{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nNEK2 is a serine/threonine kinase that plays a central role in mitosis by regulating centrosome cohesion and separation as well as ensuring accurate chromosome segregation. It phosphorylates key centrosomal proteins including C‐Nap1 to trigger centrosome disjunction"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": ", and modifies kinetochore components such as Hec1"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "2", "end_ref": "4"}]}, {"type": "t", "text": "as well as Sgo1"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "5"}]}, {"type": "t", "text": "to promote the establishment of proper microtubule–kinetochore attachments. In addition, phosphorylation of other substrates like centrobin"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "and beta‐catenin"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "7"}]}, {"type": "t", "text": "further underlines its role in coordinating mitotic events."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}, {"type": "fg_f", "ref": "1"}, {"type": "fg_f", "ref": "9"}, {"type": "fg_f", "ref": "3"}, {"type": "fg_fs", "start_ref": "5", "end_ref": "7"}, {"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNEK2 activity and localization are tightly regulated during the cell cycle. Its dynamic centrosomal recruitment involves interaction with microtubule‐associated proteins"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": "and is modulated by alternative splicing."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " Moreover, its function is controlled by upstream signaling events: for example, Plk1 phosphorylation"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": ", Hippo pathway components"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": ", and protein phosphatase complexes"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}, {"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "modulate its activity in response to cell cycle cues and DNA damage."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "15"}]}, {"type": "t", "text": "."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "10", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn cancer, NEK2 is frequently overexpressed and has been implicated in promoting chromosomal instability, tumor progression, metastasis, and therapeutic resistance. Elevated NEK2 levels have been observed in breast"}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "18"}]}, {"type": "t", "text": ", colorectal"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": ", ovarian"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": ", and lung cancers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": " It also plays roles in pancreatic"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": ", hepatocellular"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": ", gastric"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": ", and prostate cancers"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "28"}]}, {"type": "t", "text": ", contributing to aberrant centrosome duplication, EMT, and drug resistance."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": " These studies position NEK2 not only as a critical mediator of mitotic fidelity but also as a promising prognostic biomarker and therapeutic target in various malignancies."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "16"}, {"type": "fg_f", "ref": "31"}, {"type": "fg_f", "ref": "19"}, {"type": "fg_f", "ref": "21"}, {"type": "fg_f", "ref": "18"}, {"type": "fg_f", "ref": "22"}, {"type": "fg_f", "ref": "24"}, {"type": "fg_f", "ref": "20"}, {"type": "fg_f", "ref": "29"}, {"type": "fg_f", "ref": "28"}, {"type": "fg_f", "ref": "23"}, {"type": "fg_f", "ref": "26"}, {"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical mitotic functions, NEK2 also contributes to non‐mitotic processes. It phosphorylates substrates such as Kif24 to promote cilia disassembly"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "32"}]}, {"type": "t", "text": "and targets Dishevelled to link centrosome dynamics with Wnt signaling."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "33"}]}, {"type": "t", "text": " Additionally, NEK2-mediated modifications of beta-catenin"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "34"}]}, {"type": "t", "text": "underscore its emerging role in modulating signal transduction pathways that determine cell fate. Transcriptional regulators such as E2Fs"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "35"}]}, {"type": "t", "text": "and post-translational stabilization via deubiquitinases further diversify NEK2’s regulatory network."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "32", "end_ref": "35"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nNEK2 also interfaces with cell checkpoint and immune regulatory mechanisms. Its interaction with MAD1"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "contributes to spindle assembly checkpoint signaling, while recent evidence shows that NEK2-mediated phosphorylation of PD-L1 stabilizes this immune checkpoint protein, potentially affecting the response to immunotherapy."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": " Although its role in cervical cancer radioresistance remains to be fully elucidated"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "36"}]}, {"type": "t", "text": ", the broad spectrum of NEK2 activities underscores its importance as an integrator of mitotic fidelity, signaling, and tumor cell survival."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}, {"type": "fg_f", "ref": "36"}, {"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Alison J Faragher, Andrew M Fry "}, {"type": "b", "children": [{"type": "t", "text": "Nek2A kinase stimulates centrosome disjunction and is required for formation of bipolar mitotic spindles."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2003)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.e03-02-0108"}], "href": "https://doi.org/10.1091/mbc.e03-02-0108"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "12857871"}], "href": "https://pubmed.ncbi.nlm.nih.gov/12857871"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Yumay Chen, Daniel J Riley, Lei Zheng, et al. 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