Affinage

Showing MAP3K12 — DLK is a alias.

MAP3K12

Mitogen-activated protein kinase kinase kinase 12 · UniProt Q12852

Length
859 aa
Mass
93.2 kDa
Annotated
2026-06-10
100 papers in source corpus 37 papers cited in narrative 37 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAP3K12 (DLK/MUK/ZPK) is a serine/threonine MAP3K that functions as a neuronal stress and injury sensor, coupling axonal damage and cytoskeletal perturbation to JNK-dependent apoptotic and regenerative transcriptional programs (PMID:21893599, PMID:23431164, PMID:25726747). It is a selective activator of the JNK/SAPK pathway—not ERK—acting through MKK7, which it phosphorylates and binds directly, with MKK4 contributing in some injury contexts (PMID:8798750, PMID:10187804, PMID:25100604), and signals within a JIP3-scaffolded complex to drive c-Jun phosphorylation and apoptosis while degenerating axons through distinct JNK substrates (PMID:21893599). DLK is anchored to axonal trafficking vesicles by palmitoylation adjacent to its kinase domain, a modification required for kinase activity, signaling-complex assembly, and retrograde injury signaling; the same palmitoylation co-targets JNK3, which it preferentially engages and which reciprocally phosphorylates DLK in a positive-feedback loop that locks the module in an active state (PMID:26719418, PMID:35349303). Its abundance is set by competing regulators: JNK-mediated phosphorylation stabilizes DLK by reducing PHR1-dependent ubiquitination (with USP9X deubiquitination), HSP90 chaperones and stabilizes the protein, while the Highwire/DFsn ubiquitin ligase system restrains levels, MBIP inhibits JNK activation via the leucine zipper, and tissue transglutaminase cross-links and inactivates DLK during apoptosis (PMID:23979718, PMID:30275300, PMID:17697379, PMID:10801814, PMID:10922377). Genetic loss of DLK protects neurons from developmental and axotomy-induced death and from demyelination- and optic-nerve-injury-evoked apoptosis, but also limits axon regrowth, establishing DLK as a dual gatekeeper of neuronal survival and regenerative competence (PMID:21593306, PMID:23431164, PMID:25100604, PMID:39443516). Beyond neurons, DLK phosphorylates histone H3 at Thr11 at centromeres during mitosis, phosphorylates the pro-apoptotic protein Par-4 at Thr155 to drive cytoskeleton-associated apoptosis, and promotes keratinocyte terminal differentiation (PMID:12560483, PMID:19625447, PMID:15695824).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1996 Medium

    Established DLK as a MAP3K-level kinase that selectively routes upstream signals to the JNK/SAPK pathway rather than ERK, defining its core pathway position.

    Evidence Transient overexpression and kinase-inactive dominant-negative mutants with epistasis in NIH3T3/COS cells

    PMID:8637721 PMID:8798750

    Open questions at the time
    • Based on overexpression, not endogenous protein
    • Direct downstream MAP2K substrate not yet identified
    • No physiological stimulus defined
  2. 1998 Medium

    Placed DLK within the C3G→MLK family→JNK cascade and identified its biochemical activity as a threonine-autophosphorylating kinase with chromatin association and histone/myosin-light-chain substrates in vitro.

    Evidence Dominant-negative epistasis, co-IP with MLK3, in vitro kinase assays and nuclear fractionation

    PMID:9430657 PMID:9840928

    Open questions at the time
    • In vitro substrate set may not reflect physiological targets
    • Nuclear chromatin association function not mechanistically resolved
  3. 1999 High

    Defined MKK7 as the direct and selective DLK substrate (excluding MKK4) and identified Par-4 and ATF-4/AATF as binding partners linking DLK to apoptosis and transcription, with subcellular compartment dictating apoptotic output.

    Evidence In vitro kinase assays, co-IP, subcellular fractionation, yeast two-hybrid, GFP-deletion localization with heterologous NLS rescue

    PMID:10187804 PMID:10580117 PMID:10602474 PMID:10602480

    Open questions at the time
    • AATF interaction rests on yeast two-hybrid only
    • Physiological trigger for cytoplasmic relocalization not defined
    • MKK4 contribution in vivo unresolved
  4. 2000 Medium

    Identified negative-regulatory mechanisms: MBIP binds the leucine zipper to inhibit JNK activation, and tissue transglutaminase cross-links DLK into inactive oligomers during apoptosis.

    Evidence Co-IP, JNK activation assays, in vitro transglutaminase assay and pharmacological inhibition

    PMID:10801814 PMID:10922377

    Open questions at the time
    • MBIP regulation tested in overexpression only
    • tTG oligomerization role appears context-dependent
  5. 2003 High

    Demonstrated a cell-cycle role: DLK phosphorylates histone H3 at Thr11 specifically at centromeres during mitosis, where it transiently localizes.

    Evidence In vitro kinase assay with phosphosite mapping, phosphospecific antibody, GFP localization

    PMID:12560483

    Open questions at the time
    • Functional consequence of H3 Thr11 phosphorylation not established
    • Regulation of mitotic DLK activation unknown
  6. 2009 High

    Genetic loss-of-function established DLK as required in vivo for injury-induced c-Jun phosphorylation, neurite extension, and developmental/axotomy-induced motoneuron apoptosis, and identified Par-4 Thr155 as an essential phosphorylation event for apoptosis.

    Evidence Gene-trap and knockout mice, axotomy models, motoneuron counting, in vitro kinase assay with phosphospecific Par-4 antibody

    PMID:19358824 PMID:19625447 PMID:19808064 PMID:21593306

    Open questions at the time
    • Mechanism coupling axonal DLK to nuclear c-Jun not yet defined
    • Balance between apoptotic and regenerative outputs unresolved
  7. 2011 High

    Resolved DLK as a JIP3-scaffolded prodegenerative stress module in which local axonal activation drives both c-Jun-dependent somal apoptosis and c-Jun-independent axon degeneration via distinct JNK substrates.

    Evidence Co-IP of DLK-JIP3, DLK-null mice, siRNA, immunofluorescence, pathway epistasis

    PMID:21893599

    Open questions at the time
    • Identity of degeneration-specific JNK substrates not defined
    • Spatial signal transmission from axon to soma incompletely mapped
  8. 2013 High

    Established the stabilization feedback loop—JNK phosphorylation reduces PHR1-mediated ubiquitination (with USP9X deubiquitination)—and showed DLK is the upstream gate for both apoptotic and regenerative transcriptional responses to optic nerve injury.

    Evidence Mass spectrometry phosphosite mapping, co-IP, ubiquitination assays, conditional DLK deletion with transcriptomics and PTEN epistasis

    PMID:23431164 PMID:23979718

    Open questions at the time
    • Survival-versus-regeneration trade-off not mechanistically separable
    • How distinct transcriptional outputs are selected unknown
  9. 2014 High

    Defined a DLK–MKK4 gateway to axotomy-induced motoneuron death, showed compartment-specific JNK regulation (somal but not axonal), and provided the first DLK crystal structure enabling selective brain-penetrant inhibitors.

    Evidence Multiple genetic KO lines, compartment-specific phospho-JNK imaging, X-ray crystallography with structure-based drug design

    PMID:24878510 PMID:25100604 PMID:26431428

    Open questions at the time
    • Upstream kinase governing axonal JNK distinct from DLK not identified
    • MKK4 versus MKK7 selectivity reconciliation across contexts incomplete
  10. 2016 High

    Identified palmitoylation as the master regulator targeting DLK to trafficking vesicles and licensing kinase activity and signaling-complex assembly, and placed cAMP/PKA as a conserved direct upstream activator of injury signaling.

    Evidence Acyl-RAC, palmitoylation-site mutant rescue, live vesicle imaging, retrograde signaling assays, Drosophila and DRG genetic epistasis

    PMID:26719418 PMID:27268300

    Open questions at the time
    • Palmitoyl-acyltransferase responsible for DLK modification not identified
    • How PKA mechanistically activates DLK not resolved
  11. 2018 High

    Showed HSP90 chaperones DLK to maintain its stability in vivo, adding a chaperone-dependent layer to DLK abundance control conserved to Drosophila.

    Evidence Co-IP, pharmacological HSP90 inhibition, in vivo protein-level measurement, Drosophila knockdown

    PMID:30275300

    Open questions at the time
    • Interplay between HSP90 chaperoning and PHR1 ubiquitination not integrated
    • Co-chaperone requirements unknown
  12. 2019 Medium

    Connected DLK activation to downstream axon-vulnerability effectors by showing it lowers NMNAT2/SCG10 to predispose axons to SARM1-dependent degeneration, and showed DLK is required for the neuronal intrinsic immune response and neuropathic pain after nerve injury.

    Evidence DLK gain-of-function and inhibition, SARM1 KO epistasis, conditional DLK KO with cytokine qRT-PCR, immune-cell/glia immunohistochemistry and pain behavior

    PMID:31494101 PMID:31696428

    Open questions at the time
    • Direct DLK substrates controlling NMNAT2/SCG10 levels not identified
    • Mechanism linking DLK to cytokine transcription not defined
  13. 2020 Medium

    Expanded DLK roles beyond injury: selective DLK–JNK3 engagement drives cyclin expression and postnatal beta-cell proliferation, and DLK activity is required for stress-induced HSV-1 reactivation via histone phosphorylation.

    Evidence Co-IP of Dlk-Jnk3, siRNA, kinase activity and replication assays; DLK inhibition with histone phosphorylation assay in latently infected neurons

    PMID:32189007 PMID:33350386

    Open questions at the time
    • JNK3 selectivity mechanism in non-neuronal cells unclear
    • Histone substrate of DLK-driven reactivation not directly mapped
  14. 2022 High

    Defined the JNK3 positive-feedback and co-palmitoylation mechanism that locks the DLK-JNK3 module active on shared axonal vesicles, and showed DLK with LZK is jointly required for PTEN-deletion-induced corticospinal regeneration independent of mTOR.

    Evidence In vitro feedback kinase assay, Acyl-RAC, co-vesicle imaging, JNK3 palmitoylation-mutant rescue in optic nerve crush; inducible DLK/LZK double-KO with axon tracing and mTOR analysis

    PMID:35349303 PMID:35361703

    Open questions at the time
    • Redundancy boundaries between DLK and LZK incompletely defined
    • How injury signaling and regenerative competence are coordinated still unresolved
  15. 2024 High

    Demonstrated DLK couples chronic demyelination to neuronal apoptosis via c-Jun phosphorylation, extending its injury-sensor role to a disease-relevant stressor blockable by DLK inhibition.

    Evidence Inducible demyelination mouse models with pharmacological and genetic DLK disruption, p-c-Jun immunofluorescence and TUNEL

    PMID:39443516

    Open questions at the time
    • Upstream signal sensing demyelination not identified
    • Therapeutic window between neuroprotection and regeneration impairment undefined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How DLK integrates competing stabilization (JNK feedback, HSP90), degradation (PHR1/Highwire, USP9X), palmitoylation, and direct activators (PKA) into a quantitative threshold that selects survival versus regeneration versus apoptosis outcomes remains unresolved.
  • No unified model linking DLK abundance to output selection
  • Palmitoyltransferase and the full degeneration-specific substrate set unidentified
  • Mechanism distinguishing apoptotic from regenerative transcriptional programs unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5 GO:0140096 catalytic activity, acting on a protein 3 GO:0042393 histone binding 2
Localization
GO:0005634 nucleus 2 GO:0005856 cytoskeleton 2 GO:0031410 cytoplasmic vesicle 2 GO:0005694 chromosome 1
Pathway
R-HSA-5357801 Programmed Cell Death 4 R-HSA-1266738 Developmental Biology 3 R-HSA-162582 Signal Transduction 3
Partners
HSP90JIP3MAP2K4MAP2K7MAPK10MBIPPHR1USP9X
Complex memberships
DLK-JIP3 JNK signaling complexDLK-JNK3 palmitoylated vesicle module

Evidence

Reading pass · 37 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 MAP3K12 (MUK/DLK) activates JNK1/SAPK and p38 MAP kinase but not ERK2 when overexpressed in NIH3T3 or COS cells; a catalytically inactive K185A mutant acts dominantly negatively; DLK lies distal to Rac1/Cdc42 but proximal to MEKK1 in the v-Src-to-SAPK pathway Transient transfection overexpression, kinase-inactive dominant-negative mutant, co-transfection epistasis in COS7/NIH3T3 cells The Journal of biological chemistry Medium 8798750
1996 MAP3K12 (MUK) activates JNK1 and induces hyper-phosphorylated c-Jun when overexpressed in NIH3T3 or COS1 cells; unlike MEKK, MUK is a selective activator of the JNK pathway and does not activate ERK; MUK shares leucine-zipper-like motifs with mixed lineage kinases Transient overexpression, JNK1 kinase assay, c-Jun phosphorylation by immunoblot in NIH3T3/COS1 cells Oncogene Medium 8637721
1999 DLK phosphorylates and activates MKK7 in vitro and in vivo, but does not phosphorylate or activate MKK4; DLK co-immunoprecipitates with MKK7; DLK and MKK7 share similar subcellular compartments in neurons, distinct from MKK4 In vitro kinase assay with recombinant MKK4 and MKK7, co-immunoprecipitation, subcellular fractionation, immunocytochemistry in neuronal cultures The Journal of biological chemistry High 10187804
1998 MAP3K12 (DLK/ZPK) is a serine/threonine kinase that undergoes autophosphorylation predominantly on threonine residues, phosphorylates myosin light chain (at serine residues) and core histones H3, H2A, and H4 in vitro, and is tightly associated with insoluble nuclear structures (chromatin), released partially by DNase I digestion In vitro kinase assay, autophosphorylation assay, nuclear fractionation + DNase I digestion, GFP-fusion localization Oncogene High 9840928
1999 DLK/ZIP kinase interacts with the pro-apoptotic protein Par-4 via an arginine-rich region (residues 338–417), not the leucine zipper; co-expression of DLK and Par-4 relocates DLK from nucleus to cytoplasm/actin filaments, causes cytoskeletal reorganization and morphological apoptosis Yeast two-hybrid, GST pull-down, in vitro kinase assay, co-expression in vivo, confocal microscopy Oncogene High 10602480
1999 DLK interacts with the transcription factor ATF-4 via its leucine zipper domain; DLK also binds the transcription factor AATF, and AATF overexpression interferes with DLK-induced apoptosis Yeast two-hybrid, co-expression apoptosis assay FEBS letters Low 10580117
1999 DLK nuclear localization requires the most C-terminal NLS; the leucine zipper is required for association with nuclear speckles; a C-terminal deletion mutant lacking nuclear transport co-localizes with actin filaments and is a potent inducer of apoptosis; retargeting this mutant to the nucleus via a heterologous NLS abrogates its apoptotic activity, demonstrating that DLK exerts apoptotic activity only in the cytoplasm GFP-fusion deletion/point mutagenesis, confocal immunofluorescence, apoptosis assays, heterologous NLS rescue Oncogene High 10602474
2000 DLK protein is oligomerized by tissue transglutaminase (tTG) during apoptosis into SDS- and mercaptoethanol-resistant high molecular weight species; tTG inhibitor monodansylcadaverine blocks DLK oligomerization and apoptosis; DLK is a substrate for tTG-dependent cross-linking in vitro, which functionally inactivates DLK Immunoblot, tTG inhibitor treatment, in vitro transglutaminase assay, calphostin C-induced apoptosis model The Journal of biological chemistry High 10922377
2000 MBIP (MUK-binding inhibitory protein) binds to one of the two leucine-zipper-like motifs of MAP3K12 (MUK/DLK) and inhibits its ability to activate JNK/SAPK; MBIP overexpression partially inhibits sorbitol-induced JNK activation in 293T cells; this inhibition is specific to MUK and not seen with COT/Tpl-2 Co-immunoprecipitation, JNK activation assay, overexpression in 293T cells The Journal of biological chemistry Medium 10801814
2002 MAP3K12 (MUK/DLK/ZPK) protein levels and JNK activity increase in newly generated neurons during radial migration in developing mouse telencephalon; ectopic expression of MUK impairs radial migration; MUK is associated with dotted structures along microtubules and Golgi in cortical cells; MUK overexpression impairs radial microtubule organization without massive depolymerization In utero electroporation, immunofluorescence, Western blot, COS-1 cell overexpression microtubule assay Development (Cambridge, England) Medium 12223406
2003 DLK/ZIP kinase phosphorylates histone H3 at Thr11 (not Ser10) in vitro; phosphorylation of H3 Thr11 occurs in vivo specifically during mitosis (prophase to early anaphase) and is enriched at centromeres; GFP-DLK associates with centromeres during this same mitotic window In vitro kinase assay with phosphosite determination, phosphospecific antibody generation, immunoblot, confocal immunofluorescence, GFP-fusion stable expression Nucleic acids research High 12560483
1998 Kinase-negative forms of DLK and MLK3 inhibit C3G-induced JNK1 activation; kinase-negative DLK also inhibits MLK3-induced JNK1 activation; kinase-negative DLK binds MLK3, placing DLK in the C3G→MLK family→JNK pathway Transient co-expression, dominant-negative constructs, co-immunoprecipitation, JNK1 kinase assay in 293T cells The Journal of biological chemistry Medium 9430657
2005 DLK acts as a key regulator of keratinocyte terminal differentiation: adenoviral DLK expression in human keratinocytes induced suprabasal localization, compacted cytoplasm, DNA fragmentation, filaggrin upregulation, and transglutaminase activity leading to cornified envelope formation; kinase-inactive DLK did not induce these effects Recombinant adenovirus overexpression, kinase-inactive mutant control, biochemical assays (transglutaminase activity), morphological analysis The Journal of biological chemistry Medium 15695824
2008 DLK-mediated apoptosis in response to calphostin C requires tissue transglutaminase (TG2)-dependent oligomerization/activation of DLK upstream of JNK; siRNA depletion of TG2 strongly reduces DLK-dependent JNK activity and apoptosis; combined depletion of TG2 and DLK further attenuates JNK activation, Bax translocation, and caspase-3 activation siRNA knockdown, pharmacological JNK inhibition, immunoblot for pathway components, cell viability assay in NIH3T3 and MDA-MB-231 cells Cell death and differentiation Medium 18497756
2009 MAP3K12 (ZPK/DLK) is required for c-Jun phosphorylation in DRG neurons after sciatic nerve axotomy; ZPK/DLK gene-trap mice show significantly fewer phospho-c-Jun-positive DRG neurons at 24 h post-axotomy and reduced neurite extension in vitro Gene-trap loss-of-function mice, sciatic nerve axotomy, immunohistochemistry for phospho-c-Jun, in vitro neurite extension assay Biochemical and biophysical research communications Medium 19358824
2009 DLK regulates axonal elongation in developing cortical neurons and PC12 cells; DLK knockdown decreases JNK phosphorylation and phosphorylation of MAP1B, a substrate known to regulate axonal growth; DLK protein is preferentially transported into axons shRNA knockdown, immunoblot for pJNK and pMAP1B, neurite outgrowth assay in dissociated cortical neurons and PC12 cells Neuroscience research Medium 19808064
2011 MAP3K12 (DLK) selectively regulates a prodegenerative JNK stress-response pathway via interaction with scaffolding protein JIP3 to form a specialized JNK signaling complex; local DLK activation in axons leads to phosphorylation of c-Jun and apoptosis after JNK redistribution to the cell body; axon degeneration by DLK is c-Jun independent and mediated by distinct JNK substrates; DLK-null mice show reduced apoptosis in multiple neuronal populations during development Co-immunoprecipitation (DLK-JIP3 complex), DLK-null mouse analysis, immunofluorescence, siRNA knockdown, pathway epistasis The Journal of cell biology High 21893599
2011 MAP3K12 (ZPK/DLK)-deficient mice have twice as many spinal motoneurons as wild-type due to reduced developmental apoptosis; ZPK/DLK-deficient motoneurons are completely resistant to axotomy-induced death, demonstrating that ZPK/DLK is a critical mediator of programmed motoneuron death Genetic knockout mice, motoneuron counting, TUNEL apoptosis assay, axotomy model The Journal of neuroscience : the official journal of the Society for Neuroscience High 21593306
2013 DLK is an essential upstream mediator of both apoptotic and regenerative transcriptional responses to optic nerve crush in retinal ganglion cells (RGCs); DLK protein rapidly elevates in axons then cell bodies after injury; DLK deletion provides robust and sustained RGC neuroprotection but reduces axon regrowth beyond the injury site even when PTEN is deleted Conditional DLK deletion in retina, optic nerve crush, RGC survival quantification, transcriptome analysis, immunofluorescence Proceedings of the National Academy of Sciences of the United States of America High 23431164
2013 After neuronal insult, JNK phosphorylates specific sites throughout the length of DLK; these phosphorylation events stabilize DLK by reducing its ubiquitination mediated by E3 ubiquitin ligase PHR1; de-ubiquitination by USP9X also contributes; DLK abundance in turn controls downstream JNK signaling levels and apoptosis — a positive feedback loop Mass spectrometry phosphosite identification, immunoblot, co-immunoprecipitation (DLK-PHR1, DLK-USP9X), ubiquitination assay, siRNA knockdown The Journal of cell biology High 23979718
2014 MAP3K12 (DLK) crystal structure obtained; structure-based drug design used to generate potent, selective, brain-penetrant inhibitors; this is the first reported crystal structure of DLK X-ray crystallography, structure-based drug design, in vitro kinase assay, in vivo nerve injury model Journal of medicinal chemistry High 26431428
2014 DLK (MAP3K12) deficiency significantly delays axonal-injury-induced RGC somal death and attenuates somal JNK activation; however, DLK deficiency does not alter axonal degeneration or axonal JNK activation, demonstrating that JNK activation in different cellular compartments is regulated by distinct upstream kinases Conditional DLK knockout in optic cup, optic nerve crush, RGC survival counting, phospho-JNK immunofluorescence in soma vs. axon compartments Neurobiology of disease Medium 24878510
2014 ZPK/DLK and MKK4/MAP2K4 form a critical gateway to axotomy-induced motoneuron death in neonates; deletion of either ZPK/DLK or MKK4 doubles facial motoneuron numbers and renders them completely resistant to axotomy; MKK7 plays a synergistic but non-essential role in axotomy-induced death Genetic knockout mice (ZPK/DLK KO, MKK4 conditional KO, MKK7 conditional KO), facial motoneuron counting, axotomy survival assay The Journal of neuroscience : the official journal of the Society for Neuroscience High 25100604
2015 DLK is palmitoylated at a conserved site adjacent to its kinase domain; palmitoylation targets DLK to trafficking vesicles, is required to assemble DLK signaling complexes, and is essential for DLK kinase activity; palmitoylation-deficient DLK cannot mediate retrograde injury signaling in sensory axons; homologous kinases that lack this palmitoylation site cannot compensate shRNA knockdown/rescue with palmitoylation-site mutants, acyl-resin assisted capture (Acyl-RAC) palmitoylation assay, live vesicle imaging, in vitro kinase assay, retrograde signaling assay in sensory neurons Proceedings of the National Academy of Sciences of the United States of America High 26719418
2015 Pharmacological disruption of actin or microtubule cytoskeleton in mammalian sensory neurons activates the DLK pathway independently of calcium influx or axon degeneration; DLK pathway activation by cytoskeletal perturbation induces a pro-regenerative state and enhances subsequent axon regeneration; DLK is required for these responses Pharmacological cytoskeletal disruption, DLK pathway activity assay (pJNK/pJun), DLK siRNA knockdown, axon regeneration assay Neurobiology of disease Medium 25726747
2016 cAMP/PKA directly activates DLK (Wnd) as a conserved upstream kinase in injured axons; PKA is required for DLK/Wnd signaling activation after injury; DLK is essential for the regenerative effects of cAMP in mammalian DRG neurons; this places cAMP/PKA upstream of DLK in an evolutionarily conserved regeneration pathway Genetic epistasis in Drosophila (PKA loss-of-function and gain-of-function), DLK knockout DRG neurons, cAMP-induced regeneration assay, immunoblot for pathway activation eLife High 27268300
2018 HSP90 physically binds DLK and acts as its chaperone; HSP90 inhibition leads to rapid degradation of existing DLK protein; HSP90 is required for DLK stability in vivo in sciatic nerve; this mechanism is evolutionarily conserved (Drosophila Hsp83 knockdown decreases Wallenda/DLK levels) Co-immunoprecipitation (HSP90-DLK), pharmacological HSP90 inhibition, in vivo DLK protein level measurement, Drosophila genetic knockdown Proceedings of the National Academy of Sciences of the United States of America High 30275300
2019 DLK activation reduces levels of axon survival factors NMNAT2 and SCG10 in axons and thereby predisposes axons to SARM1-dependent degeneration; mitochondrial dysfunction independently decreases NMNAT2 and SCG10, and combined with DLK activation leads to spontaneous axon degeneration DLK gain-of-function, DLK inhibition, NMNAT2/SCG10 immunoblot in severed axons, SARM1 KO epistasis Molecular neurobiology Medium 31696428
2019 DLK is required for the neuronal intrinsic immune response after nerve injury; sensory neuron-specific DLK deletion blocks injury-induced upregulation of cytokines/chemokines (Ccl2, Ccl7, Ccl12), reduces CD11b+ immune cell infiltration in DRG, attenuates spinal microgliosis/astrogliosis, and dramatically alleviates neuropathic pain Wnt1a-Cre conditional DLK knockout, sciatic nerve CCI model, qRT-PCR for cytokines, immunohistochemistry for immune cells and glia, pain behavioral assays Experimental neurology Medium 31494101
2009 Par-4 is an essential downstream target of DLK in apoptosis induction: Dlk phosphorylates Par-4 at T155 in vitro; T155 phosphorylation is essential for apoptosis induction in vivo; Par-4 T155A mutant prevents Dlk from fully localizing to actin filaments and abolishes apoptosis; phospho-T155 Par-4 detected in vivo In vitro kinase assay with Par-4 phosphorylation mutants, co-expression in REF52.2 cells, phosphospecific Par-4 antibody, confocal microscopy Molecular biology of the cell High 19625447
2005 DLK in Drosophila (Wallenda) is regulated by the E3 ubiquitin ligase Highwire and an associated F-box protein DFsn; DFsn binds Highwire and regulates Wallenda/DLK protein levels; loss of DFsn causes synaptic terminal overgrowth dependent on elevated Wallenda, phenocopying highwire mutants Genetic interaction analysis, immunoblot for Wallenda protein levels, co-immunoprecipitation (DFsn-Highwire), Drosophila NMJ analysis Neural development Medium 17697379
2020 MAP3K12 (DLK) activity is required for the DLK/JNK pathway-dependent wave of HSV-1 lytic gene expression during reactivation from latency; DLK-dependent reactivation involves histone phosphorylation and is independent of histone demethylase activity; neuronal hyperexcitability (induced by IL-1β or forskolin) triggers DLK-dependent HSV-1 reactivation DLK inhibitor treatment, pharmacological and genetic manipulation of neuronal excitability, HSV-1 reporter virus, histone phosphorylation assay, latently infected mouse neurons eLife Medium 33350386
2020 MAP3K12 (Dlk) associates with and activates JNK3 (not other JNK isoforms) to stimulate expression of cyclins Ccnd1 and Ccnd2, driving postnatal beta-cell proliferation; silencing Dlk or JNK3 in neonatal islet cells dramatically reduces beta-cell replication and cyclin expression Co-immunoprecipitation (Dlk-Jnk3), siRNA knockdown of Dlk/Jnk3, STK activity assay, primary beta-cell replication assay, immunofluorescence for Dlk subcellular localization Cellular and molecular life sciences : CMLS Medium 32189007
2022 DLK and LZK together (but not individually) are required for PTEN deletion-induced corticospinal tract axon regeneration and compensatory sprouting after spinal cord injury; DLK/LZK deletion does not interfere with PTEN/mTOR signaling, indicating injury signaling and regenerative competence are independent pathways Inducible neuronal double-knockout mice (DLK and LZK), PTEN conditional deletion, CST axon tracing, mTOR pathway analysis by immunoblot The Journal of neuroscience : the official journal of the Society for Neuroscience High 35361703
2022 JNK3 catalyzes positive feedback phosphorylation of DLK that further activates DLK, locking the DLK-JNK3 module in a highly active state; both DLK and JNK3 (but not JNK1/2) are endogenously palmitoylated, targeting them to the same axonal vesicles; JNK3 palmitoylation is essential for axonal retrograde signaling after optic nerve crush in vivo In vitro kinase assay (positive feedback phosphorylation), Acyl-RAC palmitoylation assay, co-vesicle localization imaging, JNK3 palmitoylation-site mutant rescue in optic nerve crush model Science signaling High 35349303
2023 DLK-JNK signaling mediates regulated degradation of stathmin-3 (Stmn3) in axons; the Stmn2 membrane-targeting domain (driven by palmitoylation) is necessary and sufficient for localization to a specific vesicle population and confers sensitivity to DLK-dependent degradation; palmitoylation is critical for Stmn-mediated axon protection Structure-function mutagenesis of Stmn2, live imaging of Stmn2/Stmn3 vesicles, DLK inhibitor treatment, axon degeneration assay in primary sensory neurons The Journal of biological chemistry Medium 37236359
2024 Chronic demyelination activates kinases downstream of DLK and leads to c-Jun phosphorylation in neuronal nuclei followed by neuronal apoptosis; pharmacological DLK inhibition or genetic DLK disruption blocks c-Jun phosphorylation and prevents demyelination-induced neuronal apoptosis Genetic mouse models of inducible demyelination, DLK pharmacological inhibition, DLK genetic disruption, immunofluorescence for pJNK/p-c-Jun, TUNEL apoptosis assay Nature communications High 39443516

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 The DLK-1 kinase promotes mRNA stability and local translation in C. elegans synapses and axon regeneration. Cell 294 19737525
2005 Regulation of a DLK-1 and p38 MAP kinase pathway by the ubiquitin ligase RPM-1 is required for presynaptic development. Cell 282 15707898
2003 Isolation of hepatoblasts based on the expression of Dlk/Pref-1. Journal of cell science 279 12665558
2013 DLK initiates a transcriptional program that couples apoptotic and regenerative responses to axonal injury. Proceedings of the National Academy of Sciences of the United States of America 268 23431164
2010 Calcium and cyclic AMP promote axonal regeneration in Caenorhabditis elegans and require DLK-1 kinase. The Journal of neuroscience : the official journal of the Society for Neuroscience 246 20203177
2010 Protein turnover of the Wallenda/DLK kinase regulates a retrograde response to axonal injury. The Journal of cell biology 229 20921142
1993 dlk, a putative mammalian homeotic gene differentially expressed in small cell lung carcinoma and neuroendocrine tumor cell line. The Journal of biological chemistry 181 8095043
2011 DLK induces developmental neuronal degeneration via selective regulation of proapoptotic JNK activity. The Journal of cell biology 180 21893599
2004 dlk acts as a negative regulator of Notch1 activation through interactions with specific EGF-like repeats. Experimental cell research 177 15652348
2000 The role of the epidermal growth factor-like protein dlk in cell differentiation. Histology and histopathology 149 10668203
2003 Novel mitosis-specific phosphorylation of histone H3 at Thr11 mediated by Dlk/ZIP kinase. Nucleic acids research 143 12560483
1994 Protein structure of fetal antigen 1 (FA1). A novel circulating human epidermal-growth-factor-like protein expressed in neuroendocrine tumors and its relation to the gene products of dlk and pG2. European journal of biochemistry 138 7925474
2000 Suppression of chromosome segregation defects of Escherichia coli muk mutants by mutations in topoisomerase I. Proceedings of the National Academy of Sciences of the United States of America 137 10660686
1996 Activation of the JNK pathway by distantly related protein kinases, MEKK and MUK. Oncogene 127 8637721
2013 JNK-mediated phosphorylation of DLK suppresses its ubiquitination to promote neuronal apoptosis. The Journal of cell biology 126 23979718
1996 Dual leucine zipper-bearing kinase (DLK) activates p46SAPK and p38mapk but not ERK2. The Journal of biological chemistry 126 8798750
2008 Origin, evolution, and biological role of miRNA cluster in DLK-DIO3 genomic region in placental mammals. Molecular biology and evolution 118 18281269
1999 Adipocyte differentiation is modulated by secreted delta-like (dlk) variants and requires the expression of membrane-associated dlk. Differentiation; research in biological diversity 112 10234807
2009 Histologic subtypes of hepatoblastoma are characterized by differential canonical Wnt and Notch pathway activation in DLK+ precursors. Human pathology 110 19200579
2013 The DLK signalling pathway--a double-edged sword in neural development and regeneration. EMBO reports 102 23681442
2015 Cytoskeletal disruption activates the DLK/JNK pathway, which promotes axonal regeneration and mimics a preconditioning injury. Neurobiology of disease 98 25726747
1998 Cloning and characterization of Dlk, a novel serine/threonine kinase that is tightly associated with chromatin and phosphorylates core histones. Oncogene 97 9840928
2015 Palmitoylation controls DLK localization, interactions and activity to ensure effective axonal injury signaling. Proceedings of the National Academy of Sciences of the United States of America 94 26719418
1999 Interaction partners of Dlk/ZIP kinase: co-expression of Dlk/ZIP kinase and Par-4 results in cytoplasmic retention and apoptosis. Oncogene 91 10602480
1999 The mixed lineage kinase DLK utilizes MKK7 and not MKK4 as substrate. The Journal of biological chemistry 88 10187804
2012 Regulation of DLK-1 kinase activity by calcium-mediated dissociation from an inhibitory isoform. Neuron 84 23141066
2012 A conditioning lesion protects axons from degeneration via the Wallenda/DLK MAP kinase signaling cascade. The Journal of neuroscience : the official journal of the Society for Neuroscience 80 22238096
2009 Impaired regenerative response of primary sensory neurons in ZPK/DLK gene-trap mice. Biochemical and biophysical research communications 79 19358824
2010 Dlk-1, a cell surface antigen on foetal hepatic stem/progenitor cells, is expressed in hepatocellular, colon, pancreas and breast carcinomas at a high frequency. Journal of biochemistry 77 20356822
2014 DLK-dependent signaling is important for somal but not axonal degeneration of retinal ganglion cells following axonal injury. Neurobiology of disease 74 24878510
2004 Long-term culture of hepatic progenitors derived from mouse Dlk+ hepatoblasts. Journal of cell science 74 15572411
1999 AATF, a novel transcription factor that interacts with Dlk/ZIP kinase and interferes with apoptosis. FEBS letters 74 10580117
2014 Dendrite injury triggers DLK-independent regeneration. Cell reports 72 24412365
2014 Discovery of dual leucine zipper kinase (DLK, MAP3K12) inhibitors with activity in neurodegeneration models. Journal of medicinal chemistry 69 25341110
2004 Expression of Dlk/Pref-1 defines a subpopulation in the oval cell compartment of rat liver. Gene expression patterns : GEP 68 15567716
2002 MAPK-upstream protein kinase (MUK) regulates the radial migration of immature neurons in telencephalon of mouse embryo. Development (Cambridge, England) 67 12223406
1998 Guanine-nucleotide exchange protein C3G activates JNK1 by a ras-independent mechanism. JNK1 activation inhibited by kinase negative forms of MLK3 and DLK mixed lineage kinases. The Journal of biological chemistry 65 9430657
2001 dlk inhibits stem cell factor-induced colony formation of murine hematopoietic progenitors: Hes-1-independent effect. Stem cells (Dayton, Ohio) 63 11209092
2019 DLK Activation Synergizes with Mitochondrial Dysfunction to Downregulate Axon Survival Factors and Promote SARM1-Dependent Axon Degeneration. Molecular neurobiology 61 31696428
2016 An evolutionarily conserved mechanism for cAMP elicited axonal regeneration involves direct activation of the dual leucine zipper kinase DLK. eLife 60 27268300
2013 Loss of the spectraplakin short stop activates the DLK injury response pathway in Drosophila. The Journal of neuroscience : the official journal of the Society for Neuroscience 60 24198375
2019 DLK regulates a distinctive transcriptional regeneration program after peripheral nerve injury. Neurobiology of disease 59 30735704
2007 DFsn collaborates with Highwire to down-regulate the Wallenda/DLK kinase and restrain synaptic terminal growth. Neural development 59 17697379
1995 dlk, pG2 and Pref-1 mRNAs encode similar proteins belonging to the EGF-like superfamily. Identification of polymorphic variants of this RNA. Biochimica et biophysica acta 59 7711066
2018 An axonal stress response pathway: degenerative and regenerative signaling by DLK. Current opinion in neurobiology 56 30053694
1998 Modulated expression of the epidermal growth factor-like homeotic protein dlk influences stromal-cell-pre-B-cell interactions, stromal cell adipogenesis, and pre-B-cell interleukin-7 requirements. Molecular and cellular biology 54 9710609
2010 DLK-1 as a marker to distinguish unrestricted somatic stem cells and mesenchymal stromal cells in cord blood. Stem cells and development 53 20331358
2001 Neurons in the monoaminergic nuclei of the rat and human central nervous system express FA1/dlk. Neuroreport 53 11742219
2002 The EGF-like homeotic protein dlk affects cell growth and interacts with growth-modulating molecules in the yeast two-hybrid system. Biochemical and biophysical research communications 50 11846389
2001 Dlk/ZIP kinase-induced apoptosis in human medulloblastoma cells: requirement of the mitochondrial apoptosis pathway. British journal of cancer 50 11742505
2020 Neuronal hyperexcitability is a DLK-dependent trigger of herpes simplex virus reactivation that can be induced by IL-1. eLife 49 33350386
2002 Sporadic diffuse lamellar keratitis (DLK) after LASIK. Cornea 49 12131030
1997 Glycosylation analysis and protein structure determination of murine fetal antigen 1 (mFA1)--the circulating gene product of the delta-like protein (dlk), preadipocyte factor 1 (Pref-1) and stromal-cell-derived protein 1 (SCP-1) cDNAs. European journal of biochemistry 49 9118998
2017 Selective Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12) with Activity in a Model of Alzheimer's Disease. Journal of medicinal chemistry 47 28929759
2002 dlk modulates mitogen-activated protein kinase signaling to allow or prevent differentiation. Experimental cell research 47 11900478
2015 Scaffold-Hopping and Structure-Based Discovery of Potent, Selective, And Brain Penetrant N-(1H-Pyrazol-3-yl)pyridin-2-amine Inhibitors of Dual Leucine Zipper Kinase (DLK, MAP3K12). Journal of medicinal chemistry 45 26431428
2005 Expression of MUK/DLK/ZPK, an activator of the JNK pathway, in the nervous systems of the developing mouse embryo. Gene expression patterns : GEP 45 15749080
2016 DLK-1, SEK-3 and PMK-3 Are Required for the Life Extension Induced by Mitochondrial Bioenergetic Disruption in C. elegans. PLoS genetics 44 27420916
1999 C-terminal truncation of Dlk/ZIP kinase leads to abrogation of nuclear transport and high apoptotic activity. Oncogene 43 10602474
2018 DLK proteins modulate NOTCH signaling to influence a brown or white 3T3-L1 adipocyte fate. Scientific reports 38 30446682
2000 MAPK upstream kinase (MUK)-binding inhibitory protein, a negative regulator of MUK/dual leucine zipper-bearing kinase/leucine zipper protein kinase. The Journal of biological chemistry 38 10801814
2016 Bortezomib, thalidomide, dexamethasone, and panobinostat for patients with relapsed multiple myeloma (MUK-six): a multicentre, open-label, phase 1/2 trial. The Lancet. Haematology 37 27843120
2014 RPM-1 uses both ubiquitin ligase and phosphatase-based mechanisms to regulate DLK-1 during neuronal development. PLoS genetics 37 24810406
2018 Aryl hydrocarbon receptor enhances the expression of miR-150-5p to suppress in prostate cancer progression by regulating MAP3K12. Archives of biochemistry and biophysics 36 30009782
2011 ZPK/DLK, a mitogen-activated protein kinase kinase kinase, is a critical mediator of programmed cell death of motoneurons. The Journal of neuroscience : the official journal of the Society for Neuroscience 36 21593306
2008 Calphostin C-induced apoptosis is mediated by a tissue transglutaminase-dependent mechanism involving the DLK/JNK signaling pathway. Cell death and differentiation 36 18497756
2013 Independent pathways downstream of the Wnd/DLK MAPKKK regulate synaptic structure, axonal transport, and injury signaling. The Journal of neuroscience : the official journal of the Society for Neuroscience 35 23904612
2024 Remyelination protects neurons from DLK-mediated neurodegeneration. Nature communications 33 39443516
2016 Novel DLK-independent neuronal regeneration in Caenorhabditis elegans shares links with activity-dependent ectopic outgrowth. Proceedings of the National Academy of Sciences of the United States of America 32 27078101
2015 MicroRNA-130a Targets MAP3K12 to Modulate Diabetic Endothelial Progenitor Cell Function. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 32 25999017
2005 The mitogen-activated protein kinase kinase kinase dual leucine zipper-bearing kinase (DLK) acts as a key regulator of keratinocyte terminal differentiation. The Journal of biological chemistry 32 15695824
2000 The mixed lineage kinase DLK is oligomerized by tissue transglutaminase during apoptosis. The Journal of biological chemistry 32 10922377
2018 Distinct homeostatic modulations stabilize reduced postsynaptic receptivity in response to presynaptic DLK signaling. Nature communications 31 29748610
2008 Delta-like 1 (Dlk-1), a novel marker of prostate basal and candidate epithelial stem cells, is downregulated by notch signalling in intermediate/transit amplifying cells of the human prostate. European urology 30 18375047
2018 HSP90 is a chaperone for DLK and is required for axon injury signaling. Proceedings of the National Academy of Sciences of the United States of America 29 30275300
2017 Restraint of presynaptic protein levels by Wnd/DLK signaling mediates synaptic defects associated with the kinesin-3 motor Unc-104. eLife 29 28925357
2005 Binding of Par-4 to the actin cytoskeleton is essential for Par-4/Dlk-mediated apoptosis. Experimental cell research 29 15817164
2014 RHGF-1/PDZ-RhoGEF and retrograde DLK-1 signaling drive neuronal remodeling on microtubule disassembly. Proceedings of the National Academy of Sciences of the United States of America 28 25359212
2008 Delta-like protein (DLK) is a novel immunohistochemical marker for human hepatoblastomas. Virchows Archiv : an international journal of pathology 28 18236070
2007 Negative regulation of MEKK1/2 signaling by serine-threonine kinase 38 (STK38). Oncogene 28 17906693
2019 Identification of Novel Inhibitors of DLK Palmitoylation and Signaling by High Content Screening. Scientific reports 26 30842471
2019 DLK mediates the neuronal intrinsic immune response and regulates glial reaction and neuropathic pain. Experimental neurology 26 31494101
2022 A Critical Role for DLK and LZK in Axonal Repair in the Mammalian Spinal Cord. The Journal of neuroscience : the official journal of the Society for Neuroscience 25 35361703
2017 DLK silencing attenuated neuron apoptosis through JIP3/MA2K7/JNK pathway in early brain injury after SAH in rats. Neurobiology of disease 25 28396258
2016 Tozasertib attenuates neuronal apoptosis via DLK/JIP3/MA2K7/JNK pathway in early brain injury after SAH in rats. Neuropharmacology 25 27084696
2015 DLK-1/p38 MAP Kinase Signaling Controls Cilium Length by Regulating RAB-5 Mediated Endocytosis in Caenorhabditis elegans. PLoS genetics 25 26657059
2009 Role of dual leucine zipper-bearing kinase (DLK/MUK/ZPK) in axonal growth. Neuroscience research 25 19808064
2001 The homeotic protein dlk is expressed during peripheral nerve development. FEBS letters 24 11749965
2003 Differential expression of Dlk-1 in bovine adipose tissue depots. Comparative biochemistry and physiology. Part B, Biochemistry & molecular biology 23 12568810
2000 Null mutation of the dam or seqA gene suppresses temperature-sensitive lethality but not hypersensitivity to novobiocin of muk null mutants. Journal of bacteriology 23 11004192
2022 Palmitoylation couples the kinases DLK and JNK3 to facilitate prodegenerative axon-to-soma signaling. Science signaling 22 35349303
2022 DLK-Dependent Biphasic Reactivation of Herpes Simplex Virus Latency Established in the Absence of Antivirals. Journal of virology 22 35608347
2010 A novel regulatory mechanism for Fgf18 signaling involving cysteine-rich FGF receptor (Cfr) and delta-like protein (Dlk). Development (Cambridge, England) 22 20023171
1996 Cell-specific expression of the ZPK gene in adult mouse tissues. DNA and cell biology 22 8769565
2023 The Stathmin-2 membrane-targeting domain is required for axon protection and regulated degradation by DLK signaling. The Journal of biological chemistry 21 37236359
2009 Par-4 is an essential downstream target of DAP-like kinase (Dlk) in Dlk/Par-4-mediated apoptosis. Molecular biology of the cell 21 19625447
2021 MiR-191-5p alleviates microglial cell injury by targeting Map3k12 (mitogen-activated protein kinase kinase kinase 12) to inhibit the MAPK (mitogen-activated protein kinase) signaling pathway in Alzheimer's disease. Bioengineered 19 34818971
2020 The Map3k12 (Dlk)/JNK3 signaling pathway is required for pancreatic beta-cell proliferation during postnatal development. Cellular and molecular life sciences : CMLS 19 32189007
2014 ZPK/DLK and MKK4 form the critical gateway to axotomy-induced motoneuron death in neonates. The Journal of neuroscience : the official journal of the Society for Neuroscience 19 25100604
2001 Specific regions of the extracellular domain of dlk, an EGF-like homeotic protein involved in differentiation, participate in intramolecular interactions. Frontiers in bioscience : a journal and virtual library 19 11689349

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