Affinage

NLK

Serine/threonine-protein kinase NLK · UniProt Q9UBE8

Length
527 aa
Mass
58.3 kDa
Annotated
2026-06-10
68 papers in source corpus 33 papers cited in narrative 33 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

NLK is an evolutionarily conserved, predominantly nuclear proline-directed serine/threonine kinase that acts as a signal-integrating node downstream of the TAK1 MAP3K to phosphorylate transcriptional regulators and thereby tune developmental and stress-response programs (PMID:10391247, PMID:9448268). Its activation is scaffolded by TAB2, which bridges TAK1 and NLK and is required for TAK1-dependent NLK activation upon Wnt3a stimulation (PMID:20194509), and its activity is set bidirectionally by the phosphatase WIP1 (which dephosphorylates the activation site to inactivate NLK) and the deubiquitinase USP14 (which stabilizes NLK) (PMID:28185954, PMID:41353967). NLK was first defined as a negative regulator of canonical Wnt/β-catenin signaling: acting downstream of TAK1 (and of the Wnt-5a/Ca2+/CaMKII branch), it phosphorylates TCF/LEF factors to block β-catenin–TCF DNA binding, and promotes ubiquitin-dependent degradation of TCF/LEF via the RING ligase NARF and of c-Myb via HIPK2 and SCF^Fbxw7α (PMID:10391247, PMID:12482967, PMID:16714285, PMID:15082531, PMID:18765672). In a context-dependent reversal, NLK phosphorylates LEF1 downstream of Dishevelled in neural progenitors to dissociate LEF1 from HDAC and activate transcription, and phosphorylates HDAC1 at Ser421 to repress Wnt output (PMID:22373574, PMID:27903773). Beyond Wnt, NLK phosphorylates substrates that reprogram multiple pathways: YAP at Ser128 to block 14-3-3 binding and drive nuclear YAP accumulation under osmotic stress (PMID:27979972, PMID:27979971); Raptor at Ser863 to disrupt the Rag-GTPase interaction and inhibit mTORC1 lysosomal recruitment during stress (PMID:26588989); STAT3 at serine residues to enable TGF-β/activin mesoderm induction (PMID:15004007); SRF at Ser101/103 to shift it from MKL toward ELK co-activation and restrain myoblast differentiation in vivo (PMID:35013153); and PERIOD in the Drosophila circadian clock to set clock speed (PMID:21514639). NLK also restrains innate immune and inflammatory signaling, phosphorylating MAVS to promote its degradation and suppress antiviral IRF3 activation, and disrupting the TAK1–IKKβ interaction to block TNFα-induced NF-κB activation (PMID:31324787, PMID:24721172). In macrophages it scaffolds Caspase-8 within FADD-RIPK1/3 PANoptosome complexes to favor apoptotic/PANoptotic cleavage over necroptosis (PMID:41674095).

Mechanistic history

Synthesis pass · year-by-year structured walk · 16 steps
  1. 1998 High

    Establishing NLK as a bona fide autophosphorylating serine/threonine kinase with a defined catalytic lysine and a predominantly nuclear distribution set the biochemical foundation for all later substrate work.

    Evidence Autophosphorylation kinase assays with ATP-binding (K155M) and activation-loop mutants, plus subcellular fractionation and immunofluorescence in murine cells

    PMID:9448268

    Open questions at the time
    • No physiological substrate identified at this stage
    • Upstream activator not yet defined
  2. 1999 High

    Linking NLK to the TAK1 cascade and showing it phosphorylates TCF/LEF to block β-catenin–TCF DNA binding answered how a kinase could antagonize Wnt signaling at the transcriptional endpoint.

    Evidence In vitro kinase assay, Xenopus axis-duplication injection, reporter and DNA-binding assays

    PMID:10391247

    Open questions at the time
    • Did not define the upstream stimulus activating TAK1-NLK
    • Phosphosites on TCF/LEF not mapped here
  3. 2003 High

    Identifying the Wnt-5a/Ca2+/CaMKII branch as an upstream activator placed NLK at the convergence of non-canonical and canonical Wnt inputs.

    Evidence Kinase assays, chimeric Rfz-2 receptor stimulation, and reporter assays in HEK293 cells

    PMID:12482967

    Open questions at the time
    • How CaMKII connects mechanistically to TAK1 not resolved
    • Other upstream stimuli not surveyed
  4. 2004 High

    Demonstrating NLK-driven ubiquitination/degradation of c-Myb (with HIPK2) and serine phosphorylation of STAT3 expanded NLK's substrate repertoire beyond TCF/LEF and into developmental induction.

    Evidence Co-IP, in vitro kinase assays, ubiquitination/proteasome-inhibitor experiments (c-Myb); kinase assay plus Xenopus morpholino depletion (STAT3)

    PMID:15004007 PMID:15082531

    Open questions at the time
    • E3 ligase for c-Myb not yet identified
    • STAT3 phosphosites not mapped
  5. 2006 High

    Identifying NARF as an NLK-associated E3 ligase that ubiquitylates TCF/LEF explained how NLK couples phosphorylation to substrate degradation in Wnt suppression.

    Evidence Yeast two-hybrid, reciprocal Co-IP, in vitro ubiquitylation reconstitution, Xenopus axis-duplication assay

    PMID:16714285

    Open questions at the time
    • In vivo requirement of NARF for endogenous Wnt regulation not established
  6. 2008 High

    Showing that NLK phosphorylation of c-Myb enhances its recognition by SCF^Fbxw7α defined the degradation machinery for an NLK substrate and a phospho-degron logic.

    Evidence Co-IP, in vitro ubiquitination, phosphosite-mutant binding assays, siRNA knockdown

    PMID:18765672

    Open questions at the time
    • Whether Fbxw7α acts on other NLK substrates not tested
  7. 2010 High

    Defining TAB2 as the scaffold bridging TAK1 and NLK answered how the kinase is recruited and activated within the Wnt-responsive complex.

    Evidence Reciprocal Co-IP, domain mapping (TAB2 residues 292–417), siRNA knockdown, ubiquitylation and kinase assays with Wnt3a stimulation

    PMID:20194509

    Open questions at the time
    • Structural basis of the TAK1-TAB2-NLK complex unresolved
    • Whether TAB2 governs non-Wnt NLK functions untested
  8. 2011 High

    Cross-species work revealed NLK as a clock-setting kinase (PERIOD phosphorylation in Drosophila) and a Wnt-independent cytoskeletal/glial regulator (LIT-1 binding actin and WASP in C. elegans), broadening its functional scope.

    Evidence Drosophila genetic epistasis and phosphosite mapping (PER); C. elegans genetic screen, EM, yeast two-hybrid and Co-IP (LIT-1)

    PMID:21514639 PMID:21857800

    Open questions at the time
    • Mammalian circadian role of NLK not demonstrated
    • Direct actin/WASP binding by mammalian NLK not shown
  9. 2012 High

    Discovering that NLK can positively activate Wnt by phosphorylating LEF1 to release it from HDAC, downstream of Dishevelled, established context-dependent bidirectionality in NLK's Wnt output.

    Evidence Zebrafish morpholino knockdown, epistasis, in vitro kinase assay, Co-IP, reporter assay in neural progenitors

    PMID:22373574

    Open questions at the time
    • What determines positive vs negative Wnt outcome not defined
    • LEF1 phosphosites not fully mapped
  10. 2015 High

    Identifying Raptor Ser863 as an NLK target that disrupts Rag-GTPase binding placed NLK as a stress-responsive inhibitor of mTORC1 lysosomal recruitment.

    Evidence In vitro kinase assay, phosphosite mutagenesis, Co-IP, lysosomal fractionation, Nlk knockout and S863 knock-in mouse cells

    PMID:26588989

    Open questions at the time
    • How stress signals activate NLK toward Raptor not defined
  11. 2016 High

    Defining YAP Ser128 phosphorylation (blocking 14-3-3 binding) and HDAC1 Ser421 phosphorylation connected NLK to Hippo/YAP and refined its Wnt-repressive mechanism.

    Evidence In vitro kinase assays, Co-IP, nuclear fractionation, reporter assays, Drosophila genetics (YAP); kinase assay with catalytic mutant and NLK-knockout cells (HDAC1); independent concurrent replication of YAP finding

    PMID:27903773 PMID:27979971 PMID:27979972

    Open questions at the time
    • How osmotic stress directs NLK toward YAP vs other substrates unresolved
  12. 2014 Medium

    Showing NLK disrupts the TAK1-IKKβ interaction to block TNFα-induced NF-κB defined a kinase-substrate-independent, scaffold-disruption mode of NLK action in inflammatory signaling.

    Evidence Co-IP, overexpression, NLK genetic inactivation, NF-κB reporter and IKKβ phosphorylation assays

    PMID:24721172

    Open questions at the time
    • Whether NLK kinase activity is required for IKKβ inhibition not clarified
    • Endogenous physiological context limited
  13. 2019 High

    Establishing that NLK phosphorylates MAVS to drive its degradation positioned NLK as a negative regulator of antiviral innate immunity.

    Evidence Co-IP, in vitro phosphorylation, NLK knockdown/reconstitution, IRF3 readouts, mouse viral infection model

    PMID:31324787

    Open questions at the time
    • MAVS phosphosites and the responsible E3 ligase not defined
  14. 2022 High

    Identifying SRF Ser101/103 phosphorylation that shifts SRF from MKL to ELK co-activation, with a muscle phenotype in conditional knockouts, defined NLK's role in restraining myogenic differentiation in vivo.

    Evidence In vitro kinase assay, phosphosite mutagenesis, Co-IP, skeletal-muscle-specific Nlk conditional knockout mice

    PMID:35013153

    Open questions at the time
    • Upstream signal directing NLK to SRF in muscle not defined
  15. 2025 Medium

    Defining WIP1 and USP14 as negative and positive regulators of NLK stability/activity, respectively, clarified how NLK output is tuned post-translationally across Wnt and NF-κB contexts.

    Evidence Co-IP, in vitro phosphatase/kinase assays, WIP1-knockout cells (WIP1); Co-IP, deubiquitination and reporter assays (USP14)

    PMID:28185954 PMID:41353967

    Open questions at the time
    • The ubiquitin ligase counteracting USP14 on NLK unidentified
    • USP14-NLK study is single-lab with limited mechanistic depth
  16. 2026 Medium

    Showing NLK scaffolds Caspase-8 within PANoptosome complexes to bias cell death away from necroptosis extended NLK into programmed cell death control in macrophages.

    Evidence Co-IP with DED domain mapping, Csf1r-iCre Nlk conditional knockout mice, Caspase-8 cleavage and rescue assays, mouse sepsis model

    PMID:41674095

    Open questions at the time
    • Whether NLK kinase activity (vs scaffolding) is required not resolved
    • Direct Caspase-8 phosphorylation not demonstrated

Open questions

Synthesis pass · forward-looking unresolved questions
  • It remains unresolved what determines NLK substrate selection and the positive-versus-negative direction of its outputs across the many pathways it touches, and whether a unifying activation logic links its Wnt, Hippo, mTOR, immune, and cell-death roles.
  • No structural model of substrate recognition
  • No comprehensive phosphoproteomic substrate map
  • Context determinants of positive vs negative regulation undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 9 GO:0016740 transferase activity 4 GO:0140110 transcription regulator activity 3 GO:0140657 ATP-dependent activity 1
Localization
GO:0005634 nucleus 1 GO:0005739 mitochondrion 1 GO:0005829 cytosol 1
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-162582 Signal Transduction 5 R-HSA-1266738 Developmental Biology 4 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 1 R-HSA-9909396 Circadian clock 1
Partners
HIPK2MAVSTAB2TAK1TCF/LEF (LEF1)USP14WIP1YAP
Complex memberships
PANoptosome (FADD-RIPK1/3-Caspase-8)TAK1-TAB2-NLK complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1999 TAK1 activation stimulates NLK kinase activity, and NLK phosphorylates TCF/LEF transcription factors, inhibiting the interaction of the β-catenin-TCF complex with DNA, thereby negatively regulating the Wnt/β-catenin signaling pathway. Injection of NLK suppresses β-catenin-induced axis duplication in Xenopus embryos. In vitro kinase assay, Xenopus microinjection, transcriptional reporter assay, DNA-binding assay Nature High 10391247
1998 Murine NLK (Nlk) is a serine/threonine kinase that autophosphorylates; mutation of the ATP-binding Lys-155 to methionine or the activating threonine in kinase domain VIII abolishes autophosphorylation. NLK localizes predominantly to the nucleus (60–70%) with 30–40% cytoplasmic. Autophosphorylation kinase assay, site-directed mutagenesis, subcellular fractionation, immunofluorescence microscopy Proceedings of the National Academy of Sciences of the United States of America High 9448268
2003 The Wnt-5a/Ca2+ pathway activates CaMKII, which in turn stimulates the TAK1-NLK cascade. Wnt-5a overexpression in HEK293 cells activates NLK through TAK1, and activation of the chimeric receptor Rfz-2 activates endogenous CaMKII, TAK1, and NLK, inhibiting β-catenin-induced transcriptional activation. Kinase activity assay, chimeric receptor stimulation, transcriptional reporter assay, overexpression in HEK293 cells Molecular and cellular biology High 12482967
2004 NLK binds directly to c-Myb together with HIPK2, phosphorylates c-Myb at multiple sites, leading to its ubiquitination and proteasome-dependent degradation in response to Wnt-1 signaling via the TAK1-HIPK2-NLK pathway. Co-immunoprecipitation, in vitro kinase assay, ubiquitination assay, proteasome inhibitor experiments Genes & development High 15082531
2004 The TAK1-NLK cascade phosphorylates STAT3 at serine residues; this phosphorylation is essential for TGF-β/activin-mediated mesoderm induction in Xenopus. Activin activates NLK, which directly phosphorylates STAT3. In vitro kinase assay, Xenopus morpholino depletion, co-expression rescue experiments, phosphorylation assay Genes & development High 15004007
2006 NLK associates with NARF (NLK-associated RING finger protein), an E3 ubiquitin ligase that uses E2-25K to ubiquitylate TCF/LEF. NLK kinase activity augments NARF binding and ubiquitylation of TCF/LEF, leading to proteasomal degradation of TCF/LEF and suppression of Wnt/β-catenin signaling. Yeast two-hybrid, Co-IP, in vitro ubiquitylation assay, Xenopus axis duplication assay The Journal of biological chemistry High 16714285
2005 NLK phosphorylates A-Myb (but does not induce its degradation), inhibits the association between A-Myb and the coactivator CBP, and induces methylation of histone H3 at lysine-9 at A-Myb-bound promoters. NLK and HIPK2 both bind directly to A-Myb. Co-IP, in vitro kinase assay, chromatin immunoprecipitation, transcriptional reporter assay Molecular biology of the cell Medium 16055500
2008 Fbxw7α (F-box protein of SCF complex) directly binds c-Myb via its WD40 domain and induces c-Myb ubiquitination in a Wnt-1- and NLK-dependent manner. NLK phosphorylation of c-Myb enhances the c-Myb/Fbxw7α interaction; a c-Myb phosphorylation-site mutant fails to interact with Fbxw7α. NLK also binds Cul1 (SCF component). Co-IP, in vitro ubiquitination assay, mutant binding assay, siRNA knockdown The Journal of biological chemistry High 18765672
2003 HMG2L1 is an NLK-interacting protein identified by yeast two-hybrid screening; interaction confirmed in mammalian cells. HMG2L1 negatively regulates Wnt/β-catenin signaling, inhibiting β-catenin-stimulated transcriptional activity and Wnt-induced axis duplication in Xenopus. Yeast two-hybrid, Co-IP in mammalian cells, Xenopus axis duplication assay, transcriptional reporter assay Genes to cells : devoted to molecular & cellular mechanisms Medium 12875653
2010 TAB2 directly interacts with NLK and functions as a scaffold protein to facilitate the interaction between TAK1 and NLK. The intermediate region (residues 292–417) of TAB2 mediates NLK binding. TAB2 knockdown abolishes the TAK1-NLK interaction and NLK activation; TAB2 mediates TAK1-dependent NLK activation and LEF1 polyubiquitylation, inhibiting canonical Wnt signaling. Wnt3a stimulation increases the TAK1-TAB2-NLK complex. Co-IP, siRNA knockdown, domain-mapping mutant analysis, ubiquitylation assay, kinase assay The Journal of biological chemistry High 20194509
2011 NLK phosphorylates the PERIOD (PER) protein at the 'per-short' domain in Drosophila, initiating a hierarchical phosphorylation cascade: NLK/NEMO phosphorylation at the per-short domain stimulates DOUBLETIME (DBT/CK1δ/ε) phosphorylation at nearby sites, delaying progressive DBT phosphorylation at distal sites required for SLIMB/β-TrCP recognition and proteasomal degradation, thereby setting circadian clock speed. Genetic epistasis in Drosophila, in vitro kinase assay, phosphorylation site mapping, mutant analysis Cell High 21514639
2011 LIT-1 (C. elegans NLK ortholog) acts within glia to promote sensory compartment expansion in a Wnt-independent manner. LIT-1 localizes to the glial sensory compartment via its conserved C-terminus, which binds both actin and the Wnt-Aldrich syndrome protein (WASP) by two-hybrid and Co-IP. LIT-1 C-terminus localization requires neuronal signals and is necessary for its function. Genetic suppressor screen, electron microscopy reconstruction, yeast two-hybrid, Co-IP, fluorescence microscopy, fluorescence EM PLoS biology High 21857800
2012 NLK (Nlk2 in zebrafish) positively regulates Wnt/β-catenin signaling by phosphorylating LEF1, which causes LEF1 dissociation from HDAC, enabling transcriptional activation. NLK functions downstream of Dishevelled (Dvl) in Wnt/β-catenin signaling in neural progenitor cells. Zebrafish morpholino knockdown, epistasis analysis, in vitro kinase assay, Co-IP, reporter assay The EMBO journal High 22373574
2015 NLK phosphorylates Raptor at Ser863, disrupting its interaction with Rag GTPase, which is required for mTORC1 lysosomal recruitment. This inhibits mTORC1 lysosomal localization and suppresses mTORC1 activation in response to osmotic and oxidative stress. Cells with Nlk deletion or Raptor S863 phosphorylation-site knock-in are defective in rapid mTORC1 inhibition upon osmotic stress. In vitro kinase assay, phosphorylation site mutagenesis, Co-IP, lysosomal fractionation, Nlk knockout and knock-in mouse cells, mTORC1 activity assay Genes & development High 26588989
2016 NLK phosphorylates YAP at Ser128 (both in vitro and in vivo), blocking YAP interaction with 14-3-3 and enhancing YAP nuclear localization and transcriptional activity. This is distinct from LATS-mediated Ser127 phosphorylation. Depletion of NLK increases YAP pSer127 and reduces YAP reporter activity. In Drosophila, Nemo knockdown reduces Yorkie target gene expression. In vitro kinase assay, co-immunoprecipitation, nuclear fractionation, luciferase reporter assay, Drosophila genetics EMBO reports High 27979971 27979972
2016 Osmotic stress activates NLK to phosphorylate YAP at Ser128, interfering with 14-3-3 binding even when YAP Ser127 is phosphorylated, resulting in YAP nuclear accumulation and induction of target gene expression, enhancing cellular stress adaptation. In vitro kinase assay, phosphorylation assay, nuclear/cytoplasmic fractionation, target gene expression analysis, reporter assay EMBO reports High 27979971
2016 NLK phosphorylates HDAC1 at Serine 421 (kinase-inactive NLK fails to do so), and this phosphorylation negatively regulates Wnt signaling. NLK-deficient primary embryonic fibroblasts show sustained β-catenin/Lef1 interaction and elevated Wnt reporter activity. In vitro kinase assay, catalytically inactive mutant, NLK-knockout mouse cells, luciferase reporter, Co-IP Molecular biology of the cell High 27903773
2019 NLK interacts with MAVS on mitochondria and peroxisomes and phosphorylates MAVS at multiple sites, inducing MAVS degradation and subsequent inactivation of IRF3, thereby inhibiting antiviral innate immune responses. NLK depletion promotes virus-induced antiviral cytokine production and decreases viral replication in vitro and in vivo. Co-IP, in vitro kinase/phosphorylation assay, NLK knockdown/reconstitution, mouse viral infection model, IRF3 activation assay Nature communications High 31324787
2014 NLK interacts with the IKK-associated complex and disrupts the TAK1-IKKβ interaction, thereby inhibiting IKKβ phosphorylation and blocking TNFα-induced NF-κB activation, p65 nuclear localization, and IκBα degradation. Co-IP, overexpression, NLK genetic inactivation, NF-κB reporter assay, IKKβ phosphorylation assay Biochimica et biophysica acta Medium 24721172
2011 ZIPK (zipper-interacting protein kinase) is a novel NLK-binding partner; ZIPK regulates NLK-mediated repression of canonical Wnt/β-catenin signaling and affects the NLK-TCF4 complex formation. ZIPK siRNA reduces Wnt/β-catenin signaling and cell growth. Co-IP, siRNA knockdown, luciferase reporter assay The Journal of biological chemistry Medium 21454679
2009 NLK interacts with SMAD4 (identified by yeast two-hybrid, confirmed by Co-IP in vitro and in vivo) and phosphorylates SMAD4 at Thr9 and Ser138 within the MH1 domain in vitro, via the linker sequence of SMAD4. Yeast two-hybrid, Co-IP, in vitro kinase assay, phosphorylation site mapping Molecular and cellular biochemistry Medium 19690946
2017 The phosphatase WIP1 directly interacts with NLK and dephosphorylates its activation site, thereby inhibiting NLK kinase activity. WIP1-mediated inhibition of NLK markedly decreases LEF1 phosphorylation, enhancing LEF1 interaction with β-catenin and increasing Wnt activity during germ cell development. Co-IP, in vitro phosphatase assay, NLK kinase activity assay, LEF1 phosphorylation assay, WIP1 knockout mouse embryonic stem cells Biochimica et biophysica acta. Molecular basis of disease Medium 28185954
2018 NLK interacts with the E2F1 complex and promotes disassembly of the E2F1/HDAC1 complex, diminishing HDAC1's ability to repress E2F1 target genes and boosting cell cycle progression. NLK-deficient colorectal tumor cells show G1/S arrest and reduced E2F1 target gene expression; wild-type but not kinase-mutant NLK restores the phenotype. Co-IP, NLK deletion, RNA-seq, reporter assay, kinase-mutant rescue experiment Cancer letters Medium 29803790
2022 NLK phosphorylates SRF at serine residues 101/103, enhancing the SRF-ELK association and antagonizing the SRF/MKL pathway, thereby inhibiting myoblast differentiation in vitro. Skeletal muscle-specific Nlk conditional knockout mice show hypertrophic muscle growth with increased muscle and body mass, confirming NLK's role in modulating muscle development in vivo. In vitro kinase assay, phosphorylation site mutagenesis, Co-IP, Nlk conditional knockout mouse model, muscle phenotype analysis Cell death discovery High 35013153
2019 NLK interacts with STAT3 and inhibits CCL2 expression by regulating STAT3 phosphorylation and O-GlcNAcylation, thereby inhibiting macrophage recruitment in the tumor microenvironment. Co-IP, reporter assay, macrophage co-culture assay Journal of experimental & clinical cancer research : CR Low 38008713
2016 NLK interacts with the transcription factor STAT1 in cardiomyocytes; NLK transgenic mice show increased STAT1 levels and develop cardiac hypertrophy, fibrosis, and heart failure, while cardiac-specific Nlk deletion protects from cardiac dysfunction. NLK expression is induced by pathological cardiac stimuli. Cardiac-specific transgenic mice, cardiac-specific Nlk knockout (loxP/Cre), Co-IP, cardiac functional assays PloS one Medium 27764156
2012 NLK is synthetically lethal with PTEN deficiency; this lethality is mediated through FOXO1 (a proposed NLK substrate), as FOXO1 knockdown reverses the selectivity of NLK silencing for PTEN-deficient cells. NLK-depleted PTEN-deficient cells undergo senescence. High-throughput RNAi screen, isogenic PTEN-deficient cell models, FOXO1 knockdown rescue, senescence assay PloS one Medium 23144700
2020 NLK interacts with 14-3-3ζ (YWHAZ) and prevents its dimerization; this interaction restores E-cadherin expression suppressed by 14-3-3ζ. A non-dissociable 14-3-3ζ dimer cannot be disrupted by NLK, confirming that NLK acts by preventing 14-3-3ζ dimerization. Co-IP, overexpression, 14-3-3ζ fusion dimer experiment, migration assay, western blot Oncology reports Medium 32236580
2002 Xenopus NLK (xNLK) interacts with xSox11 in mammalian cells; kinase-inactive xNLK suppresses xSox11-induced neural marker gene expression. xNLK induces the anterior-neural marker Otx-2 and cooperates with xSox11 in neural induction. Co-IP in mammalian cells, dominant-negative kinase mutant, Xenopus embryo injection, neural marker gene expression assay Genes to cells : devoted to molecular & cellular mechanisms Medium 12047350
2025 USP14 (a deubiquitinase) interacts with NLK and facilitates its deubiquitination, thereby stabilizing NLK activity. This USP14-NLK interaction suppresses Wnt/β-catenin signaling and concurrently activates the NF-κB pathway in macrophages. Co-IP, USP14 overexpression/knockdown, deubiquitination assay, NF-κB reporter assay, Wnt reporter assay Cytokine Medium 41353967
2026 NLK associates with the N-terminal death effector domains (DEDs, amino acids 1–216) of Caspase-8 and enhances Caspase-8 recruitment and proximity-induced activation within FADD-RIPK1/3-containing PANoptosome complexes. NLK deletion impairs Caspase-8 cleavage and promotes RIPK1-RIPK3 necrosome assembly, redirecting cell death towards necroptosis in macrophages during sepsis. Co-IP, Nlk conditional knockout mice (Csf1r-iCre), LPS-stimulated bone-marrow-derived macrophages, Caspase-8 cleavage assay, Caspase-8 overexpression rescue, mouse sepsis model Clinical and translational medicine Medium 41674095
2025 NLK promotes mislocalization of TDP43 and other RNA-binding proteins by disrupting nuclear import. NLK levels are elevated in neurons exhibiting TDP43 mislocalization in ALS patient tissues, and genetic reduction of NLK reduces toxicity in human neuron models of ALS. Human ALS patient tissue analysis, human neuron ALS models, genetic NLK reduction, TDP43 localization assay bioRxivpreprint Low bio_10.1101_2025.01.27.635090
2010 NLK forms a complex with the histone H3-K9 methyltransferase SETDB1 and suppresses PPARγ action in mesenchymal cells. NLK suppresses osteoblastic differentiation markers (ALP, type I collagen, runx2, osterix, osteocalcin) in a kinase-activity-dependent manner; kinase-inactive NLK fails to suppress differentiation. NLK also suppresses Runx2-driven osteocalcin promoter activity. Retrovirus-mediated overexpression, kinase-inactive NLK mutant, siRNA knockdown, alkaline phosphatase assay, bone marker gene expression, luciferase reporter assay Experimental cell research Medium 20116374

Source papers

Stage 0 corpus · 68 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1999 The TAK1-NLK-MAPK-related pathway antagonizes signalling between beta-catenin and transcription factor TCF. Nature 518 10391247
2003 The TAK1-NLK mitogen-activated protein kinase cascade functions in the Wnt-5a/Ca(2+) pathway to antagonize Wnt/beta-catenin signaling. Molecular and cellular biology 461 12482967
2016 Phosphorylation by NLK inhibits YAP-14-3-3-interactions and induces its nuclear localization. EMBO reports 153 27979972
2004 Wnt-1 signal induces phosphorylation and degradation of c-Myb protein via TAK1, HIPK2, and NLK. Genes & development 146 15082531
2011 NEMO/NLK phosphorylates PERIOD to initiate a time-delay phosphorylation circuit that sets circadian clock speed. Cell 145 21514639
2016 Osmotic stress-induced phosphorylation by NLK at Ser128 activates YAP. EMBO reports 140 27979971
1998 Nlk is a murine protein kinase related to Erk/MAP kinases and localized in the nucleus. Proceedings of the National Academy of Sciences of the United States of America 122 9448268
2006 NARF, an nemo-like kinase (NLK)-associated ring finger protein regulates the ubiquitylation and degradation of T cell factor/lymphoid enhancer factor (TCF/LEF). The Journal of biological chemistry 111 16714285
2004 Role of the TAK1-NLK-STAT3 pathway in TGF-beta-mediated mesoderm induction. Genes & development 95 15004007
2012 NLK positively regulates Wnt/β-catenin signalling by phosphorylating LEF1 in neural progenitor cells. The EMBO journal 64 22373574
2008 Fbxw7 acts as an E3 ubiquitin ligase that targets c-Myb for nemo-like kinase (NLK)-induced degradation. The Journal of biological chemistry 56 18765672
2002 Involvement of NLK and Sox11 in neural induction in Xenopus development. Genes to cells : devoted to molecular & cellular mechanisms 52 12047350
2019 Phosphorylation of MAVS/VISA by Nemo-like kinase (NLK) for degradation regulates the antiviral innate immune response. Nature communications 51 31324787
2006 Nemo-like kinase (NLK) acts downstream of Notch/Delta signalling to downregulate TCF during mesoderm induction in the sea urchin embryo. Development (Cambridge, England) 50 17038519
2001 Abnormal bone marrow stroma in mice deficient for nemo-like kinase, Nlk. European journal of immunology 49 11745377
2011 Opposing activities of LIT-1/NLK and DAF-6/patched-related direct sensory compartment morphogenesis in C. elegans. PLoS biology 46 21857800
2015 NLK phosphorylates Raptor to mediate stress-induced mTORC1 inhibition. Genes & development 44 26588989
2015 NLK functions to maintain proliferation and stemness of NSCLC and is a target of metformin. Journal of hematology & oncology 39 26503334
2014 Nemo-like kinase (NLK) inhibits the progression of NSCLC via negatively modulating WNT signaling pathway. Journal of cellular biochemistry 39 23904219
2012 NLK is a key regulator of proliferation and migration in gallbladder carcinoma cells. Molecular and cellular biochemistry 39 22733362
2015 MiR-197 induces Taxol resistance in human ovarian cancer cells by regulating NLK. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 38 25833695
2005 The Wnt-NLK signaling pathway inhibits A-Myb activity by inhibiting the association with coactivator CBP and methylating histone H3. Molecular biology of the cell 36 16055500
2014 NLK, a novel target of miR-199a-3p, functions as a tumor suppressor in colorectal cancer. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 34 24972723
2023 Hsa_circ_0009092/miR-665/NLK signaling axis suppresses colorectal cancer progression via recruiting TAMs in the tumor microenvironment. Journal of experimental & clinical cancer research : CR 32 38008713
2014 Nemo-like kinase (NLK) negatively regulates NF-kappa B activity through disrupting the interaction of TAK1 with IKKβ. Biochimica et biophysica acta 32 24721172
2017 The effect of EBV on WIF1, NLK, and APC gene methylation and expression in gastric carcinoma and nasopharyngeal cancer. Journal of medical virology 31 28543390
2016 NLK-mediated phosphorylation of HDAC1 negatively regulates Wnt signaling. Molecular biology of the cell 30 27903773
2010 TAB2 scaffolds TAK1 and NLK in repressing canonical Wnt signaling. The Journal of biological chemistry 30 20194509
2003 Negative regulation of Wnt signalling by HMG2L1, a novel NLK-binding protein. Genes to cells : devoted to molecular & cellular mechanisms 29 12875653
2015 MicroRNA-92b promotes tumor growth and activation of NF-κB signaling via regulation of NLK in oral squamous cell carcinoma. Oncology reports 26 26503628
2011 Zipper-interacting protein kinase (ZIPK) modulates canonical Wnt/beta-catenin signaling through interaction with Nemo-like kinase and T-cell factor 4 (NLK/TCF4). The Journal of biological chemistry 26 21454679
2011 Expression of NLK and its potential effect in ovarian cancer chemotherapy. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 26 22027747
2018 Nemo-like kinase (NLK) primes colorectal cancer progression by releasing the E2F1 complex from HDAC1. Cancer letters 22 29803790
2012 NLK is a novel therapeutic target for PTEN deficient tumour cells. PloS one 20 23144700
2015 In vivo RNAi screen identifies NLK as a negative regulator of mesenchymal activity in glioblastoma. Oncotarget 19 26023737
2015 The emerging role of Nemo-like kinase (NLK) in the regulation of cancers. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 19 26427665
2019 Sishen Wan® Ameliorated Trinitrobenzene-Sulfonic-Acid-Induced Chronic Colitis via NEMO/NLK Signaling Pathway. Frontiers in pharmacology 18 30894816
2010 Nemo-like kinase (NLK) expression in osteoblastic cells and suppression of osteoblastic differentiation. Experimental cell research 18 20116374
2011 Nemo-like kinase (NLK) involves in neuronal apoptosis after traumatic brain injury. Cellular and molecular neurobiology 15 22127415
2016 MicroRNA-208a Potentiates Angiotensin II-triggered Cardiac Myoblasts Apoptosis via Inhibiting Nemo-like Kinase (NLK). Current pharmaceutical design 14 26861724
2016 Association of NLK polymorphisms with intramuscular fat content and fatty acid composition traits in pigs. Meat science 13 27050409
2021 NLK suppresses MAVS-mediated signaling in black carp antiviral innate immunity. Developmental and comparative immunology 12 33872658
2002 Genomic structure of the human NLK (nemo-like kinase) gene and analysis of its promoter region. Gene 11 12039044
2017 Wip1 directly dephosphorylates NLK and increases Wnt activity during germ cell development. Biochimica et biophysica acta. Molecular basis of disease 9 28185954
2024 MSI2 regulates NLK-mediated EMT and PI3K/AKT/mTOR pathway to promote pancreatic cancer progression. Cancer cell international 8 39097735
2016 Nemo-Like Kinase (NLK) Is a Pathological Signaling Effector in the Mouse Heart. PloS one 8 27764156
2016 Lentivirus-mediated knockdown of NLK inhibits small-cell lung cancer growth and metastasis. Drug design, development and therapy 8 27895463
2000 Characterization of the Fugu rubripes NLK and FN5 genes flanking the NF1 (Neurofibromatosis type 1) gene in the 5' direction and mapping of the human counterparts. Gene 8 10863097
2019 Effect of NLK on the proliferation and invasion of laryngeal carcinoma cells by regulating CDCP1. European review for medical and pharmacological sciences 7 31364124
2019 Somatic Mutations and Intratumoral Heterogeneity of Cancer-Related Genes NLK, YY1 and PA2G4 in Gastric and Colorectal Cancers. Pathology oncology research : POR 7 31828582
2013 Expression of Nemo-like kinase (NLK) in the brain in a rat experimental subarachnoid hemorrhage model. Cell biochemistry and biophysics 7 23325309
2009 Human SMAD4 is phosphorylated at Thr9 and Ser138 by interacting with NLK. Molecular and cellular biochemistry 7 19690946
2022 Nemo-like kinase (NLK) gene regulates apoptosis via the p53 signaling pathway in Litopenaeus vannamei under low-temperature stress. Developmental and comparative immunology 6 35231467
2020 NLK interacts with 14‑3‑3ζ to restore the expression of E‑cadherin. Oncology reports 6 32236580
2013 Lentivirus-based RNA silencing of Nemo-like kinase (NLK) inhibits the CAL 27 human adenosquamos carcinoma cells proliferation and blocks G0/G1 phase to S phase. International journal of medical sciences 6 23983589
2022 NLK is required for Ras/ERK/SRF/ELK signaling to tune skeletal muscle development by phosphorylating SRF and antagonizing the SRF/MKL pathway. Cell death discovery 4 35013153
2001 The minisatellite of the GPI/AMF/NLK/MF gene: interspecies conservation and transcriptional activity. Gene 4 11376940
2026 NLK facilitates Caspase-8 activation to drive macrophage PANoptosis in sepsis. Clinical and translational medicine 3 41674095
2021 The expression of NLK is functionally associated with colorectal cancers (CRC). Journal of Cancer 3 34729110
2025 The exosomal miRNA-3184-3p derived from highly metastatic melanoma cells promotes metastatic competency via the positive feedback loop of NLK/Wnt/S100A11. Biochemical pharmacology 2 40578571
2026 Tim-3 agonist restrains ILC2 function and attenuates airway hyperreactivity via NLK pathway. Nature communications 1 41922900
2025 Grain proteins ameliorate glucose metabolism disorders by activating intestinal AhR and the hepatic NLK/FOXO1 pathway via gut microbiota-derived indole metabolites. Journal of advanced research 1 41390118
2017 In vitro NLK Kinase Assay. Bio-protocol 1 34595271
2025 NLK knockdown in hBMSCs enhance repair of critical-size bone defects by modulating neurogenic and osteogenic differentiation. Biochimica et biophysica acta. Molecular basis of disease 0 40280200
2025 [Retracted] MicroRNA‑92b promotes tumor growth and activation of NF‑κB signaling via regulation of NLK in oral squamous cell carcinoma. Oncology reports 0 41235675
2025 Macrophage USP14 suppresses Wnt/β-catenin signaling via NLK deubiquitination to enhance immune response. Cytokine 0 41353967
2025 Evolutionary analysis through structural modeling of FAM222 proteins reveals a novel disordered conserved domain in vertebrates that interacts with NLK. Scientific reports 0 41365991
2025 Crosstalk of Nemo-Like Kinase (NLK) and Yes-Associated Protein (YAP) Phosphorylation in Endometrial Epithelial Cells. Development & reproduction 0 41573688

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