{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nRSPO2 is a secreted protein that modulates Wnt signaling by acting as an agonist of the canonical Wnt/β‐catenin pathway and, in some contexts, by influencing noncanonical Wnt responses. RSPO2 binds to receptors such as LGR4–6 and can also engage alternative co‐receptors like heparan sulfate proteoglycans to fine‐tune Wnt responsiveness. Moreover, RSPO2 gene rearrangements (fusions) have been identified in colorectal cancers, highlighting its role as a driver when aberrantly expressed, while mutations in RSPO2 have been linked to severe developmental disorders like tetra‐amelia syndrome."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn cancer settings RSPO2 exerts multifaceted functions. Its fusion transcripts have been detected in subsets of colorectal tumors and digestive system cancers where they are implicated in potentiating oncogenic Wnt signaling, promoting cell proliferation and invasion. In pancreatic cancer, increased RSPO2 expression marks subpopulations with cancer stem cell properties and high metastatic potential, while in nasopharyngeal, gastric, hepatocellular, and squamous cell carcinomas, RSPO2 has been shown to modulate epithelial–mesenchymal transition, tumor cell migration, and stemness. In some contexts, RSPO2 signaling via LGR receptors (or through alternative partners) also influences premetastatic niche formation such as in bone metastasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its oncogenic and tumor‐suppressive roles, RSPO2 is crucial in normal development and tissue homeostasis. It acts as a paracrine factor in the ovary, where oocyte‐derived RSPO2 promotes granulosa cell cycle progression and follicular maturation. RSPO2 also regulates chondrocyte differentiation with implications in skeletal diseases such as ossification of the posterior longitudinal ligament, influences epithelial–mesenchymal interactions in keloids, and modulates adipogenesis and adipose tissue remodeling. In addition, RSPO2 impacts liver fibrogenesis, arterial lymphangiogenesis and cholesterol efflux, contributes to the regulation of idiopathic pulmonary fibrosis, and even participates in midbrain dopaminergic neuron formation—all underscoring its broad biological significance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "28"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRSPO2’s activity is subject to multiple layers of regulation. Post‐translational modifications, such as C‐mannosylation, can alter its extracellular secretion and its ability to activate Wnt signaling. In addition, its expression is modulated by epigenetic mechanisms and microRNAs, and specific genetic variants in RSPO2 have been associated with altered disease susceptibilities, including Dupuytren's contracture and variations in cancer outcomes. 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