{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSULF2 is an extracellular endosulfatase that is synthesized as a prepro‐enzyme, undergoes proteolytic processing in the secretory pathway, and is subsequently released into the extracellular milieu. It catalyzes the removal of 6‑O‑sulfate groups from glucosamine residues within heparan sulfate (HS) chains, thereby editing the sulfation pattern of HS proteoglycans. Such precise desulfation determines the binding affinity of HS for a variety of growth factors and morphogens, and detailed biochemical analyses have revealed that SULF2 functions at a near‐neutral pH with a substrate–restricted, processive mechanism that is essential to modulate HS–ligand interactions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer, aberrant regulation of SULF2 contributes to tumor progression by reshaping the extracellular HS landscape and consequently modulating several growth factor–dependent signaling pathways. Up‑regulation of SULF2 has been reported in a variety of malignancies—including breast, lung, hepatocellular, and glioblastoma—where its enzymatic activity diminishes HS 6‑O‑sulfation and thereby enhances the bioavailability and signaling of ligands such as fibroblast growth factors, Wnts, and vascular endothelial growth factor. This deregulated signaling stimulates oncogenic cascades (including Akt, MAPK, and Wnt/β‑catenin pathways), promoting cell proliferation, invasiveness, angiogenesis, altered cell adhesion, and resistance to chemotherapeutic agents. Conversely, experimental inhibition or knockdown of SULF2 reverses such transformed phenotypes, underscoring its potential as a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "29"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its prominent role in cancer, SULF2 also participates in diverse physiological and pathological processes by finely tuning extracellular matrix signaling. Altered SULF2 expression has been linked to changes in cartilage glycosaminoglycan sulfation, which can affect tissue remodeling, while in the nervous system its activity modulates axon guidance through the regulation of repellent cues. Additionally, SULF2 influences inflammatory responses—for example, by modulating cytokine signaling in rheumatoid arthritis—and can impact the cellular response to stressors such as ionizing radiation, thereby affecting tumor cell invasion and metastasis. Recent studies also implicate SULF2 in mediating epithelial–mesenchymal transition via microRNA pathways, as well as in determining the aggressiveness of neoplasms such as neuroblastoma, cholangiocarcinoma, and glioblastoma. Collectively, these observations emphasize the multifaceted impact of SULF2 on key signaling events in both normal tissue homeostasis and disease, highlighting its emerging potential as a biomarker and a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "30", "end_ref": "44"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Megumi Morimoto-Tomita, Kenji Uchimura, Zena Werb, et al. 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