{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nSalt‐inducible kinase 2 (SIK2) is a multifunctional serine/threonine kinase of the AMP‐activated protein kinase family that integrates diverse extracellular cues to regulate cancer cell metabolism and cell cycle progression. In ovarian cancer, for example, adipocyte‐rich microenvironments trigger calcium‐dependent activation and autophosphorylation of SIK2, thereby enhancing both AMPK‐dependent phosphorylation of metabolic enzymes and PI3K/AKT signaling to promote metastasis and metabolic reprogramming (e.g., increased glycolysis), while its localization at centrosomes facilitates the initiation of mitosis and modulates sensitivity to taxane chemotherapy."}, {"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": "\nSIK2 activity is tightly regulated by a series of post‐translational modifications and protein–protein interactions. Hormonal signals—such as parathyroid hormone in osteocytes—elicit SIK2 modulation that culminates in altered expression of regulators like SOST and RANKL, impacting bone formation. In adipocytes, cAMP‐elevating agents drive PKA‐dependent phosphorylation (notably at Ser358) and 14–3–3 binding, which govern SIK2’s subcellular distribution and catalytic function. In addition, SIK2 influences CREB–mediated gene expression through interactions with class IIa histone deacetylases and is itself subject to regulation by microRNAs (e.g., miR‑874 and miR‑203) as well as degradation via ubiquitin ligases such as Fbxw7. Collectively, these regulatory mechanisms enable SIK2 to control key signaling networks that affect cell differentiation, insulin and cytokine signaling, and survival in various contexts including prostate and epithelial ovarian cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "16"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond these roles in primary tumorigenesis, SIK2 functions within an extensive regulatory network that influences autophagy, endoplasmic reticulum–associated degradation, and stress responses by interacting with partners such as p97/VCP and PP2A. In several malignancies—including diffuse large B‐cell, pancreatic, colorectal, gastric, hepatocellular, triple‐negative breast, and uveal melanoma—dysregulated SIK2 signaling modulates pathways such as Wnt/β‐catenin, TORC2/AKT, and TGF‑β, thereby affecting epithelial–mesenchymal transition, cytoskeletal dynamics, chemoresistance, and cell survival. Moreover, SIK2 has emerged as an important mediator in non–cancerous pathologies, regulating glucose uptake in adipocytes, maintaining mesothelial cell viability during peritoneal dialysis, and controlling pancreatic β cell proliferation and renal tubular homeostasis in diabetic kidney disease. Through its capacity to direct metabolic reprogramming, inflammatory responses, and cytoskeletal organization—even in the context of pathogen invasion—SIK2 stands out as a promising prognostic biomarker and therapeutic target across a myriad of diseases."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "39"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Fabrizio Miranda, David Mannion, Shujuan Liu, et al. 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