Affinage

MAP2K7

Dual specificity mitogen-activated protein kinase kinase 7 · UniProt O14733

Length
419 aa
Mass
47.5 kDa
Annotated
2026-06-10
100 papers in source corpus 57 papers cited in narrative 58 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 9/9 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAP2K7 (MKK7) is a JNK-specific dual-specificity MAP kinase kinase that constitutes the principal stress- and cytokine-activated arm of the SAPK/JNK signaling module (PMID:9384583, PMID:9372971). It directly phosphorylates and activates JNK/SAPK without engaging p38 or ERK, and it does so non-redundantly with MKK4: MKK7 selectively phosphorylates the threonine (Thr183) of the JNK activation loop while MKK4 targets the tyrosine (Tyr185), so the two kinases act synergistically to achieve full dual phosphorylation and maximal JNK activity (PMID:11062067, PMID:10715136, PMID:11418587). Genetic disruption established that MKK7 alone is required for JNK activation by proinflammatory cytokines, whereas combined loss of MKK4 and MKK7 is needed to block stress-induced activation (PMID:11390361). MKK7 sits downstream of diverse stimuli—TNFα, IL-1, Fas, Rac1, and antiviral MAVS signaling—and of multiple MAP3Ks including DLK, MLK2/MST, MLK3, and MEKK2/3 that preferentially feed MKK7 over MKK4 (PMID:9362518, PMID:9414114, PMID:10187804, PMID:10347227, PMID:9516438, PMID:24651600). Substrate engagement is governed by an N-terminal regulatory domain bearing three cooperative JNK-docking D-sites, and alternative splicing of exon 2 modulates this docking to tune pathway output (PMID:16533805, PMID:25737554, PMID:26443849). MKK7 activity is constrained by an array of direct regulators: GADD45β binds and blocks its catalytic/ATP pocket downstream of NF-κB (PMID:14743220, PMID:17485467), c-FLIPL blocks upstream MAP3K recruitment (PMID:17110930), TIPRL recruits PP2A to dephosphorylate it (PMID:22841785), and SUMOylation (reversed by SENP3) and RanBP2-mediated neddylation impose additional negative control (PMID:29352108, PMID:26364603), while Filamin A and DUSP22 scaffold MKK7 with its upstream and downstream partners (PMID:20156194, PMID:27711255). Through JNK–c-Jun, MKK7 couples oncogenic and genotoxic stress to p53 stability and CDC2-dependent G2/M cell cycle control, acting as a tumor suppressor and a negative regulator of hematopoietic proliferation via the p16INK4a axis (PMID:15039780, PMID:21317887, PMID:11560992). It is additionally essential for axon elongation, adult neuronal maintenance and axonal transport, and cardiomyocyte stress adaptation (PMID:22090513, PMID:28779160, PMID:21284947). Crystallographic and NMR studies have defined its catalytic-domain plasticity, an activating N-terminal regulatory helix, a covalent inhibitor site at Cys218, and an allosteric N-lobe pocket (PMID:25529738, PMID:32783966, PMID:25737554).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1997 High

    Establishing that a dedicated JNK-specific MAPKK existed answered whether JNK activation required a kinase distinct from the p38/JNK dual activator MKK4.

    Evidence Molecular cloning of MKK7/JNKK2 with in vitro kinase assays and Drosophila Hemipterous complementation across human and murine systems

    PMID:9312105 PMID:9372971 PMID:9384583

    Open questions at the time
    • Site-specificity of MKK7 versus MKK4 on the JNK activation loop not yet resolved
    • In vivo non-redundancy not yet demonstrated genetically
  2. 1997 Medium

    Mapping MKK7 to specific receptor inputs showed it is the JNK activator selectively engaged by death-receptor and cytokine signaling rather than a generic stress kinase.

    Evidence Immune-complex kinase assays with isoform-specific antisera in Fas-stimulated cells and IL-1-stimulated rabbit liver

    PMID:9362518 PMID:9414114

    Open questions at the time
    • Direct upstream MAP3K linking receptors to MKK7 not identified
    • Single-lab observations per stimulus
  3. 1999 High

    Identifying alternatively spliced isoforms and a JNK-binding N-terminal extension explained how MKK7 docks its substrate and how basal versus inducible activity is tuned.

    Evidence Molecular cloning of six isoforms with direct binding and kinase assays plus subcellular localization

    PMID:9891090

    Open questions at the time
    • Physiological triggers selecting specific isoforms not defined
    • Structural basis of docking not yet resolved
  4. 1999 High

    Defining the MAP3K tier showed that DLK, MLK2, and MEKK2/3 preferentially activate MKK7 over MKK4, establishing pathway selectivity at the kinase-cascade level.

    Evidence In vitro reconstitution kinase assays with recombinant proteins, co-IP, and column fractionation

    PMID:10187804 PMID:10347227 PMID:9516438

    Open questions at the time
    • Determinants of MAP3K substrate preference partly defined only for MLK2
    • Quantitative contribution of each MAP3K in vivo unknown
  5. 2000 High

    Demonstrating that MKK7 phosphorylates Thr183 while MKK4 phosphorylates Tyr185 resolved the mechanistic basis of their synergistic, non-redundant cooperation.

    Evidence In vitro kinase assays with phosphoamino-acid analysis and mass spectrometry across JNK isoforms

    PMID:10715136 PMID:11062067

    Open questions at the time
    • Whether sequential ordering of the two phosphorylations is obligatory not fully settled
    • Isoform-specific kinetics in cells not measured
  6. 2001 High

    Genetic knockout established the in vivo division of labor: MKK7 is essential for cytokine-induced JNK activation, while stress activation requires both MKK7 and MKK4.

    Evidence Targeted Mkk7 and Mkk4/Mkk7 gene disruption in mice with phospho-specific JNK readouts

    PMID:11390361 PMID:11418587

    Open questions at the time
    • Cell-type-specific differences in input dependence not fully mapped
    • Isoform-specific contributions not separable by knockout
  7. 2001 High

    Conditional deletion revealed MKK7 as a negative regulator of hematopoietic proliferation acting through the p16INK4a cell-cycle brake.

    Evidence Conditional gene targeting in thymocytes, B cells, and mast cells with p16INK4a reexpression rescue

    PMID:11560992

    Open questions at the time
    • Direct molecular link between JNK signaling and p16INK4a induction not defined
    • Whether effect generalizes beyond hematopoietic lineages unknown
  8. 2004 High

    Linking MKK7-JNK-c-Jun to CDC2 placed the pathway directly in control of G2/M progression and senescence, framing its cell-cycle function.

    Evidence Gene knockout in MEFs with cell cycle analysis and c-Jun mutant epistasis

    PMID:15039780

    Open questions at the time
    • Mechanism by which c-Jun regulates CDC2 not detailed
    • Connection to p16/p53 arms not integrated
  9. 2004 High

    Identifying GADD45β as a direct catalytic inhibitor explained how NF-κB suppresses JNK and protects against TNFα cytotoxicity.

    Evidence Unbiased screen, direct binding, kinase inhibition, and disrupting-peptide rescue; later refined by structural mapping of the ATP-pocket-engaging interface

    PMID:14743220 PMID:17485467 PMID:18343408 PMID:29572137

    Open questions at the time
    • Stoichiometry and full structure of the complex defined only by prediction/NMR, not crystallography
    • Regulation of GADD45β abundance in vivo incompletely defined
  10. 2006 High

    Systematic mapping of three cooperative N-terminal D-sites established the structural logic of MKK7–JNK substrate docking.

    Evidence Site-directed mutagenesis of all three docking sites with quantitative binding and kinase assays, later extended by NMR and crystallography

    PMID:16533805 PMID:25737554

    Open questions at the time
    • Functional consequence of distinct docking-site binding modes not fully resolved
    • Regulation of docking by phosphorylation/PTMs not addressed
  11. 2010 Medium

    Discovery of scaffolds and additional binding-partner regulators (Filamin A, RASSF7/N-Ras) showed how MKK7 is spatially organized and its output set by competing inputs.

    Evidence Co-IP, loss-of-function cell lines, domain mapping, and colocalization

    PMID:20156194 PMID:21278800

    Open questions at the time
    • RASSF7 mechanism (phospho-MKK7 yet inhibited JNK output) not mechanistically explained
    • Scaffold contributions in vivo not tested genetically
  12. 2011 High

    In vivo tumor models established MKK7 as a tumor suppressor coupling oncogenic stress to p53 stability through JNK1/2.

    Evidence Tissue-specific conditional knockout in KRas- and NeuT-driven tumor models with JNK1/JNK2 epistasis and p53 stability assays

    PMID:21317887

    Open questions at the time
    • Molecular step connecting JNK to p53 stabilization not defined
    • Relevance to human tumors with MAP2K7 alterations not established here
  13. 2011 High

    Conditional deletion in neurons and cardiomyocytes defined tissue-specific physiological roles in axon elongation, neuronal maintenance, and cardiac stress adaptation.

    Evidence Nestin-Cre and cardiomyocyte-specific knockouts with histology, axon assays, pressure-overload surgery, and JNK substrate immunoblots

    PMID:21284947 PMID:22090513 PMID:28779160

    Open questions at the time
    • Which JNK substrates dominate each phenotype not fully dissected
    • Cardiac and neuronal effects characterized in single labs
  14. 2012 High

    Local mRNA translation at the growth cone and a DLK–MKK7–JNK1 module showed MKK7 can act on cytoskeletal substrates (MAP1B) spatially uncoupled from nuclear transcription.

    Evidence Genome-wide neurite mRNA screen, mRNA localization imaging, and kinase-module manipulation

    PMID:23226105

    Open questions at the time
    • Regulation of localized translation by upstream signals not defined
    • Generality beyond neurons unknown
  15. 2014 High

    Identifying MAVS-mediated mitochondrial recruitment and selective JNK2 phosphorylation defined an antiviral apoptotic function for MKK7.

    Evidence Multiple genetic knockouts, MAVS domain mapping, mitochondrial fractionation, and viral challenge in mice

    PMID:24651600

    Open questions at the time
    • Basis for JNK2 versus JNK1 selectivity not mechanistically resolved
    • Interplay with other antiviral pathways not addressed
  16. 2014 High

    Druggability was established by targeting the GADD45β/MKK7 interface and by covalent occupancy of Cys218, opening therapeutic and chemical-biology avenues.

    Evidence DTP3 complex-disruption assays with xenografts, plus crystal structures of covalent inhibitor complexes and selective inhibitor development validated in knockout cells

    PMID:25314077 PMID:25529738 PMID:29572137 PMID:30449673

    Open questions at the time
    • Clinical translation of these agents not addressed in the corpus
    • Off-target/selectivity profiles defined only for specific scaffolds
  17. 2015 High

    A layered PTM code (SUMOylation/SENP3, RanBP2 neddylation, EEF1AKMT3 methylation) and CELF2/MBNL1-controlled exon-2 splicing revealed how MKK7 activity is set post-translationally and post-transcriptionally.

    Evidence Conditional knockouts, in vitro neddylation/SUMO assays, mass-spectrometric methylation-site identification, and splicing manipulation

    PMID:26364603 PMID:26443849 PMID:29352108 PMID:32601196 PMID:35753528

    Open questions at the time
    • Hierarchy and crosstalk among the different PTMs not integrated
    • In vivo importance of each modification context-limited
  18. 2020 High

    Comprehensive crystal structures defined catalytic-domain plasticity, an activating N-terminal regulatory helix, and an allosteric N-lobe pocket, providing a structural framework for MKK7 activation and inhibition.

    Evidence Comprehensive X-ray crystallography including an active-state model plus small-molecule screening and kinase assays

    PMID:32783966

    Open questions at the time
    • Structure of full-length MKK7 with regulatory domain and docked JNK not solved
    • Conformational dynamics during the activation cycle not fully captured

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple negative regulators, PTMs, scaffolds, and isoforms are integrated to set MKK7 output in a given cell type and stimulus, and how this is therapeutically exploitable beyond GADD45β disruption, remains unresolved.
  • No unified quantitative model of MKK7 regulation across inputs
  • Context-specific dominance of each regulator unknown
  • In vivo consequences of combined PTM perturbation untested

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 3 GO:0140657 ATP-dependent activity 3
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 2 GO:0005856 cytoskeleton 2 GO:0005739 mitochondrion 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1640170 Cell Cycle 2
Partners
DUSP22FLNAGADD45BMAP2K4MAP3K12MAPK8RASSF7TIPRL
Complex memberships
ASK1–MKK7–JNK (DUSP22-scaffolded)GADD45β–MKK7 inhibitory complexMKK4–MKK7–JNK complex

Evidence

Reading pass · 58 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 MKK7 (JNKK2) was cloned and identified as a novel MAPKK that is specific for the SAPK/JNK subgroup; unlike SEK1/MKK4, it does not activate p38. MKK7 directly phosphorylates and activates JNK/SAPK. It is activated by TNFα and environmental stresses, and immunochemical studies identified MKK7 as a major JNK-activating kinase in osmotically shocked cells. Overexpression of MKK7 enhanced AP-1-dependent transcription. Molecular cloning, immunoprecipitation, in vitro kinase assay, co-expression studies, reporter assay The EMBO journal High 9384583
1997 MKK7 was identified as a murine homolog of Drosophila Hemipterous; it functionally rescues hep mutant flies. In fibroblasts, MKK7 is activated by stress and by GTPase Rac1. MKK7 directly phosphorylates and activates JNK/SAPK. Molecular cloning, Drosophila complementation rescue, in vitro kinase assay, transfection in fibroblasts The Journal of biological chemistry High 9312105
1997 Human JNKK2 (MKK7) was cloned and shown to be a highly specific JNK kinase that does not activate p38 MAPK. Unlike JNKK1/MKK4, it is JNK-specific. Database search, cDNA cloning, co-expression kinase assay Molecular and cellular biology High 9372971
1997 MKK7 (but not SEK1/MKK4) is activated by Fas signaling as the upstream activator of JNK/SAPK; MKK6 is the major p38 activator in this pathway. JNK/SAPK activation in Fas signaling does not require CPP32-like proteases. Immune complex kinase assay, peptide inhibitor pharmacology, immunoprecipitation The Journal of cell biology High 9362518
1997 MKK7 is the activator of JNK/SAPK activated by IL-1 in rabbit liver; it is not activated by MKK4 antibodies. JNK/SAPK is the only MAPK activated by IL-1 in liver. S-Sepharose purification, immunoprecipitation with anti-MKK7 and anti-MKK4 antisera, kinase assay FEBS letters Medium 9414114
1998 Human MKK7 (47 kDa) specifically phosphorylates and activates JNK1 but fails to activate p38 MAPK in co-expression studies. MKK7 is activated in hematopoietic cells by IL-3, CD40 ligation, B-cell antigen receptor, FcR, heat, UV, anisomycin, hyperosmolarity, TNFα, and by constitutively active Ras, Rac, and Cdc42. Molecular cloning, co-expression, immunoprecipitation kinase assay The Journal of biological chemistry High 9535930
1998 MKK7 plays a major role in SAPK/JNK activation in T lymphocytes responding to TCR/co-stimulation. Dominant-negative MKK7 abrogated transcriptional activation of the distal NFAT response element in the IL-2 promoter. Both the MKK6-p38 and MKK7-JNK pathways are activated in a cyclosporin A-sensitive manner and contribute to IL-2 gene expression. Dominant-negative transfection, reporter assay, kinase assay The Journal of biological chemistry Medium 9575191
1999 The MKK7 gene encodes six isoforms (α1/2, β1/2, γ1/2) by alternative splicing with three different N-termini and two C-termini. The N-terminal extension (absent in MKK7α) binds directly to the MKK7 substrate JNK. MKK7α isoforms show lower basal activity but higher inducible fold-activation than β and γ isoforms. MKK7 is detected in both cytoplasmic and nuclear compartments, but nuclear localization is not required for JNK activation in vivo. Molecular cloning, yeast two-hybrid/direct binding, kinase assay, immunofluorescence Molecular and cellular biology High 9891090
1999 DLK (dual leucine zipper-bearing kinase) associates with, phosphorylates, and activates MKK7 in vitro and in vivo, but unlike MLK3 does not phosphorylate or activate MKK4. DLK and MKK7 co-localize in neurons and occupy similar subcellular compartments, distinct from MKK4. In vitro kinase assay, co-immunoprecipitation, immunocytochemistry, subcellular fractionation The Journal of biological chemistry High 10187804
1999 MEKK3 (and MEKK2) directly activates MKK7 and MKK6 in vitro; immunoprecipitates of MEKK3 phosphorylate recombinant MKK7 in vitro. Coexpression of MKK7 with MEKK3 in COS-7 cells enhanced MKK7 autophosphorylation and its ability to activate JNK1. Co-expression, in vitro kinase assay with recombinant proteins, immunoprecipitation The Journal of biological chemistry High 10347227
1999 MST/MLK2 activates recombinant MKK7 more effectively than recombinant SEK1/MKK4 in vitro. The majority of MLK2-dependent JNK-activating activity co-fractionates with MKK7, not MKK4. The MLK2 kinase domain determines this substrate specificity. In vitro reconstitution kinase assay, column fractionation, Western blot The Journal of biological chemistry Medium 9516438
1999 A JNKK2-JNK1 fusion protein acts as a constitutively active Jun kinase; JNK1 is phosphorylated by JNKK2 at both Thr183 and Tyr185 in the fusion. The fusion protein is specific for the JNK pathway (does not activate p38 or ERK2) and is sufficient to stimulate c-Jun transcriptional activity. The fusion protein localizes predominantly to the nucleus. Fusion protein construction, immunoblotting with phospho-specific antibodies, in vitro kinase assay, reporter assay, immunofluorescence The Journal of biological chemistry High 10506143
1999 G protein βγ subunit activates MKK7 by ~2-fold in a Rac-dependent manner; this is distinct from Gbγ-induced MKK4 activation which depends on Rho and Cdc42. MKK7 activation by Gbγ is not blocked by tyrosine kinase inhibitors PP2/PP1, unlike MKK4 activation. Transfection with kinase-deficient mutants, dominant-negative GTPases, kinase activity assay The Journal of biological chemistry Medium 9890951
2000 MKK4 shows a striking preference for phosphorylating Tyr185 of SAPK1/JNK isoforms, while MKK7 shows a striking preference for Thr183. Together, MKK4 and MKK7 produce a synergistic increase in JNK activity in vitro. MKK7β is several hundred-fold more efficient than MKK7α' in activating JNK isoforms. In vitro kinase assay, phosphoamino acid analysis, mass spectrometry The Biochemical journal High 11062067
2000 MKK7 monophosphorylates JNK3α1 at Thr183 (Thr residue) in vitro; both MKK4 and MKK7 are required for bisphosphorylation and maximal enzyme activity of JNK3α1. MKK4 alone shows no phosphorylation of JNK3α1 by mass spectrometry. In vitro kinase assay, mass spectral phosphorylation analysis, kinetic measurements Biochemistry High 10715136
2001 Genetic disruption of Mkk7 alone was sufficient to prevent JNK activation by proinflammatory cytokines, whereas simultaneous disruption of Mkk4 and Mkk7 was required to block JNK activation by environmental stress. MKK7 preferentially phosphorylates JNK on Thr and MKK4 on Tyr. Targeted gene disruption (knockout mice), JNK kinase assay, phospho-specific analysis Genes & development High 11390361
2001 MKK7 is an essential and specific regulator of SAPK/JNK activation in hematopoietic cells. Loss of MKK7 in thymocytes, mature B cells, and mast cells causes hyperproliferation; SAPK/JNK activation was completely abolished in mkk7−/− mast cells despite normal MKK4 phosphorylation. MKK7 negatively regulates proliferation through a pathway involving p16INK4a; reexpression of p16INK4a abrogates the hyperproliferative response. Conditional gene targeting, kinase assay, flow cytometry, Western blotting, reexpression rescue The Journal of experimental medicine High 11560992
2001 PKCδ mediates ionizing radiation-induced JNK activation through MKK7 (not MKK4) in human thyroid cells. IR activates MKK7 but not MKK4; this was blocked by the PKCδ inhibitor rottlerin and by kinase-deficient MKK7, defining a PKCδ→MKK7→JNK→AP-1 cascade. Dominant-negative adenoviral expression, immune-complex kinase assay, pharmacological inhibitor Oncogene Medium 11314034
2001 SEK1 (MKK4) and MKK7 show synergistic SAPK/JNK activation in embryonic stem cells. MKK7 is responsible for Thr phosphorylation of JNK; without MKK7, Thr phosphorylation is lost but Tyr phosphorylation remains. MKK7α1 requires prior Tyr phosphorylation by SEK1 before it can phosphorylate JNK Thr; MKK7γ1 phosphorylates Thr independently; MKK7γ2 can phosphorylate both Thr and Tyr. Knockout ES cells, dual phosphorylation analysis, co-transfection with kinase-dead mutants The Journal of biological chemistry High 11418587
2002 SKRP1, a novel dual-specificity phosphatase, interacts with MKK7 (co-precipitation in vitro and in vivo) and inactivates the JNK pathway by dephosphorylating JNK. SKRP1 does not bind directly to JNK but gains access to it through MKK7. SKRP1 does not interfere with MKK7-JNK co-precipitation. Co-immunoprecipitation, in vitro binding assay, in vitro phosphatase assay, overexpression The Journal of biological chemistry Medium 11959861
2002 ZAK MAP3K utilizes MKK7 (not MKK4) to activate JNK/SAPK; dominant-negative MKK7 (but not MKK4) attenuated ZAK-induced JNK activation. ZAK activity disrupts actin stress fibers and causes G2/M cell cycle arrest. Co-expression, dominant-negative kinase mutants, flow cytometry, Western blot Biochemical and biophysical research communications Low 12220515
2003 In fibroblast-like synoviocytes, JNK, MKK4, and MKK7 form a stable complex detectable by co-immunoprecipitation, and MKK4 co-precipitates with MKK7. The complex localizes in the cytoplasm by confocal microscopy; JNK migrates to the nucleus after IL-1 stimulation. The complex is functionally active and phosphorylates c-Jun after IL-1. Co-immunoprecipitation, confocal microscopy, in vitro kinase assay Arthritis and rheumatism Medium 13130464
2003 In mkk7−/− embryonic stem cells, Thr phosphorylation of JNK is lost while Tyr phosphorylation remains. In 293T cells, SEK1-induced Tyr phosphorylation of JNK1 is followed by additional Thr phosphorylation by MKK7. SEK1 (but not MKK7) binds to JNK1 in 293T cells, indicating sequential rather than independent phosphorylation. Knockout ES cells, phospho-specific immunoblot, co-immunoprecipitation, Thr-Pro-Phe JNK1 mutant The Journal of biological chemistry High 12624093
2004 GADD45β mediates NF-κB suppression of JNK signaling by directly binding MKK7 and blocking its catalytic activity. Gadd45β binds MKK7 directly; peptides disrupting the GADD45β/MKK7 interaction hinder the ability of both GADD45β and NF-κB to suppress TNFα-induced cytotoxicity. Unbiased screen, direct binding assay, kinase activity assay, peptide disruption, cell viability assay Nature cell biology High 14743220
2004 MKK7 couples stress signaling to G2/M cell cycle progression and cellular senescence. Genetic inactivation of MKK7 in MEFs leads to premature senescence and G2/M cell cycle arrest. The CDC2 kinase is a downstream target of the MKK7-JNK-c-Jun pathway; loss of c-Jun or JNK phosphorylation sites on c-Jun produces the same G2/M block. Gene knockout (MEFs), cell cycle analysis, epistasis with c-Jun mutants, CDC2 target identification Nature cell biology High 15039780
2005 MLK3 activates MKK7 in the MLK3→MKK7→JNK cascade in hippocampal CA1 neurons after cerebral ischemia; K252a (MLK3 inhibitor) blocked MKK7 and JNK3 activation and was neuroprotective. In vivo ischemia model, immunoprecipitation kinase assay, pharmacological inhibition Neuroscience Medium 15680699
2006 MKK7 contains three JNK-docking D-sites (D1, D2, D3) in its N-terminal domain that cooperatively promote binding to JNK1. Mutation of any single site reduces binding by 50–70%; mutation of all three reduces binding by 95%. Full-length MKK7 with D1/D2 mutations has reduced JNK1 kinase activation. D-site peptides from MKK7 inhibit JNK1 and JNK2 substrate phosphorylation selectively over ERK2. Site-directed mutagenesis, binding assay, JNK kinase assay, peptide inhibition The Journal of biological chemistry High 16533805
2006 c-FLIPL directly interacts with MKK7 in a TNFα-dependent manner and inhibits the interactions of MKK7 with MEKK1, ASK1, and TAK1. This interaction selectively suppresses the prolonged phase of JNK activation and reduces ROS accumulation in NF-κB-deficient fibroblasts. Co-immunoprecipitation, Western blot, c-Flip knockout cells, overexpression The EMBO journal Medium 17110930
2006 In fibroblast-like synoviocytes, IL-1β-induced JNK phosphorylation and activity (measured by kinase assay), AP-1 binding, AP-1-driven transcription, and MMP-3 production are dependent on MKK7 but not MKK4. Anisomycin-induced JNK activation requires both MKK4 and MKK7. siRNA knockdown, in vitro kinase assay, EMSA, AP-1 reporter assay, ELISA Arthritis and rheumatism High 16802349
2007 GADD45β is a structured protein whose helices α3/α4 and loops 1/2 mediate association with MKK7. Helix α3 primarily mediates docking; loop 1 and α4-loop 2 engage the ATP-binding site of MKK7 and cause conformational changes that impede catalytic function. Structural prediction, mutagenesis, binding/inhibition assays The Journal of biological chemistry Medium 17485467
2008 GADD45β forms homodimers in solution (via helices 1 and 5) and binds tightly to MKK7; the dimerization interface (helices 1 and 5) is distinct from the MKK7-binding region. The complex may form at least a tetrameric MKK7–GADD45β:GADD45β–MKK7 unit. Size exclusion chromatography, NMR, biophysical binding assays Journal of molecular biology Medium 18343408
2008 The IL-1–MKK7–JNK–c-Jun signaling pathway induces EGR-1 transcription via an AP-1 site and three distal SREs. c-Jun is required for EGR-1 transcription through both elements; IL-1-inducible c-Jun recruitment to both AP-1 and SRE regions was confirmed by ChIP. EGR-1 in turn binds promoters of IL-6, IL-8, and CCL2. JNK-MKK7 fusion protein, genome-wide microarray, qPCR, reporter assay, chromatin immunoprecipitation, siRNA knockdown The Journal of biological chemistry High 18281687
2009 Rac1/MKK7/JNK signaling upregulates Atg5 in response to oncogenic H-Ras, which is critically required for autophagic cell death. Inhibition of MKK7 (but not MKK4) attenuated H-Ras(V12)-induced JNK activation; Rac1 siRNA or dominant-negative Rac1 inhibited MKK7-JNK activation and Atg5 upregulation. siRNA knockdown, dominant-negative GTPase, immunoblotting, cell death assays Carcinogenesis Medium 19783847
2010 Filamin A (and B, C) binds to MKK7 (specifically to the N-terminal residues 31–60 present in MKK7β and MKK7γ but not MKK7α) and also binds MKK4, connecting them in close proximity. MKK7γ (but not MKK7α) co-localizes with actin stress fibers and Filamin A. In Filamin A-deficient cells, MKK7 activation is reduced and stress-induced synergistic JNK activation is impaired. Co-immunoprecipitation, Filamin A-deficient cell line, deletion mutant analysis, confocal microscopy, kinase assay The Biochemical journal High 20156194
2011 MKK7 acts as a tumor suppressor coupling oncogenic/genotoxic stress to p53 stability in vivo. Tissue-specific inactivation of MKK7 in KRas(G12D)-driven lung and NeuT-driven mammary tumors markedly accelerates tumor onset. Mechanistically, MKK7 acts through JNK1 and JNK2, and this pathway directly couples oncogenic stress to p53 stability, required for cell cycle arrest. Conditional knockout (tissue-specific), tumor model, epistasis with JNK1/JNK2 knockouts, p53 stability assays Nature genetics High 21317887
2011 MKK7-deficient MEFs display premature senescence and G2/M arrest; MKK7 deletion in cardiomyocytes leads to heart failure under pressure overload with increased apoptosis (elevated p53, reduced MnSOD) and fibrosis (upregulated TGF-β signaling). Cardiomyocyte-specific conditional knockout, pressure overload surgery, cell death assays, Western blot Journal of molecular and cellular cardiology Medium 21284947
2011 In mkk7−/− mast cells, expression of JunB and p16INK4a are reduced and cyclin D1 is upregulated; reexpression of p16INK4a abrogates the hyperproliferative response. MKK7-regulated JNK signaling thus maintains cell cycle brakes via the p16INK4a axis. Gene knockout, flow cytometry, Western blot, adenoviral reexpression rescue The Journal of experimental medicine Medium 11560992
2011 Neuron-specific deletion of MKK7 impairs brain development: mice show enlarged ventricles, reduced striatum, absent axon tracts, and abnormal filamentous accumulations. MKK7 regulates axon elongation in a cell-autonomous manner and is required for contralateral axon projection by cortical neurons. JNK substrate phosphorylation (c-Jun, neurofilament heavy chain, MAP1B, doublecortin) is reduced in MKK7-deficient brain. Nestin-Cre conditional knockout, histology, electron microscopy, in utero electroporation, in vitro axon elongation assay, immunoblot of JNK substrates The Journal of neuroscience High 22090513
2012 MKK7 mRNA localizes to the growth cone where it can be translated. MKK7 protein is phosphorylated specifically in the neurite shaft and is part of a DLK–MKK7–JNK1 module that triggers MAP1b phosphorylation to regulate microtubule bundling and neurite elongation. This local translation mechanism positions JNK signaling to microtubule regulation while uncoupling it from nuclear/transcriptional functions. Genome-wide screen for neurite-enriched mRNAs, FISH/imaging for mRNA localization, live cell imaging, immunofluorescence, pharmacological and genetic manipulation PLoS biology High 23226105
2012 TIPRL (TOR signaling pathway regulator-like protein) binds to MKK7 and promotes the interaction between MKK7 and PP2Ac (protein phosphatase 2A catalytic subunit), resulting in dephosphorylation/inactivation of MKK7 and JNK, thereby conferring resistance to TRAIL-induced apoptosis in HCC cells. Co-immunoprecipitation, GST pulldown, siRNA knockdown, phospho-immunoblot, confocal microscopy Gastroenterology High 22841785
2013 Neuregulin/ErbB2 signaling activates Rac1, which activates MKK7 and JNK to upregulate c-Jun and downregulate Krox20 during Schwann cell dedifferentiation after nerve injury. Rac inhibition blocked MKK7 activation and c-Jun induction in sciatic nerves after axotomy. Primary Schwann cell culture, pharmacological Rac inhibition, immunoblot, ErbB2 inhibitor, microarray, axotomy model Glia Medium 23505039
2014 GADD45β/MKK7 interaction was identified as a therapeutic target in multiple myeloma. DTP3, a D-tripeptide, disrupts the GADD45β/MKK7 complex, restores MKK7/JNK kinase activity, and kills MM cells selectively. DTP3 ablates myeloma xenografts in mice. Drug discovery/screening, co-immunoprecipitation disruption assay, JNK kinase assay, cell viability, xenograft mouse model Cancer cell High 25314077
2014 MAVS recruits MKK7 onto mitochondria via its 3D domain upon viral infection. MKK7 subsequently phosphorylates JNK2 (not JNK1) to activate virus-induced apoptosis. Mkk7−/− cells fail to initiate virus-induced apoptosis; MAVS-MKK7-JNK2 defines a novel antiviral apoptotic pathway. Knockout cell lines (Mkk7−/−, Jnk1−/−, Jnk2−/−), co-immunoprecipitation, mitochondrial fractionation, viral challenge, Jnk2−/− mice PLoS pathogens High 24651600
2014 5Z-7-Oxozeaenol covalently binds to MAP2K7 at Cys218 (located at the end of the hinge region), not at the gatekeeper-2 cysteine, as revealed by crystal structure of the MAP2K7/5Z7O complex. X-ray crystallography Bioorganic & medicinal chemistry letters High 25529738
2015 NMR spectroscopy revealed the conformational behavior of the MKK7 regulatory domain: three docking sites (D1, D2, D3) show diverse intrinsic conformational propensities and different interaction kinetics with JNK1, though similar affinities. Crystal structure of JNK1 in complex with the second D-site of MKK7 revealed two different binding modes correlating with NMR exchange spectroscopy observations. NMR spectroscopy (atomic-resolution ensemble), X-ray crystallography PNAS High 25737554
2015 MKK7 alternative splicing during T-cell activation (skipping exon 2, mediated by CELF2 RNA-binding protein) restores a JNK-docking site disrupted in the larger isoform, enhancing JNK pathway activity (c-Jun phosphorylation, TNF-α upregulation). This splicing event is itself JNK-dependent, creating a positive feedback loop. Alternative splicing analysis, CELF2 knockdown/overexpression, phospho-immunoblot, CLIP/RNA binding assay Genes & development High 26443849
2015 Knockdown of MKK7 or ASK1 blocked DSS-induced tight junction disruption and barrier dysfunction. A Ca2+/Ask1/MKK7/JNK2/c-Src signaling cascade mediates DSS-induced tight junction disruption; JNK2-dependent Src activation leads to tyrosine phosphorylation of junctional proteins. siRNA knockdown, intracellular Ca2+ measurement, in vitro kinase assay with recombinant JNK2 and c-Src, mouse colitis model The Biochemical journal Medium 25377781
2016 DUSP22 acts as a scaffold protein for the ASK1–MKK7–JNK signal transduction pathway by selectively associating with ASK1, MKK7, and JNK1/2; it increases JNK phosphorylation independently of its phosphatase activity. Co-immunoprecipitation, overexpression of phosphatase-dead mutant, JNK kinase assay PloS one Medium 27711255
2016 KLF4 transcriptionally represses the MAP2K7 gene. In T-ALL cells with KLF4 inactivation, aberrant activation of MAP2K7 and downstream JNK and ATF2 occurs. JNK inhibitors reduce expansion of leukemia cells in patient-derived xenograft models. ChIP/gene expression, CRISPR/shRNA knockdown, xenograft model, phospho-immunoblot Leukemia Medium 27872496
2018 SENP3-mediated deSUMOylation of MKK7 (SUMO2/3 removal) favors MKK7 binding to JNK and potentiates LPS-induced JNK phosphorylation and inflammatory cytokine production. SENP3 deficiency impairs MKK7 activity and JNK phosphorylation; ROS-dependent SENP3 accumulation after LPS drives MKK7 deSUMOylation. Conditional knockout mice, co-immunoprecipitation, in vivo and in vitro SUMO assay, phospho-immunoblot, septic shock model The Journal of biological chemistry High 29352108
2018 Covalent virtual screening identified selective covalent MKK7 inhibitors. Crystal structure of lead compound bound to MKK7 confirmed the predicted binding mode. Inhibitors block JNK phosphorylation in cells, validated using MKK7 knockout cell lines, and block B-cell activation by LPS. Covalent virtual screening, X-ray crystallography, kinase selectivity panel (76 kinases), proteomics, knockout cell line validation Cell chemical biology High 30449673
2018 Chemical cross-linking mass spectrometry showed that the GADD45β–MKK7 interaction largely occurs between GADD45β loop 2 (residues 103–117) and the MKK7 kinase enzymatic pocket. DTP3 disrupts this interaction by contacting MKK7 peptides 113–136 and 259–274. Chemical cross-linking mass spectrometry (CX-MS), enzymatic MS footprinting, fluorescence quenching with truncation mutants International journal of biological macromolecules Medium 29572137
2020 Crystal structures of MKK7 revealed the structural basis of catalytic domain plasticity and the role of the N-terminal regulatory helix in mediating kinase activation (active-state structure). An allosteric pocket in the N-terminal lobe was identified where ibrutinib binds. Type II irreversible inhibitor binding mode and multiple novel scaffolds were identified. X-ray crystallography (comprehensive set of structures), small-molecule screening, biochemical kinase assays Cell chemical biology High 32783966
2020 A MAP2K7 splice variant lacking exon 2 (MAP2K7Δexon2), induced by loss of MBNL1, activates JNK and promotes tumor dedifferentiation. This is the same exon-2-skipping isoform favored during T-cell activation; JNK inhibition reverses MAP2K7Δexon2-driven dedifferentiation. Alternative splicing analysis (TCGA/cancer genome), MBNL1 knockdown/overexpression, JNK inhibitor treatment, in vitro and in vivo tumor assays PNAS Medium 32601196
2022 EEF1AKMT3 methyltransferase catalyzes monomethylation of MAP2K7 at K296, which decreases MAP2K7 phosphorylation, ubiquitination, and degradation of TP53. Loss of EEF1AKMT3 leads to MAP2K7 activation, increased tumor invasiveness and migration in gastric cancer. Mass spectrometry (substrate identification), gain/loss-of-function studies, phospho-antibody array, RNA-seq Cancer letters Medium 35753528
2015 MKK7 neddylation (by RanBP2ΔFG E3 ligase) reduces its basal kinase activity. RanBP2 knockdown increases MKK7 kinase activity; ectopic RanBP2ΔFG reduces it. In vitro neddylation of purified MKK7 by RanBP2ΔFG directly reduces basal kinase activity. Co-immunoprecipitation, in vitro neddylation assay, kinase activity assay, siRNA knockdown Oncogene Medium 26364603
2010 RASSF7 interacts with N-Ras and MKK7 to negatively regulate JNK signaling. RASSF7 promotes the phosphorylated state of MKK7 but inhibits its ability to activate JNK. RASSF7 requires its RA domain for interaction with GTP-bound N-Ras and the anti-apoptotic effect. RASSF7 undergoes proteasomal degradation under prolonged stress, allowing MKK7/JNK death signaling to proceed. Co-immunoprecipitation, RNAi knockdown, kinase assay, domain-deletion analysis, ubiquitin-proteasome pathway assay Cell death and differentiation Medium 21278800
2017 Neuron-specific MKK7 knockout mice display age-dependent motor dysfunction, axonal degeneration in the spinal cord, and accumulation of axonal transport proteins JIP1 and APP in brain and spinal cord, establishing that MKK7-JNK signaling is required for neuronal maintenance and axonal transport in adult neurons. Conditional knockout (neuron-specific), behavioral analysis, histology, immunoblot for axonal transport proteins Scientific reports Medium 28779160

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines. Genes & development 310 11390361
2004 Gadd45 beta mediates the NF-kappa B suppression of JNK signalling by targeting MKK7/JNKK2. Nature cell biology 292 14743220
1997 A novel SAPK/JNK kinase, MKK7, stimulated by TNFalpha and cellular stresses. The EMBO journal 232 9384583
1998 T lymphocyte activation signals for interleukin-2 production involve activation of MKK6-p38 and MKK7-SAPK/JNK signaling pathways sensitive to cyclosporin A. The Journal of biological chemistry 178 9575191
2000 Synergistic activation of stress-activated protein kinase 1/c-Jun N-terminal kinase (SAPK1/JNK) isoforms by mitogen-activated protein kinase kinase 4 (MKK4) and MKK7. The Biochemical journal 164 11062067
1997 MKK7 is a stress-activated mitogen-activated protein kinase kinase functionally related to hemipterous. The Journal of biological chemistry 155 9312105
1999 The MKK7 gene encodes a group of c-Jun NH2-terminal kinase kinases. Molecular and cellular biology 153 9891090
2006 Physiological roles of MKK4 and MKK7: insights from animal models. Biochimica et biophysica acta 146 17157936
2001 Induction of inducible nitric oxide synthase-NO* by lipoarabinomannan of Mycobacterium tuberculosis is mediated by MEK1-ERK, MKK7-JNK, and NF-kappaB signaling pathways. Infection and immunity 141 11254551
1997 Fas induces cytoplasmic apoptotic responses and activation of the MKK7-JNK/SAPK and MKK6-p38 pathways independent of CPP32-like proteases. The Journal of cell biology 136 9362518
2004 MKK7 couples stress signalling to G2/M cell-cycle progression and cellular senescence. Nature cell biology 127 15039780
2021 Anti-inflammatory Effects of Empagliflozin and Gemigliptin on LPS-Stimulated Macrophage via the IKK/NF-κB, MKK7/JNK, and JAK2/STAT1 Signalling Pathways. Journal of immunology research 119 34124273
2009 The Rac1/MKK7/JNK pathway signals upregulation of Atg5 and subsequent autophagic cell death in response to oncogenic Ras. Carcinogenesis 117 19783847
2011 The bottleneck of JNK signaling: molecular and functional characteristics of MKK4 and MKK7. European journal of cell biology 114 21333379
1999 The JNKK2-JNK1 fusion protein acts as a constitutively active c-Jun kinase that stimulates c-Jun transcription activity. The Journal of biological chemistry 100 10506143
2007 Activation of c-Jun N-terminal kinase (JNK) by widely used specific p38 MAPK inhibitors SB202190 and SB203580: a MLK-3-MKK7-dependent mechanism. Cellular signalling 99 18222647
2014 Cancer-selective targeting of the NF-κB survival pathway with GADD45β/MKK7 inhibitors. Cancer cell 95 25314077
1997 Molecular cloning and characterization of human JNKK2, a novel Jun NH2-terminal kinase-specific kinase. Molecular and cellular biology 94 9372971
2015 Calcium/Ask1/MKK7/JNK2/c-Src signalling cascade mediates disruption of intestinal epithelial tight junctions by dextran sulfate sodium. The Biochemical journal 88 25377781
1999 The mixed lineage kinase DLK utilizes MKK7 and not MKK4 as substrate. The Journal of biological chemistry 88 10187804
2011 The stress kinase MKK7 couples oncogenic stress to p53 stability and tumor suppression. Nature genetics 86 21317887
2008 Transcriptional regulation of EGR-1 by the interleukin-1-JNK-MKK7-c-Jun pathway. The Journal of biological chemistry 84 18281687
1999 MEK kinase 3 directly activates MKK6 and MKK7, specific activators of the p38 and c-Jun NH2-terminal kinases. The Journal of biological chemistry 83 10347227
1998 Multiple signaling pathways for the activation of JNK in mast cells: involvement of Bruton's tyrosine kinase, protein kinase C, and JNK kinases, SEK1 and MKK7. Journal of immunology (Baltimore, Md. : 1950) 80 9712046
1998 Human mitogen-activated protein kinase kinase 7 (MKK7) is a highly conserved c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) activated by environmental stresses and physiological stimuli. The Journal of biological chemistry 79 9535930
2005 Suppression of metastatic colonization by the context-dependent activation of the c-Jun NH2-terminal kinase kinases JNKK1/MKK4 and MKK7. Cancer research 72 16322247
2006 An antiapoptotic protein, c-FLIPL, directly binds to MKK7 and inhibits the JNK pathway. The EMBO journal 69 17110930
2002 Possible involvement of IkappaB kinase 2 and MKK7 in osteoclastogenesis induced by receptor activator of nuclear factor kappaB ligand. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 67 11918218
2003 Different properties of SEK1 and MKK7 in dual phosphorylation of stress-induced activated protein kinase SAPK/JNK in embryonic stem cells. The Journal of biological chemistry 66 12624093
2000 Activation of JNK3 alpha 1 requires both MKK4 and MKK7: kinetic characterization of in vitro phosphorylated JNK3 alpha 1. Biochemistry 66 10715136
2006 Interacting JNK-docking sites in MKK7 promote binding and activation of JNK mitogen-activated protein kinases. The Journal of biological chemistry 64 16533805
2007 Insights into the structural basis of the GADD45beta-mediated inactivation of the JNK kinase, MKK7/JNKK2. The Journal of biological chemistry 62 17485467
2015 Structure and dynamics of the MKK7-JNK signaling complex. Proceedings of the National Academy of Sciences of the United States of America 60 25737554
2015 Widespread JNK-dependent alternative splicing induces a positive feedback loop through CELF2-mediated regulation of MKK7 during T-cell activation. Genes & development 60 26443849
2001 Impaired synergistic activation of stress-activated protein kinase SAPK/JNK in mouse embryonic stem cells lacking SEK1/MKK4: different contribution of SEK2/MKK7 isoforms to the synergistic activation. The Journal of biological chemistry 59 11418587
2011 Stress-activated protein kinase MKK7 regulates axon elongation in the developing cerebral cortex. The Journal of neuroscience : the official journal of the Society for Neuroscience 58 22090513
2010 The NF (Nuclear factor)-κB inhibitor parthenolide interacts with histone deacetylase inhibitors to induce MKK7/JNK1-dependent apoptosis in human acute myeloid leukaemia cells. British journal of haematology 57 20701602
1998 Differential activation of stress-activated protein kinase kinases SKK4/MKK7 and SKK1/MKK4 by the mixed-lineage kinase-2 and mitogen-activated protein kinase kinase (MKK) kinase-1. The Biochemical journal 55 9639556
2018 Covalent Docking Identifies a Potent and Selective MKK7 Inhibitor. Cell chemical biology 54 30449673
2012 TGF-β-associated miR-27a inhibits dendritic cell-mediated differentiation of Th1 and Th17 cells by TAB3, p38 MAPK, MAP2K4 and MAP2K7. Genes and immunity 54 23034448
2003 Expression of the MAPK kinases MKK-4 and MKK-7 in rheumatoid arthritis and their role as key regulators of JNK. Arthritis and rheumatism 54 13130464
2001 The stress kinase mitogen-activated protein kinase kinase (MKK)7 is a negative regulator of antigen receptor and growth factor receptor-induced proliferation in hematopoietic cells. The Journal of experimental medicine 54 11560992
2005 The neuroprotective effects of K252a through inhibiting MLK3/MKK7/JNK3 signaling pathway on ischemic brain injury in rat hippocampal CA1 region. Neuroscience 53 15680699
1999 Differential regulation of mitogen-activated protein kinase kinase 4 (MKK4) and 7 (MKK7) by signaling from G protein beta gamma subunit in human embryonal kidney 293 cells. The Journal of biological chemistry 53 9890951
2001 PKC delta mediates ionizing radiation-induced activation of c-Jun NH(2)-terminal kinase through MKK7 in human thyroid cells. Oncogene 52 11314034
2009 A non-redundant role for Drosophila Mkk4 and hemipterous/Mkk7 in TAK1-mediated activation of JNK. PloS one 51 19888449
2007 Up-regulation of MKK4, MKK6 and MKK7 during prostate cancer progression: an important role for SAPK signalling in prostatic neoplasia. The Journal of pathology 51 17577251
2012 Inhibition of MKK7-JNK by the TOR signaling pathway regulator-like protein contributes to resistance of HCC cells to TRAIL-induced apoptosis. Gastroenterology 49 22841785
1998 Differential activation of two JNK activators, MKK7 and SEK1, by MKN28-derived nonreceptor serine/threonine kinase/mixed lineage kinase 2. The Journal of biological chemistry 45 9516438
2018 DeSUMOylation of MKK7 kinase by the SUMO2/3 protease SENP3 potentiates lipopolysaccharide-induced inflammatory signaling in macrophages. The Journal of biological chemistry 44 29352108
2008 Elucidation of the signaling network of COX-2 induction in sheared chondrocytes: COX-2 is induced via a Rac/MEKK1/MKK7/JNK2/c-Jun-C/EBPbeta-dependent pathway. American journal of physiology. Cell physiology 44 18367585
2014 MAVS-MKK7-JNK2 defines a novel apoptotic signaling pathway during viral infection. PLoS pathogens 43 24651600
2012 Converging evidence that sequence variations in the novel candidate gene MAP2K7 (MKK7) are functionally associated with schizophrenia. Human molecular genetics 43 22899651
2012 Growth cone MKK7 mRNA targeting regulates MAP1b-dependent microtubule bundling to control neurite elongation. PLoS biology 43 23226105
2008 Gadd45 beta forms a homodimeric complex that binds tightly to MKK7. Journal of molecular biology 43 18343408
2013 The Neuregulin-Rac-MKK7 pathway regulates antagonistic c-jun/Krox20 expression in Schwann cell dedifferentiation. Glia 42 23505039
2014 MKK7 mediates miR-493-dependent suppression of liver metastasis of colon cancer cells. Cancer science 41 24533778
2006 Regulation of JNK by MKK-7 in fibroblast-like synoviocytes. Arthritis and rheumatism 41 16802349
2002 A novel dual specificity phosphatase SKRP1 interacts with the MAPK kinase MKK7 and inactivates the JNK MAPK pathway. Implication for the precise regulation of the particular MAPK pathway. The Journal of biological chemistry 40 11959861
2019 MKK7, the essential regulator of JNK signaling involved in cancer cell survival: a newly emerging anticancer therapeutic target. Therapeutic advances in medical oncology 39 31579105
2019 Phosphatidic acid promotes the activation and plasma membrane localization of MKK7 and MKK9 in response to salt stress. Plant science : an international journal of experimental plant biology 38 31481213
2016 miR-125b inhibited epithelial-mesenchymal transition of triple-negative breast cancer by targeting MAP2K7. OncoTargets and therapy 38 27226726
2020 A tumor-associated splice-isoform of MAP2K7 drives dedifferentiation in MBNL1-low cancers via JNK activation. Proceedings of the National Academy of Sciences of the United States of America 37 32601196
2016 Inactivation of KLF4 promotes T-cell acute lymphoblastic leukemia and activates the MAP2K7 pathway. Leukemia 37 27872496
2019 Histone deacetylase 6 promotes growth of glioblastoma through the MKK7/JNK/c-Jun signaling pathway. Journal of neurochemistry 36 31390677
2002 Mixed lineage kinase ZAK utilizing MKK7 and not MKK4 to activate the c-Jun N-terminal kinase and playing a role in the cell arrest. Biochemical and biophysical research communications 36 12220515
2011 Alpinetin suppresses proliferation of human hepatoma cells by the activation of MKK7 and elevates sensitization to cis-diammined dichloridoplatium. Oncology reports 35 22159816
1997 Selective activation of JNK/SAPK by interleukin-1 in rabbit liver is mediated by MKK7. FEBS letters 35 9414114
2016 Scaffold Role of DUSP22 in ASK1-MKK7-JNK Signaling Pathway. PloS one 34 27711255
2012 HBx activates FasL and mediates HepG2 cell apoptosis through MLK3-MKK7-JNKs signal module. World journal of gastroenterology 34 22509080
2010 Diverse physiological functions of MKK4 and MKK7 during early embryogenesis. Journal of biochemistry 34 20801953
2010 RASSF7 negatively regulates pro-apoptotic JNK signaling by inhibiting the activity of phosphorylated-MKK7. Cell death and differentiation 34 21278800
2017 Role of p-MKK7 in myricetin-induced protection against intestinal ischemia/reperfusion injury. Pharmacological research 30 29154988
2015 Exploring the role of MKK7 in excitotoxicity and cerebral ischemia: a novel pharmacological strategy against brain injury. Cell death & disease 30 26270349
2011 Deprivation of MKK7 in cardiomyocytes provokes heart failure in mice when exposed to pressure overload. Journal of molecular and cellular cardiology 29 21284947
2006 D-MEKK1, the Drosophila orthologue of mammalian MEKK4/MTK1, and Hemipterous/D-MKK7 mediate the activation of D-JNK by cadmium and arsenite in Schneider cells. BMC cell biology 29 16451733
2022 The EEF1AKMT3/MAP2K7/TP53 axis suppresses tumor invasiveness and metastasis in gastric cancer. Cancer letters 27 35753528
2010 Filamin associates with stress signalling kinases MKK7 and MKK4 and regulates JNK activation. The Biochemical journal 27 20156194
2021 The bacterial effector HopZ1a acetylates MKK7 to suppress plant immunity. The New phytologist 26 33960430
2018 Mkk4 and Mkk7 are important for retinal development and axonal injury-induced retinal ganglion cell death. Cell death & disease 26 30367030
2006 A change of expression in the conserved signaling gene MKK7 is associated with a selective sweep in the western house mouse Mus musculus domesticus. Journal of evolutionary biology 26 16910979
2001 Expression of human cystatin A by keratinocytes is positively regulated via the Ras/MEKK1/MKK7/JNK signal transduction pathway but negatively regulated via the Ras/Raf-1/MEK1/ERK pathway. The Journal of biological chemistry 26 11451947
2020 Catalytic Domain Plasticity of MKK7 Reveals Structural Mechanisms of Allosteric Activation and Diverse Targeting Opportunities. Cell chemical biology 24 32783966
2017 Cordycepin promotes apoptosis in renal carcinoma cells by activating the MKK7-JNK signaling pathway through inhibition of c-FLIPL expression. PloS one 24 29045468
2016 HDAC inhibitors suppress c-Jun/Fra-1-mediated proliferation through transcriptionally downregulating MKK7 and Raf1 in neuroblastoma cells. Oncotarget 24 26734995
2015 Identification and characterization of MKK7 as an upstream activator of JNK in Litopenaeus vannamei. Fish & shellfish immunology 23 26707780
2014 5Z-7-Oxozeaenol covalently binds to MAP2K7 at Cys218 in an unprecedented manner. Bioorganic & medicinal chemistry letters 23 25529738
2013 Isoangustone A, a novel licorice compound, inhibits cell proliferation by targeting PI3K, MKK4, and MKK7 in human melanoma. Cancer prevention research (Philadelphia, Pa.) 23 24104352
2019 MKK7 transcription positively or negatively regulated by SP1 and KLF5 depends on HDAC4 activity in glioma. International journal of cancer 22 30963560
2015 Neddylation controls basal MKK7 kinase activity in breast cancer cells. Oncogene 22 26364603
2014 Tussilago farfara L. augments TRAIL-induced apoptosis through MKK7/JNK activation by inhibition of MKK7‑TIPRL in human hepatocellular carcinoma cells. Oncology reports 22 24969837
2011 Distinct signaling properties of mitogen-activated protein kinase kinases 4 (MKK4) and 7 (MKK7) in embryonic stem cell (ESC) differentiation. The Journal of biological chemistry 21 22130668
2008 GADD45B inhibits MKK7-induced cardiac hypertrophy and the polymorphisms of GADD45B is associated with inter-ventricular septum hypertrophy. Biochemical and biophysical research communications 21 18515079
2018 Probing the interaction interface of the GADD45β/MKK7 and MKK7/DTP3 complexes by chemical cross-linking mass spectrometry. International journal of biological macromolecules 20 29572137
2006 Differential requirement of MKK4 and MKK7 in JNK activation by distinct scaffold proteins. FEBS letters 20 17187786
2022 Circular RNA ACTA1 Acts as a Sponge for miR-199a-5p and miR-433 to Regulate Bovine Myoblast Development through the MAP3K11/MAP2K7/JNK Pathway. Journal of agricultural and food chemistry 19 35234473
2019 Targeting the MKK7-JNK (Mitogen-Activated Protein Kinase Kinase 7-c-Jun N-Terminal Kinase) Pathway with Covalent Inhibitors. Journal of medicinal chemistry 19 30768270
2017 Age-dependent motor dysfunction due to neuron-specific disruption of stress-activated protein kinase MKK7. Scientific reports 19 28779160
2016 Heme Oxygenase-1 Inhibits Neuronal Apoptosis in Spinal Cord Injury through Down-Regulation of Cdc42-MLK3-MKK7-JNK3 Axis. Journal of neurotrauma 19 27526795
2000 Stress-activated protein kinase-dependent induction of c-fos by Cd(2+) is mediated by MKK7. Biochemical and biophysical research communications 19 10873670

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