{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nCalcium/calmodulin‐dependent protein kinase kinase 2 (CaMKK2) functions as an essential molecular sensor that couples intracellular Ca2+ signals to critical downstream responses. Under conditions of cellular stress—as seen during amino acid starvation—CaMKK2 is activated by Ca2+/calmodulin, thereby triggering kinase cascades that include AMPK and ULK1 to induce autophagy and restore energy homeostasis. In addition, CaMKK2 signaling contributes to neuronal plasticity by engaging transcription factors (such as CREB) that are instrumental for long‐term memory formation and proper cerebellar development."}, {"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": "\nBeyond its roles in the nervous system, CaMKK2 exerts pleiotropic effects in diverse tissues. It modulates adipocyte differentiation by governing the AMPK pathway in preadipocytes and regulates inflammatory responses in myeloid cells, thereby shaping both metabolic balance and immune function. In vascular endothelial cells, CaMKK2 phosphorylates SIRT1 to bolster antioxidative and anti‐inflammatory defenses, and in prostate cancer its signaling supports AR‐dependent cell cycle progression. Furthermore, CaMKK2 is pivotal for skeletal remodeling, influencing both osteoblast and osteoclast differentiation to determine bone mass and repair."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, emerging evidence indicates that CaMKK2 plays a central role in tissue regeneration and systemic metabolic regulation. It contributes to sex‐specific modulation of synaptic plasticity and, in models of stroke and ischemia, supports blood–brain barrier integrity while promoting hematopoietic stem cell recovery. CaMKK2 also governs skeletal muscle regeneration and influences insulin secretion and sensitivity, with its activity being finely tuned by regulatory molecules—including specific microRNAs and E3 ubiquitin ligases. Pharmacological inhibition (for example, with STO‐609) or genetic ablation of CaMKK2 has demonstrated therapeutic potential in improving metabolic disorders (such as non‐alcoholic fatty liver disease, diabetic kidney injury, and obesity), enhancing bone and fracture healing, and modulating the tumor microenvironment to restrain metastasis. In summary, by integrating Ca2+ signals with metabolic, inflammatory, and differentiation pathways, CaMKK2 emerges as a multifaceted regulator with broad implications for organismal homeostasis and disease intervention."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ghita Ghislat, Maria Patron, Rosario Rizzuto, et al. 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