"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": ", and in B‐cell chronic lymphocytic leukemia, proteasome inhibition leads to early loss of NOTCH2 activity, contributing to apoptosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": " Moreover, NOTCH2 signaling in CD8⁺ cytotoxic T cells is essential for mounting robust antitumor responses"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": ", and dysregulated expression of NOTCH receptors, including NOTCH2, has been observed in hepatocellular carcinoma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond developmental and neoplastic contexts, NOTCH2 plays significant roles in vascular and inflammatory regulation. In vascular smooth muscle cells, NOTCH2 contributes to differentiation by inducing smooth muscle α‑actin expression and constraining growth factor–mediated proliferation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "30"}]}, {"type": "t", "text": " In arterial endothelial cells, exposure to pro‑inflammatory cytokines such as TNF‑α up‑regulates NOTCH2 via NF‑κB and MAP kinase pathways, an effect that is associated with increased apoptosis and may underlie vascular dysfunction."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "32"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Eleftheria Zeggini, Laura J Scott, Richa Saxena, et al. 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