Affinage

Showing NEK2 — NEK2A is a alias.

NEK2

Serine/threonine-protein kinase Nek2 · UniProt P51955

Length
445 aa
Mass
51.8 kDa
Annotated
2026-06-10
100 papers in source corpus 42 papers cited in narrative 42 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 10/10 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NEK2 is a cell cycle-regulated serine/threonine kinase that accumulates through S phase, peaks in late G2, and drives centrosome disjunction at the onset of mitosis (PMID:7522034, PMID:7759549, PMID:12857871). Its kinase activity is essential for splitting the interphase centrosome and forming a bipolar spindle, as kinase-dead NEK2A produces monopolar spindles with unseparated poles (PMID:12857871). NEK2 executes disjunction by phosphorylating components of the intercentriolar linker and associated factors—beta-catenin, Nlp, DVL, and Cep68—thereby dissolving the linker and displacing it from centrosomes (PMID:15684383, PMID:18086858, PMID:25704143, PMID:27486244). Upstream control integrates the Hippo and Plk1 pathways: Mst2 and the scaffold hSav1 bind NEK2A and license its activity, while Plk1 phosphorylates Mst2 to exclude inhibitory PP1γ from the complex; PP1α conversely suppresses NEK2 in an ATM-dependent manner following DNA damage (PMID:17283141, PMID:21076410, PMID:21723128). Beyond pole separation, NEK2A localizes to kinetochores and phosphorylates Hec1/Ndc80 at Ser165 to strengthen kinetochore–microtubule attachment and ensure faithful chromosome segregation (PMID:12386167, PMID:18297113). NEK2A is held in check by checkpoint-independent destruction in prometaphase: it binds the APC/C directly through an exposed C-terminal MR dipeptide and is ubiquitinated even while the spindle checkpoint is active, using a binding mode that accesses both UbcH10 and UbcH5 E2 enzymes (PMID:11742988, PMID:16648845, PMID:32307883). Alternative splicing generates NEK2A, NEK2B, and a predominantly nuclear NEK2C variant differing in destruction motifs and nuclear localization signals (PMID:11742531, PMID:17626005). In the nucleus, NEK2 acts as a splicing-factor kinase, colocalizing with and phosphorylating SRSF1 to modulate splicing and apoptotic sensitivity (PMID:24369428). NEK2 also governs cilia disassembly by phosphorylating Kif24 to stimulate its microtubule-depolymerizing activity and by driving distal-appendage displacement from mother centrioles at G2/M (PMID:26290419, PMID:32211891). In cancer, NEK2 stabilizes oncogenic proteins by phosphorylation-dependent inhibition of their ubiquitination, including beta-catenin, EZH2, YAP1, PD-L1, and Beclin-1 (PMID:24501426, PMID:28737508, PMID:34315872, PMID:35705994, PMID:31955515).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1994 High

    Establishing when NEK2 acts in the cell cycle was prerequisite to assigning a function; periodic accumulation peaking in late G2 placed it at mitotic onset.

    Evidence Cell synchronization and immunoblotting across the cell cycle

    PMID:7522034

    Open questions at the time
    • Does not identify substrates
    • Does not establish a mechanism of cell cycle regulation
  2. 1995 High

    Defining NEK2 as a bona fide serine/threonine kinase capable of autophosphorylation established the biochemical basis for all downstream substrate work.

    Evidence In vitro kinase assay with recombinant protein and peptide substrates

    PMID:7759549

    Open questions at the time
    • No physiological substrate identified
    • Beta-casein is a generic in vitro substrate
  3. 2003 High

    Distinguishing the centrosome-splitting NEK2A from NEK2B and showing kinase activity is required for disjunction defined the core cellular function.

    Evidence Splice-variant analysis, overexpression, and wild-type vs. kinase-dead live imaging

    PMID:11742531 PMID:12857871

    Open questions at the time
    • Did not identify the linker substrates dissolved during splitting
    • Does not explain how kinase activity is spatially restricted
  4. 2002 High

    Discovery that NEK2A is destroyed at mitotic entry via APC/C-Cdc20 through a D-box and KEN-box explained why active kinase is restricted to G2/prophase.

    Evidence Cell-free degradation assays and destruction-motif mutagenesis

    PMID:11742988

    Open questions at the time
    • Did not resolve how degradation occurs independent of the spindle checkpoint
    • Mechanism of direct APC/C engagement unresolved at this stage
  5. 2006 High

    Showing NEK2A binds APC/C directly via a C-terminal MR dipeptide independent of Cdc20 explained its checkpoint-independent prometaphase destruction.

    Evidence In vitro binding to purified APC/C, peptide competition, and mutagenesis

    PMID:16648845

    Open questions at the time
    • Did not resolve E2 enzyme requirements during active checkpoint
  6. 2020 High

    Defining a conformation-specific APC/C binding mode that recruits both UbcH10 and UbcH5 E2 enzymes explained how NEK2A is ubiquitinated even while the checkpoint is on.

    Evidence Reconstitution with purified APC/C-MCC, structural analysis, and in vitro ubiquitination

    PMID:32307883

    Open questions at the time
    • Does not address in vivo dynamics of destruction relative to centrosome separation
  7. 2002 High

    Demonstrating NEK2 phosphorylates Hec1 at Ser165 and that this is essential for viability linked NEK2 directly to chromosome segregation, later mechanistically tied to Ndc80–microtubule affinity.

    Evidence In vitro kinase assay, site mutagenesis, yeast complementation, and in vitro Ndc80–microtubule binding reconstitution

    PMID:12386167 PMID:18297113

    Open questions at the time
    • Does not establish how kinetochore-localized NEK2A is regulated relative to the centrosomal pool
  8. 2005 High

    Mapping how NEK2 reaches the centrosome—microtubule trafficking, PCM-1-dependent recruitment, and rapid local turnover—explained its spatial control at the centrosome.

    Evidence Live imaging, FRAP, PCM-1 depletion, and microtubule-binding mutagenesis

    PMID:15659651

    Open questions at the time
    • Does not define how local proteasomal turnover is targeted
    • Recruitment signal that triggers activation unclear
  9. 2007 High

    Identifying beta-catenin as a direct linker-associated substrate, and later that NEK2 phosphorylation blocks beta-TrCP-mediated degradation, unified centrosome disjunction with a substrate-stabilization mechanism.

    Evidence In vitro kinase assays, co-IP, ubiquitination assays, and centrosomal epistasis

    PMID:18086858 PMID:24501426

    Open questions at the time
    • Relationship between centrosomal beta-catenin and canonical Wnt signaling not resolved
  10. 2006 High

    Crystal structures revealed an autoinhibitory activation-loop helix and dimerization-dependent allosteric regulation, defining how NEK2 catalytic activity is switched on.

    Evidence X-ray crystallography (2.2 Å and 1.55 Å), mass spectrometry of autophosphorylation sites, and mutagenesis

    PMID:17197699 PMID:19124027

    Open questions at the time
    • Structures do not capture the active full-length dimer
    • In vivo activating phosphorylations incompletely mapped
  11. 2010 High

    Placing NEK2A downstream of Mst2/hSav1 and, in turn, Plk1—with PP1γ as the counteracting phosphatase—built the upstream regulatory circuit governing disjunction timing.

    Evidence Co-IP, in vitro kinase assays, siRNA epistasis, and Plk1 inhibition

    PMID:21076410 PMID:21723128

    Open questions at the time
    • How the Eg5 and Mst2-NEK2A pathways are coordinated remains unresolved
  12. 2016 High

    Identifying DVL as a NEK2 substrate that scaffolds linker proteins and whose phosphorylation drives linker dissolution mechanistically connected NEK2 to centrosome separation, with conservation in Drosophila PCP.

    Evidence Phospho-specific antibodies, co-IP, bidirectional genetics, and Drosophila epistasis with in vitro kinase assay

    PMID:27486244 PMID:28041906

    Open questions at the time
    • Cross-talk between centrosomal DVL phosphorylation and Wnt/PCP signaling pools not delineated
  13. 2013 High

    Showing nuclear NEK2 colocalizes with and phosphorylates SRSF1 to modulate splicing extended NEK2 function beyond the centrosome to RNA processing and apoptotic control.

    Evidence Colocalization, co-IP, in vitro kinase assay, and minigene splicing reporters

    PMID:24369428

    Open questions at the time
    • Genome-wide splicing targets not defined
    • Relationship to SRPK1 regulation incomplete
  14. 2015 High

    Demonstrating NEK2 phosphorylates Kif24 and drives distal-appendage displacement defined its role in cilia disassembly and asymmetric ciliary inheritance.

    Evidence In vitro kinase assay, ciliation rescue, NEK2 knockout, and distal-appendage marker quantification

    PMID:26290419 PMID:32211891

    Open questions at the time
    • How NEK2 ciliary and centrosomal functions are temporally partitioned is unresolved
  15. 2021 Medium

    A recurring oncogenic theme emerged in which NEK2 phosphorylates client proteins (EZH2, YAP1, PD-L1, Beclin-1) to block their ubiquitination and stabilize them, linking NEK2 to immune evasion, drug resistance, and tumor progression.

    Evidence Co-IP, ubiquitination assays, phospho-site mutagenesis, and in vivo tumor models across cancer types

    PMID:28737508 PMID:31955515 PMID:34315872 PMID:35705994

    Open questions at the time
    • Most client-stabilization findings rest on single labs
    • Whether a common phospho-degron-masking mechanism applies across substrates is not established

Open questions

Synthesis pass · forward-looking unresolved questions
  • How NEK2's many functions—centrosome disjunction, kinetochore attachment, splicing, cilia disassembly, and oncoprotein stabilization—are coordinated by a single kinase across compartments and cell cycle phases remains unresolved.
  • No unifying model linking nuclear, centrosomal, and ciliary substrate selection
  • Spatiotemporal logic of substrate choice undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 7 GO:0016740 transferase activity 5 GO:0140098 catalytic activity, acting on RNA 2
Localization
GO:0005815 microtubule organizing center 5 GO:0005634 nucleus 2 GO:0005730 nucleolus 2 GO:0005929 cilium 2 GO:0005654 nucleoplasm 1
Pathway
R-HSA-1640170 Cell Cycle 6 R-HSA-392499 Metabolism of proteins 5 R-HSA-1852241 Organelle biogenesis and maintenance 2 R-HSA-8953854 Metabolism of RNA 2
Partners
CTNNB1DVLMST2PLK1PPP1CASAV1SRSF1USP7
Complex memberships
APC/C (substrate-bound)Mst2-hSav1-NEK2ANEK2A-PP1γ-Mst2

Evidence

Reading pass · 42 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 NEK2 protein kinase is cell cycle-regulated, accumulating progressively through S phase and peaking in late G2, being almost undetectable in G1, consistent with a role at the onset of mitosis. Cell synchronization (drug arrest and elutriation) + immunoblotting Cell growth & differentiation High 7522034
1995 Recombinant NEK2 functions as a serine/threonine-specific protein kinase capable of autophosphorylation; it phosphorylates beta-casein in vitro, and its substrate specificity overlaps with but is not identical to fungal NIMA. In vitro kinase assay with recombinant protein expressed in insect cells; synthetic peptide substrates The Journal of biological chemistry High 7759549
2001 NEK2A (but not NEK2B) is destroyed at mitotic entry via APC/C-Cdc20-mediated proteasomal degradation, dependent on a C-terminal extended D-box motif and a KEN-box; the C-terminal domain of NEK2A can inhibit APC/C-mediated destruction of both cyclins A and B. Cell-free degradation assays, mutagenesis of destruction motifs, immunodepletion, proteasome inhibitor studies The EMBO journal High 11742988
2002 Human NEK2 exists as two splice variants, NEK2A and NEK2B, that form homo- and hetero-dimers, both localize to centrosomes, but only NEK2A induces centrosome splitting upon overexpression; NEK2A disappears in prometaphase whereas NEK2B persists. RT-PCR, immunoblotting, antisense oligonucleotide knockdown, transfection/overexpression, immunofluorescence The Biochemical journal High 11742531
2002 NEK2 phosphorylates Hec1 at Ser165 both in vitro and in vivo during G2/M; Hec1 S165A mutation fails to rescue lethality from Hec1 deletion in yeast, demonstrating that NEK2-mediated phosphorylation of Hec1 is essential for chromosome segregation. In vitro kinase assay, in vivo phosphorylation, site-directed mutagenesis, yeast complementation assay The Journal of biological chemistry High 12386167
2003 Active NEK2A stimulates sustained splitting of interphase centrioles; kinase-dead NEK2A causes monopolar spindle formation with unseparated spindle poles, demonstrating that NEK2A kinase activity is required for centrosome disjunction and bipolar spindle formation in human cells. Tetracycline-inducible overexpression of wild-type and kinase-dead NEK2A; live cell imaging; immunofluorescence Molecular biology of the cell High 12857871
2003 NEK2 directly phosphorylates HMGA2 in vitro and interacts with it in mouse spermatocytes; phosphorylation by NEK2 decreases HMGA2 affinity for DNA, potentially facilitating its release from chromatin during meiotic G2/M progression. In vitro kinase assay, co-immunoprecipitation from spermatocytes, chromatin fractionation Molecular biology of the cell Medium 14668482
2004 NEK2A interacts with MAD1 via a leucine zipper-containing C-terminal domain in vitro and in vivo; NEK2A localizes to kinetochores in mitosis and is required for MAD2 (but not MAD1) association with kinetochores; NEK2A knockdown causes premature chromosome segregation and impairs spindle checkpoint signaling. Co-immunoprecipitation, in vitro binding, siRNA knockdown, immunofluorescence The Journal of biological chemistry Medium 14978040
2004 NEK2A interacts with Erk2 via a conserved docking site in the NEK2A C-terminus; NEK2A is required for centrosomal localization of Erk2 (RNAi depletion of NEK2A delocalizes Erk2 from centrosomes), but inhibition of Erk2 does not affect NEK2A localization. Co-immunoprecipitation, pull-down assay, siRNA knockdown, immunofluorescence Biochemical and biophysical research communications Medium 15358203
2004 NEK2A interacts with and phosphorylates Nek11 in the C-terminal non-catalytic region, stimulating Nek11 kinase activity by dissociating its autoinhibitory intramolecular interaction; autophosphorylation of NEK2A promotes its interaction with Nek11L at nucleoli in G1/S-arrested cells. Co-immunoprecipitation, pull-down with recombinant proteins, in vitro kinase assay, nucleolar localization experiments The Journal of biological chemistry Medium 15161910
2004 NEK2A kinase phosphorylates numatrin (B23/NPM1) and is required for numatrin's centrosomal localization in mitosis; siRNA depletion of NEK2A abolishes numatrin centrosomal association. Reciprocal co-immunoprecipitation, pull-down with recombinant proteins, in vitro kinase assay, siRNA knockdown with immunofluorescence FEBS letters Medium 15388344
2005 NEK2 exists in cytoplasmic particles that traffic to the centrosome along microtubules; a motif in the Nek2 C-terminal non-catalytic domain mediates both microtubule binding and centrosome localization; PCM-1 (centriolar satellite component) is required for centrosomal recruitment of NEK2 and its substrate C-Nap1; 70% of centrosomal NEK2 turns over rapidly (t1/2 ~3 s by FRAP); localized proteasomal degradation is required for rapid centrosomal NEK2 replenishment. Live cell imaging, FRAP, immunofluorescence, PCM-1 depletion, microtubule-binding assay, mutagenesis Molecular biology of the cell High 15659651
2005 Nlp (ninein-like protein) is phosphorylated by NEK2 kinase; overexpression of active NEK2 prematurely displaces Nlp from interphase centrosomes independently of Plk1 phosphorylation sites on Nlp; active NEK2 stimulates Plk1 phosphorylation of Nlp in vitro, suggesting NEK2 primes Nlp for Plk1 phosphorylation at G2/M. In vitro kinase assay, overexpression of active/kinase-dead NEK2 and Plk1, immunofluorescence, Xenopus homolog characterization Molecular and cellular biology High 15684383
2006 NEK2A binds directly to the APC/C in a manner dependent on an exposed C-terminal methionine-arginine (MR) dipeptide, even in the absence of the adaptor Cdc20; this direct binding allows checkpoint-independent, prometaphase-specific degradation of NEK2A. In vitro binding assays to purified APC/C, peptide competition, C-terminal truncation and mutagenesis, cell-based degradation assays Nature cell biology High 16648845
2006 Crystal structure of the NEK2 kinase domain in complex with a pyrrole-indolinone inhibitor at 2.2 Å reveals an inhibitory helical motif within the activation loop that creates a steric barrier to active enzyme formation; autophosphorylation sites identified by mass spectrometry have complex positive and negative regulatory effects on kinase activity correlated with centrosomal splitting efficiency. X-ray crystallography (2.2 Å), mass spectrometry, site-directed mutagenesis, in-cell centrosome splitting assay The Journal of biological chemistry High 17197699
2007 NEK2A phosphorylates human Sgo1 at Ser14 and Ser507 in vitro; NEK2A co-distributes with HsSgo1 at kinetochores; expression of non-phosphorylatable Sgo1 causes microtubule attachment errors (syntelic and monotelic), demonstrating that NEK2A-mediated Sgo1 phosphorylation is required for faithful chromosome congression. In vitro kinase assay with 32P incorporation, co-immunoprecipitation, immunofluorescence, non-phosphorylatable mutant expression Cell research Medium 17621308
2007 PP1alpha (but not PP1gamma) specifically regulates NEK2 function; both isoforms co-immunoprecipitate with NEK2, but only PP1alpha mediates ionizing radiation-induced inhibition of NEK2 activity and centrosome splitting; this response is ATM-dependent and requires PP1 binding to the NEK2 PP1-binding motif outside the kinase domain. Co-immunoprecipitation, in vitro kinase assay, siRNA knockdown of PP1alpha, PP1-binding motif mutagenesis, ionizing radiation treatment Cancer research Medium 17283141
2007 Beta-catenin is a direct substrate of NEK2 kinase; NEK2 binds to and phosphorylates beta-catenin; beta-catenin localizes with rootletin between C-Nap1 puncta in interphase (dependent on C-Nap1 and rootletin); increased NEK2 activity disrupts rootletin-centrosome interaction and promotes binding of beta-catenin to rootletin-independent centrosomal sites required for centrosome separation. Co-immunoprecipitation, in vitro kinase assay, immunofluorescence, siRNA knockdown, overexpression Genes & development High 18086858
2007 Alternative splicing controls subcellular localization of NEK2: NEK2C is predominantly nuclear due to a strong bipartite nuclear localization sequence (NLS) spanning the splice junction; NEK2A has a weak NLS and distributes between nucleus and cytoplasm; NEK2B has no NLS and is cytoplasmic. All three share kinase activity, dimerization, PP1 interaction, and centrosome localization. Subcellular fractionation, immunofluorescence, NLS mutagenesis, kinase assays The Journal of biological chemistry High 17626005
2008 NEK2A-mediated phosphorylation of Hec1 at Ser165 is required for faithful kinetochore–microtubule attachments; non-phosphorylatable Hec1(S165A) increases microtubule attachment errors; NEK2A phosphorylation of Hec1 increases the affinity of the Ndc80 complex for microtubules in vitro. Phospho-specific antibody, in vitro Ndc80 microtubule-binding reconstitution, expression of non-phosphorylatable mutant, immunofluorescence Oncogene High 18297113
2008 Crystal structures of wild-type Nek2 kinase domain bound to ADP (1.55 Å) and T175A mutant reveal multiple conformations of the nucleotide-binding site and autoinhibitory mechanisms; mutagenesis tests proposed autoinhibition mechanisms and suggests dimerization-dependent allosteric regulation combined with autophosphorylation and PP1c activity. X-ray crystallography (1.55 Å), site-directed mutagenesis, comparison with Aurora-A and Cdk2 structures Journal of molecular biology High 19124027
2009 Nek2 physically associates with Mad2 and Cdc20; Cdc20 localizes to centrosomes and spindle poles; both Mad2 and Cdc20 can be phosphorylated by Nek2 in vitro; overexpression of Nek2 enhances Mad2-induced mitotic delay. Co-immunoprecipitation, in vitro kinase assay, immunofluorescence, overexpression studies Experimental and molecular pathology Low 20034488
2010 Hippo pathway components Mst2 kinase and scaffold protein hSav1 directly interact with NEK2A and regulate its centrosomal localization and ability to phosphorylate C-Nap1 and rootletin; hSav1-Mst2-NEK2A and Eg5 constitute distinct but complementary pathways for centrosome disjunction. Co-immunoprecipitation, siRNA knockdown, immunofluorescence, in vitro kinase assay, epistasis analysis Nature cell biology High 21076410
2010 Kendrin (pericentrin) associates with NEK2A at centrosomes and inhibits NEK2A kinase activity in vitro in a dose-dependent manner through the Nek2A-binding region of kendrin; ectopic expression of this region reduces centrosome splitting at G2, indicating kendrin suppresses premature centrosome splitting by anchoring and inhibiting NEK2A. Co-immunoprecipitation, in vitro kinase inhibition assay with purified kendrin fragments, overexpression with centrosome splitting quantification Biochemical and biophysical research communications Medium 20599736
2011 Plk1 functions upstream of the Mst2-NEK2A module; Plk1 phosphorylates Mst2, which prevents PP1γ binding to the Mst2-NEK2A complex, thereby allowing NEK2A kinase activity to promote centrosome disjunction. Without Plk1-mediated Mst2 phosphorylation, PP1γ assembles into Nek2A-PP1γ-Mst2 complexes and counteracts NEK2A activity. Co-immunoprecipitation, in vitro kinase assay, Plk1 inhibition, siRNA knockdown, centrosome separation assays Current biology High 21723128
2013 NEK2 localizes to the nucleus of cancer cells, co-localizes in splicing speckles with SRSF1 and SRSF2, interacts with multiple splicing factors, and directly phosphorylates SRSF1; NEK2 overexpression affects SRSF1 splicing activity independently of SRPK1; NEK2 knockdown triggers pro-apoptotic splice variant expression and sensitizes cells to apoptosis. Immunofluorescence colocalization, co-immunoprecipitation, in vitro kinase assay, siRNA knockdown, minigene splicing reporter assays, RT-PCR for endogenous targets Nucleic acids research High 24369428
2014 NEK2 phosphorylates beta-catenin at N-terminal regulatory sites (same positions targeted by GSK3β: S33/S37/T41) as well as additional sites; NEK2 binding to beta-catenin inhibits beta-TrCP E3 ligase binding, preventing beta-catenin ubiquitination and degradation, leading to its stabilization and accumulation at mitotic centrosomes; Plk1 regulates this NEK2-mediated stabilization of beta-catenin. In vitro kinase assay, co-immunoprecipitation, ubiquitination assay, phospho-specific antibody, in vitro and cell-based assays Molecular biology of the cell High 24501426
2015 NEK2 co-localizes with Kif24 and phosphorylates it; NEK2-mediated phosphorylation stimulates Kif24 microtubule-depolymerizing activity, thereby promoting cilia disassembly and preventing cilia outgrowth in proliferating cells, independent of Aurora A and HDAC6. Co-localization, in vitro kinase assay, siRNA knockdown, ciliation quantification, rescue experiments Nature communications High 26290419
2015 Nek2 knockdown in Xenopus leads to a centriole defect at the left-right organizer; Nek2 overexpression causes premature ciliary resorption dependent on the tubulin deacetylase Hdac6; NEK2 interacts with Nup98 (a nucleoporin at the ciliary base) and this interaction regulates cilium resorption. Xenopus morpholino knockdown and overexpression, epistasis with Hippo pathway, genetic interaction with Hdac6, co-immunoprecipitation (Nek2-Nup98) Development Medium 26493400
2015 Cep68 is phosphorylated by NEK2 in vivo, which promotes Cep68 degradation at mitotic onset; the SCF complex (via beta-TrCP F-box component) also targets Cep68 for destruction at mitosis; the C-terminal 300–400 aa of Cep68 are required for interphase centrosome localization. In vivo phosphorylation assays, proteasome inhibitor treatment, SCF component co-immunoprecipitation, truncation/deletion analysis with immunofluorescence European journal of cell biology Medium 25704143
2016 DVL (Dishevelled) is a direct NEK2 substrate; NEK2 phosphorylates DVL at multiple residues, creating interfaces for binding to CDK5RAP2 and C-NAP1 at the centrosomal linker; NEK2-mediated DVL phosphorylation is coupled to dissolution of the centrosomal linker and centrosome separation; DVL depletion prevents NEK2-controlled linker dissolution; elevated DVL sequesters centrosomal NEK2 and mimics dominant-negative NEK2 phenotypes. Phospho-specific antibodies, co-immunoprecipitation, siRNA knockdown, overexpression, immunofluorescence centrosome separation assays PNAS High 27486244
2017 NEK2 interacts with hnRNPA1/2 and regulates alternative splicing of PKM pre-mRNA by binding to the intronic sequence flanking exon 9; NEK2 promotes inclusion of exon 10 over exon 9, increasing the PKM2/PKM1 ratio and promoting aerobic glycolysis in multiple myeloma cells. Tandem affinity purification-mass spectrometry (TAP-MS), co-immunoprecipitation, RNA immunoprecipitation (RIP), Western blot, RT-PCR Journal of hematology & oncology Medium 28086949
2017 NEK2 forms a protein complex with EZH2 in glioma stem cells; NEK2 kinase activity phosphorylates EZH2 and protects it from ubiquitination-dependent proteasomal degradation, stabilizing EZH2 protein levels. Co-immunoprecipitation, ubiquitination assay, kinase-dead mutant rescue, siRNA knockdown, in vivo tumor models The Journal of clinical investigation Medium 28737508
2018 NEK2 is bound to the deubiquitinase USP7; USP7 binding prevents NEK2 ubiquitination, stabilizing NEK2 protein; increased NEK2 activates the canonical NF-κB signaling pathway through the PP1α/AKT axis; NEK2 also activates heparanase in an NF-κB-dependent manner. Tandem affinity purification-mass spectrometry (TAP-MS), co-immunoprecipitation, ubiquitination assay, kinase/pathway activity assays, xenograft models The Journal of clinical investigation Medium 29863498
2020 NEK2 kinase activity at the G2/M transition is required for displacement of distal appendages (DAs) from mother centrioles before mitosis; overexpression of active (but not kinase-dead) NEK2A prematurely displaces DAs; NEK2 knockout causes incomplete DA dissociation and retention of cilia remnants in mitosis, leading to asymmetric inheritance of ciliary signaling components. NEK2 knockout, overexpression of active and kinase-dead NEK2A, immunofluorescence, live imaging, quantification of DA markers at mitotic centrosomes The Journal of cell biology High 32211891
2020 NEK2 interacts with USP7 and Beclin-1; NEK2 interaction with USP7 decreases Beclin-1 ubiquitination, stabilizing Beclin-1 protein without affecting its phosphorylation; this NEK2/USP7/Beclin-1 complex activates autophagy in multiple myeloma cells, contributing to bortezomib resistance. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown of Beclin-1 and NEK2, in vitro and in vivo drug resistance assays Molecular oncology Medium 31955515
2020 A unique binding mode allows NEK2A to be ubiquitinated by the APC/C-MCC complex in prometaphase: NEK2A binds the APC/C in a conformation-specific manner that allows it to access both UbcH10 and UbcH5 E2 enzymes, enabling efficient ubiquitination even while the spindle checkpoint is active. Biochemical reconstitution with purified APC/C and MCC, cryo-EM/structural analysis, in vitro ubiquitination assay, cell-based assays EMBO reports High 32307883
2021 NEK2 phosphorylates PD-L1 at T194 and T210 residues within the glycosylation-rich region of PD-L1 via a NEK binding motif (F/LXXS/T); this phosphorylation prevents ubiquitin-proteasome pathway-mediated degradation of PD-L1 in the ER lumen, stabilizing PD-L1 and promoting immune evasion in pancreatic cancer. Co-immunoprecipitation, in vitro kinase assay with phospho-site mapping, ubiquitination assay, siRNA knockdown, in vivo tumor-immune models Nature communications High 34315872
2022 NEK2 directly phosphorylates NIK (NF-κB-inducing kinase), increasing NIK activity and stability, thereby activating the non-canonical NF-κB signaling pathway; this promotes glioblastoma progression. High-throughput RNA sequencing, co-immunoprecipitation, in vitro phosphorylation assay, siRNA knockdown, xenograft tumor models Cell death & disease Medium 35031599
2022 NEK2 interacts with YAP1 and phosphorylates it at Thr-143, preventing YAP1 ubiquitination and proteasomal degradation; this stabilization of YAP1 by NEK2 promotes ESCC cell migration and invasion. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (T143 phosphorylation site), cycloheximide chase, in vivo xenograft Cell communication and signaling Medium 35705994
2002 p90Rsk2, activated by the MAPK/Erk1 pathway, directly phosphorylates the NEK2 kinase domain in vitro and stimulates NEK2 kinase activity in spermatocyte extracts; inhibition of the MAPK pathway (MEK inhibitor U0126) suppresses NEK2 activation during meiotic G2/M progression, placing NEK2 downstream of Erk1/p90Rsk2 in chromosome condensation. In vitro kinase assay, spermatocyte cell extracts, MEK inhibitor treatment, okadaic acid-induced G2/M progression Development Medium 11923207
2016 In Drosophila, APC/C(Fzr/Cdh1) negatively regulates Nek2 kinase as a direct substrate; Nek2 phosphorylates Dishevelled (Dsh); this APC/C→Nek2→Dsh pathway controls Dsh levels and localization required for planar cell polarity (PCP) establishment. Drosophila genetics, epistasis analysis, in vitro kinase assay (Nek2 phosphorylating Dsh), loss-of-function and gain-of-function in PCP assays Developmental cell Medium 28041906

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2003 Nek2A kinase stimulates centrosome disjunction and is required for formation of bipolar mitotic spindles. Molecular biology of the cell 213 12857871
2007 beta-Catenin is a Nek2 substrate involved in centrosome separation. Genes & development 198 18086858
2001 APC/C-mediated destruction of the centrosomal kinase Nek2A occurs in early mitosis and depends upon a cyclin A-type D-box. The EMBO journal 185 11742988
2002 The Nek2 protein kinase: a novel regulator of centrosome structure. Oncogene 181 12214248
2010 Components of the Hippo pathway cooperate with Nek2 kinase to regulate centrosome disjunction. Nature cell biology 153 21076410
2005 Nek2 kinase in chromosome instability and cancer. Cancer letters 145 16084011
1995 Substrate specificity and cell cycle regulation of the Nek2 protein kinase, a potential human homolog of the mitotic regulator NIMA of Aspergillus nidulans. The Journal of biological chemistry 141 7759549
2015 Nek2 activation of Kif24 ensures cilium disassembly during the cell cycle. Nature communications 137 26290419
2006 Early mitotic degradation of Nek2A depends on Cdc20-independent interaction with the APC/C. Nature cell biology 135 16648845
2017 NEK2 Promotes Aerobic Glycolysis in Multiple Myeloma Through Regulating Splicing of Pyruvate Kinase. Journal of hematology & oncology 128 28086949
2016 Targeting NEK2 as a promising therapeutic approach for cancer treatment. Cell cycle (Georgetown, Tex.) 115 27019372
2002 Phosphorylation of the mitotic regulator protein Hec1 by Nek2 kinase is essential for faithful chromosome segregation. The Journal of biological chemistry 114 12386167
2021 NEK2 inhibition triggers anti-pancreatic cancer immunity by targeting PD-L1. Nature communications 113 34315872
2011 Plk1 controls the Nek2A-PP1γ antagonism in centrosome disjunction. Current biology : CB 112 21723128
1994 Cell cycle-dependent expression of Nek2, a novel human protein kinase related to the NIMA mitotic regulator of Aspergillus nidulans. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 109 7522034
2004 NEK2A interacts with MAD1 and possibly functions as a novel integrator of the spindle checkpoint signaling. The Journal of biological chemistry 106 14978040
2005 Dynamic recruitment of Nek2 kinase to the centrosome involves microtubules, PCM-1, and localized proteasomal degradation. Molecular biology of the cell 98 15659651
2013 Role of Nek2 on centrosome duplication and aneuploidy in breast cancer cells. Oncogene 93 23708664
2006 Structure and regulation of the human Nek2 centrosomal kinase. The Journal of biological chemistry 90 17197699
2009 Nek2 as a novel molecular target for the treatment of breast carcinoma. Cancer science 89 19038001
2020 NEK2 induces autophagy-mediated bortezomib resistance by stabilizing Beclin-1 in multiple myeloma. Molecular oncology 87 31955515
2018 Destabilizing NEK2 overcomes resistance to proteasome inhibition in multiple myeloma. The Journal of clinical investigation 87 29863498
2018 CircRNA circPDSS1 promotes the gastric cancer progression by sponging miR-186-5p and modulating NEK2. Journal of cellular physiology 87 30417526
2014 Nek2 phosphorylates and stabilizes β-catenin at mitotic centrosomes downstream of Plk1. Molecular biology of the cell 83 24501426
2007 Nek2 as an effective target for inhibition of tumorigenic growth and peritoneal dissemination of cholangiocarcinoma. Cancer research 82 17942892
2013 The centrosomal kinase NEK2 is a novel splicing factor kinase involved in cell survival. Nucleic acids research 81 24369428
2005 Coordinate regulation of the mother centriole component nlp by nek2 and plk1 protein kinases. Molecular and cellular biology 81 15684383
2007 Protein phosphatase-1alpha regulates centrosome splitting through Nek2. Cancer research 76 17283141
2003 Phosphorylation of high-mobility group protein A2 by Nek2 kinase during the first meiotic division in mouse spermatocytes. Molecular biology of the cell 76 14668482
2011 Irreversible Nek2 kinase inhibitors with cellular activity. Journal of medicinal chemistry 74 21627121
2013 Upregulation of NEK2 is associated with drug resistance in ovarian cancer. Oncology reports 73 24337664
2002 The MAPK pathway triggers activation of Nek2 during chromosome condensation in mouse spermatocytes. Development (Cambridge, England) 73 11923207
2000 Nek2B, a novel maternal form of Nek2 kinase, is essential for the assembly or maintenance of centrosomes in early Xenopus embryos. The EMBO journal 73 10775266
2020 Targeting NEK2 impairs oncogenesis and radioresistance via inhibiting the Wnt1/β-catenin signaling pathway in cervical cancer. Journal of experimental & clinical cancer research : CR 71 32907622
2017 Targeting NEK2 attenuates glioblastoma growth and radioresistance by destabilizing histone methyltransferase EZH2. The Journal of clinical investigation 71 28737508
2008 The mitotic checkpoint kinase NEK2A regulates kinetochore microtubule attachment stability. Oncogene 70 18297113
2014 Overexpression of the Nek2 kinase in colorectal cancer correlates with beta-catenin relocalization and shortened cancer-specific survival. Journal of surgical oncology 69 25043295
2002 Alternative splice variants of the human centrosome kinase Nek2 exhibit distinct patterns of expression in mitosis. The Biochemical journal 67 11742531
2020 Circular RNA circTNPO3 Regulates Paclitaxel Resistance of Ovarian Cancer Cells by miR-1299/NEK2 Signaling Pathway. Molecular therapy. Nucleic acids 64 32791450
2014 NEK2 mediates ALDH1A1-dependent drug resistance in multiple myeloma. Oncotarget 62 25230277
2009 Increased expression and nuclear localization of the centrosomal kinase Nek2 in human testicular seminomas. The Journal of pathology 62 19023884
2007 Alternative splicing controls nuclear translocation of the cell cycle-regulated Nek2 kinase. The Journal of biological chemistry 57 17626005
2018 NEK2 promotes hepatocellular carcinoma migration and invasion through modulation of the epithelial-mesenchymal transition. Oncology reports 55 29399700
2019 FBXW7 circular RNA regulates proliferation, migration and invasion of colorectal carcinoma through NEK2, mTOR, and PTEN signaling pathways in vitro and in vivo. BMC cancer 54 31519156
2016 Dishevelled is a NEK2 kinase substrate controlling dynamics of centrosomal linker proteins. Proceedings of the National Academy of Sciences of the United States of America 54 27486244
2014 Novel small molecules disrupting Hec1/Nek2 interaction ablate tumor progression by triggering Nek2 degradation through a death-trap mechanism. Oncogene 52 24662830
2019 NEK2 Is an Effective Target for Cancer Therapy With Potential to Induce Regression of Multiple Human Malignancies. Anticancer research 47 31092416
2019 Nek2 augments sorafenib resistance by regulating the ubiquitination and localization of β-catenin in hepatocellular carcinoma. Journal of experimental & clinical cancer research : CR 47 31319849
2013 Nek2-targeted ASO or siRNA pretreatment enhances anticancer drug sensitivity in triple‑negative breast cancer cells. International journal of oncology 47 23340795
2009 Synthesis and biological evaluation of a series of novel inhibitor of Nek2/Hec1 analogues. Journal of medicinal chemistry 46 19243176
2008 Insights into the conformational variability and regulation of human Nek2 kinase. Journal of molecular biology 46 19124027
2007 Phosphorylation of human Sgo1 by NEK2A is essential for chromosome congression in mitosis. Cell research 46 17621308
2019 NEK2 promotes proliferation, migration and tumor growth of gastric cancer cells via regulating KDM5B/H3K4me3. American journal of cancer research 45 31815040
2013 Centrosomal kinase Nek2 cooperates with oncogenic pathways to promote metastasis. Oncogenesis 43 24018644
2017 Hepatoma cell functions modulated by NEK2 are associated with liver cancer progression. International journal of cancer 42 27925179
2020 Nek2 kinase displaces distal appendages from the mother centriole prior to mitosis. The Journal of cell biology 41 32211891
2015 Role of NEK2A in human cancer and its therapeutic potentials. BioMed research international 41 25705694
2020 microRNA-128-3p overexpression inhibits breast cancer stem cell characteristics through suppression of Wnt signalling pathway by down-regulating NEK2. Journal of cellular and molecular medicine 40 32558224
2013 Cdk4 and nek2 signal binucleation and centrosome amplification in a her2+ breast cancer model. PloS one 39 23776583
2009 Nek2 targets the mitotic checkpoint proteins Mad2 and Cdc20: a mechanism for aneuploidy in cancer. Experimental and molecular pathology 38 20034488
2005 Drosophila Nek2 protein kinase knockdown leads to centrosome maturation defects while overexpression causes centrosome fragmentation and cytokinesis failure. Experimental cell research 38 15572022
1999 Two structural variants of Nek2 kinase, termed Nek2A and Nek2B, are differentially expressed in Xenopus tissues and development. Developmental biology 38 10191058
1997 The in vivo expression pattern of mouse Nek2, a NIMA-related kinase, indicates a role in both mitosis and meiosis. Experimental cell research 37 9434622
2022 Genetic Aberrations and Interaction of NEK2 and TP53 Accelerate Aggressiveness of Multiple Myeloma. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 36 35088582
2015 The NIMA-like kinase Nek2 is a key switch balancing cilia biogenesis and resorption in the development of left-right asymmetry. Development (Cambridge, England) 36 26493400
2020 LIN9 and NEK2 Are Core Regulators of Mitotic Fidelity That Can Be Therapeutically Targeted to Overcome Taxane Resistance. Cancer research 33 32054769
2015 Effect of silencing NEK2 on biological behaviors of HepG2 in human hepatoma cells and MAPK signal pathway. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 33 26337275
2021 The Nek2 centrosome-mitotic kinase contributes to the mesenchymal state, cell invasion, and migration of triple-negative breast cancer cells. Scientific reports 32 33907253
2014 Aberrant expression of NEK2 and its clinical significance in non-small cell lung cancer. Oncology letters 32 25202351
2011 Abnormal expression of Nek2 and β-catenin in breast carcinoma: clinicopathological correlations. Histopathology 32 22014044
2004 Nucleolar Nek11 is a novel target of Nek2A in G1/S-arrested cells. The Journal of biological chemistry 32 15161910
2016 Molecular modeling and docking of small molecule inhibitors against NEK2. Bioinformation 31 28104962
2020 High expression of NEK2 promotes gastric cancer progression via activating AKT signaling. Journal of physiology and biochemistry 30 33201407
2016 Increased NEK2 in hepatocellular carcinoma promotes cancer progression and drug resistance by promoting PP1/Akt and Wnt activation. Oncology reports 30 27509921
2010 Cyclin A and Nek2A: APC/C-Cdc20 substrates invisible to the mitotic spindle checkpoint. Biochemical Society transactions 30 20074038
2005 Live cell imaging reveals distinct roles in cell cycle regulation for Nek2A and Nek2B. Biochimica et biophysica acta 30 15950749
2021 The oncogenic kinase NEK2 regulates an RBFOX2-dependent pro-mesenchymal splicing program in triple-negative breast cancer cells. Journal of experimental & clinical cancer research : CR 29 34930366
2022 NEK2 enhances malignancies of glioblastoma via NIK/NF-κB pathway. Cell death & disease 28 35031599
2020 Exosome-Derived miR-486-5p Regulates Cell Cycle, Proliferation and Metastasis in Lung Adenocarcinoma via Targeting NEK2. Frontiers in bioengineering and biotechnology 28 32322578
2019 Simulated microgravity inhibits the viability and migration of glioma via FAK/RhoA/Rock and FAK/Nek2 signaling. In vitro cellular & developmental biology. Animal 28 30820814
2024 Role of NEK2 in tumorigenesis and tumor progression. Trends in molecular medicine 26 39181803
2022 RPL17 Promotes Colorectal Cancer Proliferation and Stemness through ERK and NEK2/β-catenin Signaling Pathways. Journal of Cancer 25 35711835
2019 microRNA-138 induces cell survival and reduces WNT/β-catenin signaling of osteoarthritis chondrocytes through NEK2. IUBMB life 25 31034758
2012 Nek2A contributes to tumorigenic growth and possibly functions as potential therapeutic target for human breast cancer. Journal of cellular biochemistry 25 22234886
2004 Suppression of Nek2A in mouse early embryos confirms its requirement for chromosome segregation. Journal of cell science 25 15479717
2022 One shoot, three birds: Targeting NEK2 orchestrates chemoradiotherapy, targeted therapy, and immunotherapy in cancer treatment. Biochimica et biophysica acta. Reviews on cancer 24 35157980
2022 NEK2 promotes the migration and proliferation of ESCC via stabilization of YAP1 by phosphorylation at Thr-143. Cell communication and signaling : CCS 24 35705994
2004 Nek2A kinase regulates the localization of numatrin to centrosome in mitosis. FEBS letters 24 15388344
2022 NEK2 inactivates the Hippo pathway to advance the proliferation of cervical cancer cells by cooperating with STRIPAK complexes. Cancer letters 23 36115593
2024 Mesenchymal stem cell-derived exosomes carrying miR-486-5p inhibit glycolysis and cell stemness in colorectal cancer by targeting NEK2. BMC cancer 22 39506654
2014 Nek2 is a novel regulator of B cell development and immunological response. BioMed research international 22 25485281
2010 Involvement of a centrosomal protein kendrin in the maintenance of centrosome cohesion by modulating Nek2A kinase activity. Biochemical and biophysical research communications 22 20599736
2021 Silencing of Nek2 suppresses the proliferation, migration and invasion and induces apoptosis of breast cancer cells by regulating ERK/MAPK signaling. Journal of molecular histology 21 34009515
2020 A unique binding mode of Nek2A to the APC/C allows its ubiquitination during prometaphase. EMBO reports 21 32307883
2020 lncRNA SNHG1 Promotes Progression of Cervical Cancer Through miR-195/NEK2 Axis. Cancer management and research 21 33204155
2015 Cep68 can be regulated by Nek2 and SCF complex. European journal of cell biology 21 25704143
2014 Therapeutic melting pot of never in mitosis gene a related kinase 2 (Nek2): a perspective on Nek2 as an oncology target and recent advancements in Nek2 small molecule inhibition. Journal of medicinal chemistry 21 24517277
2016 High NEK2 Expression Is a Predictor of Tumor Recurrence in Hepatocellular Carcinoma Patients After Hepatectomy. Anticancer research 20 26851035
2016 APC/CFzr/Cdh1-Dependent Regulation of Planar Cell Polarity Establishment via Nek2 Kinase Acting on Dishevelled. Developmental cell 20 28041906
2004 Nek2A specifies the centrosomal localization of Erk2. Biochemical and biophysical research communications 19 15358203

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