{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nPLK2 is emerging as a critical regulator of cell‐cycle progression and centrosome dynamics. Several studies have demonstrated that PLK2 operates during early G1/S transition to ensure proper centrosome reproduction and genomic stability. In tumor cells, PLK2 functions at a mitotic checkpoint to prevent mitotic catastrophe following spindle damage, and its kinase activity is tightly controlled via interactions and phosphorylation events with key substrates such as F‐box proteins, CPAP and NPM/B23 that mediate centriole duplication and S‐phase checkpoint integrity. Moreover, loss or dysregulation of PLK2 sensitizes cells to replication stress and abnormal mitotic progression."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "9"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the cancer context, PLK2 displays a dualistic role. In tumors harboring wild‐type p53, PLK2 appears to exert tumor suppressor activity by engaging with key regulators such as TSC1 to modulate mTOR signaling, whereas in settings with mutant p53 an oncogenic feedback loop can be established to promote chemoresistance. Its expression is further modulated by miRNAs (for example, miR-27b and miR-126) and epigenetic mechanisms (including promoter methylation), which impact chemosensitivity and correlate with clinical outcomes in malignancies such as colorectal, cervical, ovarian, and hematologic cancers. These studies support the notion that PLK2 is a promising theranostic marker and therapeutic target in human cancers."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "22"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the nervous system, PLK2 has garnered significant attention for its role in modulating α‐synuclein biology—a key pathological feature in Parkinson’s disease and related synucleinopathies. PLK2 directly phosphorylates α‐synuclein at serine 129, a modification that influences aggregation, fibril formation, and, in some contexts, the clearance of toxic species via autophagy. These findings implicate PLK2 as a pivotal node in neurodegenerative disease mechanisms and a potential target for therapeutic intervention."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "29"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond cell cycle and neuronal functions, PLK2 regulates diverse cellular pathways. It contributes to the modulation of inflammatory processes through phosphorylation of ADAM17, thereby influencing ectodomain shedding of cytokine precursors. In addition, PLK2 facilitates an antioxidant response via activation of the GSK3–NRF2 pathway that protects against p53‐dependent necrosis, and it phosphorylates transcription factor TAp73, thereby modulating its tumor suppressor activity. The kinase is further regulated by post‐translational modifications—its stability and transcriptional output are fine‐tuned via acetylation (controlled by SIRT1 and GATA-1) and are responsive to ER stress, while PLK2 also modulates angiogenic sprouting by influencing Rap1 activity in endothelial cells."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "30", "end_ref": "37"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nImportantly, selective inhibition studies indicate that targeting PLK2 is pharmacologically tractable. Inhibition of PLK2 with specific small molecules did not result in genotoxicity at doses that effectively modulate its activity, underscoring the therapeutic potential of modulating PLK2 function in diseases ranging from cancer to neurodegeneration."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Timothy F Burns, Peiwen Fei, Kimberly A Scata, et al. 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