{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSPRY4 is an evolutionarily conserved intracellular inhibitor of receptor tyrosine kinase–mediated signal transduction that plays a pivotal role in fine‐tuning the mitogen‐activated protein kinase (MAPK/ERK) cascade. Detailed characterization of the human SPRY4 gene reveals a complex promoter with regulatory elements responsive to diverse stimuli such as mitogens, WNT signals, and hypoxic conditions. In response to specific growth factors (for example, vascular endothelial growth factor), SPRY4 preferentially interferes with Ras‐independent activation of Raf1 via its carboxy‐terminal cysteine‐rich domain, ensuring a context‐dependent attenuation of downstream signaling. These features underscore its function as a key negative feedback regulator in multiple cellular settings."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the realm of oncogenesis, genetic association studies have implicated SPRY4 variants in modifying susceptibility to testicular and pediatric germ cell tumors. Altered expression of SPRY4 has been observed in a variety of malignancies—including melanoma, non–small cell lung, ovarian, breast, colorectal, brain, and thyroid cancers—with loss or down‐regulation often correlating with enhanced MAPK/ERK signaling that promotes cell proliferation, migration, and invasion. Conversely, ectopic expression or enforced restoration of SPRY4 can suppress these oncogenic traits, although in some settings specific mutations confer a gain‐of‐function that potentiates proliferation. Collectively, these studies highlight a critical, though context‐dependent, tumor suppressor activity of SPRY4."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "17"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nApart from its protein‐coding capacity, the SPRY4 locus also gives rise to a long noncoding RNA (lncRNA), SPRY4–IT1, which appears to have distinct and sometimes opposing roles in cancer. Elevated levels of SPRY4–IT1 in melanoma and esophageal squamous cell carcinoma have been associated with enhanced cell proliferation, invasion, and migration, whereas its knockdown not only impairs these oncogenic properties but also induces apoptosis—partly through mechanisms involving altered lipid metabolism and epigenetic modulation of target gene promoters. These findings underscore the complexity of SPRY4’s genomic locus, where coding and noncoding transcripts differentially influence tumor behavior."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}, {"type": "fg_f", "ref": "11"}, {"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its roles in cancer, SPRY4 is a versatile regulator in several normal biological processes. It modulates angiogenesis by controlling endothelial cell migration and adhesion—actions mediated in part by regulating c‐Src activity and integrin αVβ3 levels. SPRY4 also participates in the differentiation of mesenchymal stem cells toward osteoblasts and influences immune cell function, as evidenced by its impact on Th17 cell differentiation through cytokine receptor modulation. Moreover, alterations in SPRY4 function, whether by mutation or dysregulated expression, contribute to developmental disorders such as trophoblast dysfunction in recurrent miscarriage and congenital hypogonadotropic hypogonadism, emphasizing its broader importance in cellular homeostasis and developmental signaling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "20", "end_ref": "25"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Onno C Leeksma, Tanja A E Van Achterberg, Yoshikazu Tsumura, et al. 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