{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSCUBE2 is a secreted, membrane‐associated glycoprotein characterized by an N‐terminal signal peptide, several epidermal growth factor–like repeats, a spacer region, and a CUB domain that regulates proteolytic activities. Originally identified in vascular endothelial cells, SCUBE2 is highly expressed in vascularized tissues and is believed to contribute to development, inflammation, angiogenesis, and thrombosis. In the endothelium, it appears to function in part as a coreceptor for VEGF signaling and is modulated in settings of inflammatory stimulation and vascular dysfunction, as observed in conditions such as rheumatoid arthritis and type 2 diabetes with dyslipidemia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to its vascular functions, SCUBE2 plays a pivotal role in modulating Hedgehog (HH) signaling. Biochemical and cell‐based studies have demonstrated that human SCUBE2 can interact directly with Sonic Hedgehog (SHH) and the SHH receptor Patched‐1 within cholesterol‐rich membrane microdomains, thereby enhancing downstream HH signaling. Moreover, SCUBE2 cooperates with cell‐surface sheddases and heparan sulfate proteoglycans to facilitate the proteolytic processing and release of dually lipidated SHH, a process that is crucial for proper morphogen dissemination during development and has been implicated in bone metastasis in luminal breast cancer."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nEmerging evidence also supports a tumor‐suppressor role for SCUBE2 in various malignancies including breast, colorectal, endometrial, glioma, and non–small cell lung cancer. In cancer cells, the COOH‐terminal CUB domain of SCUBE2 has been shown to directly antagonize bone morphogenetic protein activity, while the NH₂‐terminal EGF‐like repeats promote cell–cell adhesion through interactions with E‐cadherin and suppression of β‐catenin signaling. Loss or epigenetic silencing of SCUBE2 is correlated with enhanced epithelial–mesenchymal transition, increased invasiveness, and tumor progression, whereas restoration of its expression inhibits cell proliferation, migration, and invasion. These multifaceted functions underscore the potential utility of SCUBE2 as both a prognostic biomarker and a therapeutic target in cancer treatment."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ruey-Bing Yang, Chi Kin Domingos Ng, Scott M Wasserman, et al. 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