{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSTK39 encodes a serine/threonine protein kinase—commonly known as SPAK—that functions as a central node linking upstream WNK kinase activation to the phosphorylation and regulation of key cation‐coupled cotransporters. Early studies demonstrated that WNK1 phosphorylates SPAK (and its close relative OSR1), which in turn directly phosphorylate ion transporters such as the Na⁺–Cl⁻ cotransporter (NCC), Na⁺–K⁺–2Cl⁻ cotransporter (NKCC1 and NKCC2), and even modulate K⁺–Cl⁻ cotransporters; these phosphorylation events are critical for cellular ion balance and renal Na⁺ re‐absorption that ultimately influence blood pressure and systemic fluid homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "18"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic association studies have further implicated STK39 in blood pressure regulation and hypertension. Variants in STK39 have been linked to alterations in its transcriptional expression—resulting in augmented kinase activity—and are associated with increased phosphorylation of ion transporters that enhance renal salt re‐absorption. Such allelic variants have been observed in diverse populations, with meta‐analyses and case–control studies supporting a contributory role of STK39 in the development of hypertension and, in some studies, in neurodegenerative conditions like Parkinson’s disease."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "19", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical role in modulating ion homeostasis, STK39 also appears to be involved in diverse cell signaling pathways relevant to neurodevelopmental and neoplastic disorders. For example, STK39 has been identified as a candidate risk gene in autism and Parkinson’s disease, and its overexpression in various cancers—including non‐small cell lung cancer, cervical cancer, breast cancer, and hepatocellular carcinoma—has been linked to increased cell proliferation, epithelial–mesenchymal transition, invasiveness, and metastasis. 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