{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nVaccinia‐related kinase 2 (VRK2) is a serine/threonine kinase that exists in functionally distinct isoforms—with VRK2A tethered to the endoplasmic reticulum and mitochondrial membranes and VRK2B distributed in the cytosol and nucleus—which modulate key cellular signaling events. VRK2 phosphorylates targets such as p53 (at Thr18) and interacts with several partners to fine‐tune stress‐activated cascades; for example, it associates with Ran to regulate related kinase activities, forms stable complexes with scaffolding proteins (e.g. KSR1 and MEK1) to modulate MAPK/ERK signaling, and phosphorylates transcriptional regulators such as NFAT1 that subsequently affect proinflammatory genes. In addition, VRK2 influences protein homeostasis through the regulation of chaperonin complexes (e.g. TRiC) via ubiquitin–proteasome pathways and directly interacts with anti‐apoptotic factors like Bcl‑xL. These molecular interactions and modifications underscore VRK2’s role as an integrator of mitogenic, stress, and apoptotic signals."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "11"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nA wealth of genetic and expression studies have linked VRK2 to neuropsychiatric and neurodevelopmental disorders. Genome‑wide association studies and targeted SNP analyses in diverse populations have implicated variants in VRK2 with schizophrenia, epilepsy, and major depression, with some risk alleles also correlating with alterations in brain structure and sleep/circadian parameters. Moreover, altered VRK2 expression has been observed in peripheral blood and brain tissues from patients with these disorders, suggesting that VRK2-mediated modulation of intracellular signaling may contribute to abnormal neuronal development, synaptic function, and overall neural network connectivity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of oncogenesis and therapeutic response, VRK2 exerts multifaceted effects that influence cell proliferation, apoptosis, and drug sensitivity. Through its ability to interact with viral proteins (such as EBV BHRF1) and to alter key signaling pathways—including modulation of MAPK/ERK, NF‑κB, and lysosome‐associated Akt signaling—VRK2 can contribute to tumor cell survival and chemoresistance in cancers such as rectal, breast, hepatocellular, and pancreatic carcinomas. Furthermore, VRK2 levels have been linked to synthetic lethal interactions in neural tumors, and emerging structural data have paved the way for the development of selective small‑molecule inhibitors aimed at targeting VRK2’s kinase activity to perturb its pro‑survival signaling in cancer cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "26", "end_ref": "33"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Sandra Blanco, Lucia Klimcakova, Francisco M Vega, et al. 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