Affinage

MAP2K4

Dual specificity mitogen-activated protein kinase kinase 4 · UniProt P45985

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

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAP2K4 (MKK4/SEK1/JNKK1) is a dual-specificity MAP kinase kinase that operates at the core of stress-activated MAPK signaling, transducing diverse upstream inputs into JNK and p38 activation (PMID:9096336). It directly activates JNK in vivo, and its loss blocks JNK activation by MEKK1, anisomycin, and heat shock, abolishes AP-1 transcriptional activity, and causes embryonic lethality (PMID:9096336). MKK4 shows a striking substrate preference for the activating tyrosine (Tyr-185) of JNK, complementing MKK7's threonine specificity so that the two kinases act synergistically for full JNK activation; this tyrosine-directed preference extends to p38 family substrates (PMID:11062067). Specificity within the cascade is achieved through MKK4's N-terminal extension, which organizes sequential MEKK1→MKK4→JNK interactions, with MEKK1 and JNK competing for binding (PMID:9808624). MKK4 is activated by phosphorylation at Ser221/Thr225 by multiple MAPKKKs including MEKK2, MEKK3, MLK2, MEKK1, and the Parkinson-associated kinase LRRK2 (PMID:9162092, PMID:9639556, PMID:19302196); the LRRK2→MKK4(Ser257)→JNK→c-Jun axis drives dopaminergic neuron degeneration (PMID:22539006). Pathway assembly is governed by scaffold proteins—nonvisual arrestins bridge MKK4 and JNK3 (PMID:22047447), and Filamin A links MKK4 to MKK7 (PMID:20156194)—while MKK4 activity is negatively regulated by Itch-mediated ubiquitination at Lys140/143 in a JNK-dependent feedback loop (PMID:19737936) and by inactivating PI3K/Akt-driven phosphorylation at Ser80 (PMID:17276500). Physiologically, MKK4 is required for CD28-driven IL-2 production in T cells (PMID:9294148), TNF-induced NF-κB activation and survival gene expression (PMID:17641059), cardiomyocyte stress responses through NFAT (PMID:19265040), retinal ganglion cell survival after injury (PMID:30367030), and acts as a tumor suppressor in lung and metastatic cancers (PMID:16489030, PMID:21896780); structure-guided MKK4 inhibitors enhance liver regeneration and have entered phase I trials (PMID:38490194).

Mechanistic history

Synthesis pass · year-by-year structured walk · 29 steps
  1. 1997 High

    Established MKK4 as a genuine in vivo activator of JNK rather than an in vitro curiosity, defining its essential role in stress-induced AP-1 signaling and development.

    Evidence Targeted gene disruption with complementation rescue and AP-1 reporter assays; KO mice lethal before E14

    PMID:9096336

    Open questions at the time
    • Did not resolve relative contributions of JNK vs p38 downstream
    • Embryonic lethality limited adult tissue analysis
  2. 1997 High

    Identified the exact activating phosphorylation sites and multiple MAPKKK inputs, showing MKK4 integrates signals from several upstream kinases.

    Evidence In vitro kinase assays with Ser221/Thr225 mutagenesis, cotransfection of MEKK2/MEKK3 in COS-7 cells

    PMID:9162092

    Open questions at the time
    • Did not establish which MAPKKK dominates in specific physiological stimuli
    • Specificity of MEKK2/3 vs MKK3 not fully mapped
  3. 1998 High

    Defined how MKK4 organizes a discrete kinase module, revealing sequential and competitive interactions that confer stimulus-specific signaling.

    Evidence Co-IP, dominant-negative mutants, and N-terminal extension mutagenesis dissecting TNF- vs stress-induced JNK activation

    PMID:9808624

    Open questions at the time
    • Structural basis of competitive binding not solved
    • Stimulus specificity mechanism incompletely defined
  4. 1998 High

    Established differential MAPKKK preferences (MLK2 activates both MKK4 and MKK7; MEKK1 favors MKK4), explaining branch-specific upstream control of the JNK pathway.

    Evidence Cotransfection and in vitro kinase assays with recombinant proteins

    PMID:9639556

    Open questions at the time
    • Did not map endogenous cytokine-specific MAPKKK usage
    • p38 branch contribution not addressed
  5. 2000 High

    Resolved the dual-residue logic of JNK activation, showing MKK4 preferentially phosphorylates Tyr-185 and acts synergistically with MKK7's Thr-183 targeting.

    Evidence In vitro kinase assays with phosphosite mutants and phosphoamino acid analysis across JNK isoforms

    PMID:11062067

    Open questions at the time
    • In vitro preference may not reflect all cellular contexts
    • p38 phosphosite preference less quantified
  6. 1997 High

    Linked MKK4 to a defined immune output, demonstrating it is required for CD28-driven T cell IL-2 production and revealing developmentally regulated JNK signaling.

    Evidence RAG2-/- chimeras with SEK1-/- cells, proliferation and cytokine assays

    PMID:9294148

    Open questions at the time
    • Mechanism of developmental difference between thymocytes and peripheral T cells unresolved
  7. 1998 Medium

    Connected MKK4 to inflammatory gene output by placing the MEKK1→SEK1 pathway upstream of both p38 and JNK driving COX-2/PGE2.

    Evidence Constitutively active and dominant-negative SEK1 constructs with kinase and prostaglandin readouts

    PMID:9582321

    Open questions at the time
    • Overexpression-based; endogenous contribution not measured
    • Direct vs indirect COX-2 induction not separated
  8. 1999 Medium

    Defined an upstream GPCR-linked route, showing Gβγ preferentially signals to JNK through MKK4 via Rho/Cdc42 and tyrosine kinases.

    Evidence Cotransfection with dominant-negative Rho GTPases and pharmacologic inhibitors in HEK293

    PMID:9890951

    Open questions at the time
    • Intermediate MAPKKK not identified
    • Pharmacologic inhibitor specificity caveats
  9. 2002 High

    Revealed an upstream negative-feedback layer where MEKK1 autoubiquitylation limits its own ability to phosphorylate MKK4.

    Evidence In vitro kinase and ubiquitylation assays with PHD domain C441A mutant

    PMID:12456688

    Open questions at the time
    • Cellular relevance and kinetics of feedback not fully quantified
  10. 2003 Medium

    Demonstrated MKK4, MKK7, and JNK form a stable cytoplasmic ternary complex in disease tissue that phosphorylates c-Jun upon IL-1 stimulation.

    Evidence Reciprocal co-IP, confocal microscopy, and in vitro kinase assays in rheumatoid synoviocytes

    PMID:13130464

    Open questions at the time
    • Scaffold organizing the complex not identified here
    • Stoichiometry undefined
  11. 2005 Medium

    Showed MKK4 suppresses metastasis in a context-dependent manner, acting through JNK in prostate cancer with site-specific kinase activation.

    Evidence In vivo AT6.1 metastasis model with MKK6/MKK7 substitution and phospho-Western in primary vs secondary tissue

    PMID:16322247

    Open questions at the time
    • Mechanism of site-restricted activation unknown
    • Contrasts with p38-dependent suppression in ovarian cancer
  12. 2006 High

    Established that the downstream pathway mediating MKK4 metastasis suppression is tissue-dependent (p38 in ovarian cancer), using pathway-specific kinase substitution.

    Evidence Kinase-inactive MKK4 and MKK6/MKK7 substitution in SCID mouse ovarian metastasis model

    PMID:16489030

    Open questions at the time
    • Determinants of p38 vs JNK pathway choice unresolved
  13. 2006 Medium

    Demonstrated scaffold proteins differentially channel signals through MKK4 vs MKK7, defining branch selection at the scaffold level.

    Evidence JNK activity assays in MKK4-/- and MKK4-/-/7-/- MEFs with LMP-1, Axin, and Dvl

    PMID:17187786

    Open questions at the time
    • Structural basis of scaffold-MKK preference not defined
  14. 2007 High

    Connected MKK4 to canonical NF-κB survival signaling, showing its loss abrogates TNF-induced NF-κB activation and sensitizes cells to apoptosis.

    Evidence MKK4-deleted fibroblasts with NF-κB DNA binding, reporter, and anti-apoptotic gene readouts

    PMID:17641059

    Open questions at the time
    • Direct molecular link between MKK4 and IKK not established
    • Crosstalk with JNK arm not dissected
  15. 2007 Medium

    Revealed a priming layer where PKC phosphorylation of JNK must precede MKK4/7 action to augment JNK activity.

    Evidence In vitro sequential phosphorylation assays with PKC inhibition and apoptosis readout

    PMID:18182317

    Open questions at the time
    • Cellular validation limited
    • PKC isoform and JNK site not specified
  16. 2009 High

    Identified Itch-mediated ubiquitination at Lys140/143 as a JNK-dependent negative feedback controlling MKK4 stability.

    Evidence Ubiquitination assays, co-IP, proteasome inhibition, and acceptor-lysine mutagenesis after sorbitol stress

    PMID:19737936

    Open questions at the time
    • Physiological stimuli triggering this feedback beyond sorbitol unclear
  17. 2009 Medium

    Defined an inactivating phosphorylation mechanism (Ser80 via PI3K/Akt) that silences MKK4 in tumors without gene mutation.

    Evidence Phosphospecific Western blotting with wortmannin and growth factor stimulation in ovarian cells

    PMID:17276500

    Open questions at the time
    • Direct kinase-substrate relationship not demonstrated
    • Identity of the Ser80 kinase not confirmed
  18. 2009 Medium

    Connected MKK4 to neurodegeneration by identifying LRRK2 as a MAPKKK acting on MKK4, with pathogenic mutants showing enhanced activity.

    Evidence In vitro kinase assays with recombinant LRRK2 and G2019S/I2020T mutant comparison

    PMID:19302196

    Open questions at the time
    • No cellular validation of the specific MKK4 site in this study
    • Selectivity among MKKs not resolved
  19. 2009 Medium

    Established a scaffold-based assembly of the MLK3-MKK4-JNK module in ischemic neurons, with POSH disruption promoting survival.

    Evidence Co-IP from rat hippocampus and antisense knockdown after cerebral ischemia

    PMID:16248889

    Open questions at the time
    • Direct MKK4-POSH binding interface not mapped
  20. 2009 High

    Defined a cardioprotective role: cardiac MKK4 deletion exacerbates pathological hypertrophy and apoptosis via elevated NFAT activity.

    Evidence Conditional cardiac KO under pressure overload and beta-adrenergic stress with NFAT reporter and patient correlation

    PMID:19265040

    Open questions at the time
    • Mechanistic link between MKK4 and NFAT suppression not fully defined
  21. 2010 High

    Identified Filamin A as a scaffold physically linking MKK4 and MKK7 to enable their synergistic stress-induced JNK activation.

    Evidence Reciprocal co-IP, deletion mapping, Filamin-A-deficient cells, and kinase assays

    PMID:20156194

    Open questions at the time
    • Whether Filamin A also organizes JNK in the complex not shown
  22. 2011 High

    Reconstituted arrestin-3 as a bona fide scaffold for MKK4-mediated JNK3 phosphorylation, demonstrating classic scaffold concentration dependence.

    Evidence In vitro reconstitution from purified proteins with binding and dose-response kinase assays

    PMID:22047447

    Open questions at the time
    • In vivo relevance of arrestin scaffolding for MKK4 not established
  23. 2011 High

    Established MKK4 as a lung adenocarcinoma tumor suppressor acting through noncanonical substrates (PPARγ2), with cancer mutations impairing stability or kinase activity.

    Evidence Conditional KO in Kras/Tp53 mice, biochemical mutant characterization, and PPARγ2 epistasis

    PMID:21896780

    Open questions at the time
    • Direct MKK4 substrate driving PPARγ2 regulation not identified
  24. 2011 High

    Showed MKK4 is required for p38 activation during cardiomyocyte differentiation, with MKK4 and MKK7 exerting opposing effects on p38 output.

    Evidence Mkk4-/- and Mkk7-/- ESC differentiation assays with phospho-ATF2/MEF2C readouts and MKK4 rescue

    PMID:22130668

    Open questions at the time
    • Mechanism by which MKK7 antagonizes p38 not resolved
  25. 2012 Medium

    Validated the LRRK2→MKK4(Ser257)→JNK→c-Jun axis as a driver of dopaminergic neuron degeneration in cells and transgenic mice.

    Evidence Cell-based kinase assays in HEK293, phosphospecific Western in G2019S-LRRK2 transgenic substantia nigra, pathway component measurement

    PMID:22539006

    Open questions at the time
    • Causal requirement of MKK4 for neurodegeneration not tested by MKK4 deletion
  26. 2018 Medium

    Revealed MKK4 deficiency as a determinant of MEK inhibitor sensitivity by disabling a JNK-JUN feedback loop that normally restores MAPK activity.

    Evidence Loss-of-function analysis in cancer cell lines and a 168-tumor PDX panel with DUSP4 modulation

    PMID:29795445

    Open questions at the time
    • Direct MKK4 substrates in the feedback loop not enumerated
  27. 2018 High

    Demonstrated individual and redundant roles of MKK4 and MKK7 in retinal ganglion cell survival and development through single and double KO.

    Evidence Conditional retina-specific KO with optic nerve crush and quantitative RGC survival counts

    PMID:30367030

    Open questions at the time
    • Molecular basis of developmental redundancy not dissected
  28. 2020 Medium

    Delivered a covalent MKK4/7 inhibitor targeting a conserved pre-DFG cysteine, enabling combinatorial pathway suppression in cancer cells.

    Evidence Covalent inhibitor design with MS-based target engagement and TNBC cell viability assays

    PMID:32916088

    Open questions at the time
    • Dual MKK4/7 inhibition complicates attribution to MKK4 alone
    • In vivo efficacy not established here
  29. 2024 High

    Translated MKK4 inhibition into a regenerative therapy, with structure-based MKK4 inhibitors enhancing liver regeneration and entering first-in-human testing.

    Evidence Structure-based design with NMR, mouse and pig hepatectomy models, liver disease models, and phase I trial of HRX215

    PMID:38490194

    Open questions at the time
    • Long-term safety and efficacy from larger trials pending
    • Tumor-suppressor role raises theoretical oncogenic risk not resolved here

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MKK4 selects between JNK and p38 outputs in different tissues, and how its substrate choice is reconciled with its dual tumor-suppressor and pro-survival roles, remains unresolved.
  • No unifying model for tissue-specific JNK vs p38 channeling
  • Noncanonical substrates largely uncharacterized
  • Reconciliation of tumor suppression with regenerative inhibitor strategy incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0060090 molecular adaptor activity 3 GO:0016740 transferase activity 2 GO:0140657 ATP-dependent activity 2
Localization
GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-168256 Immune System 2
Partners
ARRB1ARRB2FLNAITCHLRRK2MAP2K7MAP3K1MAPK8
Complex memberships
MKK4-MKK7-JNK ternary complex

Evidence

Reading pass · 33 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 MKK4 (JNKK1) functions as a direct activator of JNK in vivo; targeted disruption of MKK4 blocked JNK activation caused by MEKK1, anisomycin, and heat shock, and abolished regulated AP-1 transcriptional activity. MKK4 knockout mice die before embryonic day 14, and complementation with MKK4 expression vector restored AP-1 activity in KO cells. Gene knockout (targeted disruption), cell-based kinase assays, complementation transfection, AP-1 reporter assay Proceedings of the National Academy of Sciences of the United States of America High 9096336
1998 JNKK1/MKK4 organizes a MAP kinase module by interacting with both MEKK1 (upstream) and JNK (downstream) through its amino-terminal extension. JNK and MEKK1 compete for binding to JNKK1, and activation of JNKK1 prevents its re-binding to MEKK1, indicating sequential MEKK1:JNKK1 and JNKK1:JNK interactions. Mutations in the N-terminal extension disrupt TNF-induced (but not stress-induced) JNK activation. Dominant-negative mutant analysis, co-immunoprecipitation, cell-based signaling assays Genes & development High 9808624
2000 MKK4 shows a striking substrate preference for phosphorylation of the tyrosine residue (Tyr-185) in JNK1 isoforms, while MKK7 preferentially phosphorylates the threonine residue (Thr-183). Because both residues must be phosphorylated for full JNK activation, MKK4 and MKK7 act synergistically in vitro to maximally activate JNK. MKK4 also shows tyrosine-preference for p38 family substrates. In vitro kinase assay with phosphospecific site mutants, phosphoamino acid analysis of JNK1 isoforms The Biochemical journal High 11062067
1997 MEKK2 and MEKK3 both phosphorylate and activate MKK4. The activating phosphorylation sites in MKK4 were mapped to Ser221 and Thr225 within kinase subdomains VII/VIII. Mutation of these residues abolished MKK4 activation by MEKK2 and MEKK3. Immunoprecipitated MEKK2 directly activated recombinant MKK4 in vitro but failed to activate MKK3. In vitro kinase assay, site-directed mutagenesis, cotransfection in COS-7 cells The Journal of biological chemistry High 9162092
1998 MLK2 activates both MKK4 (SKK1) and MKK7 (SKK4) in transfection studies and in vitro, whereas MEKK1 activates MKK4 much more efficiently than MKK7 and barely activates MKK7. This differential activation suggests MEKK1 does not mediate cytokine (IL-1, TNF)-induced MKK7/JNK activation, while MLK2 can activate both arms. Cotransfection kinase assays, in vitro kinase assay with recombinant proteins The Biochemical journal High 9639556
1998 The activated MEKK1→SEK1/MKK4 pathway induces COX-2 expression and PGE2 production, functioning as an upstream kinase capable of activating both p38 MAPK and JNK/SAPK. A constitutively active SEK1-ED increased p38 and JNK phosphorylation and PGE2/COX-2, while a dominant-negative SEK1-AL decreased these outputs. Overexpression of constitutively active and dominant-negative constructs, kinase activity assays, pharmacologic p38 inhibitor The Journal of biological chemistry Medium 9582321
1997 SEK1/MKK4-deficient T cells show decreased proliferation and IL-2 production after CD28 costimulation and PMA/Ca2+ ionophore activation, establishing MKK4 as a required effector of CD28 signaling to IL-2 production. JNK activation in response to PMA/Ca2+ ionophore was absent in KO thymocytes but present in peripheral T cells, indicating developmentally regulated signaling. RAG2-/-chimeric mice with SEK1-/- cells, genetic KO, functional proliferation and cytokine assays The Journal of experimental medicine High 9294148
2002 MEKK1 phosphorylates and activates MKK4 (and MKK1), and MEKK1's own ubiquitylation (mediated by its PHD/E3 ligase domain, requiring kinase activity and Cys441) inhibits its ability to phosphorylate MKK4, thereby suppressing ERK1/2 and JNK activation. Mutation C441A prevents ubiquitylation and preserves MEKK1→MKK4 phosphorylation. In vitro kinase assay, ubiquitylation assay, site-directed mutagenesis (C441A PHD domain) The Journal of biological chemistry High 12456688
2009 MKK4/SEK1 undergoes ubiquitination and proteasomal degradation following cellular stress (sorbitol). The HECT-domain E3 ubiquitin ligase Itch binds MKK4, ubiquitinates lysines 140 and 143, and promotes MKK4 degradation through a JNK-dependent feedback loop (JNK kinase activity is required for MKK4 ubiquitination). Ubiquitination assays, co-immunoprecipitation, proteasome inhibitor treatment, site-directed mutagenesis of ubiquitin acceptor lysines The Journal of biological chemistry High 19737936
2011 Nonvisual arrestins (arrestin-2 and arrestin-3) directly bind both MKK4 and JNK3α2 and act as scaffolds facilitating MKK4-mediated phosphorylation of JNK3α2. Reconstitution with purified proteins showed bell-shaped concentration dependence of JNK3α2 phosphorylation and JNK activity at low vs. high arrestin-3 concentration, consistent with true scaffold behavior. Arrestin-3 has higher affinity for both kinases than arrestin-2. In vitro reconstitution with purified proteins, direct binding assays, kinase activity assays Biochemistry High 22047447
2003 In fibroblast-like synoviocytes from rheumatoid arthritis tissue, MKK4 and MKK7 co-immunoprecipitate with JNK, and MKK4 co-precipitates with MKK7, forming a stable ternary complex. This complex localizes to the cytoplasm by confocal microscopy, with JNK translocating to the nucleus after IL-1 stimulation. The complex phosphorylates c-Jun upon IL-1 stimulation. Co-immunoprecipitation, confocal microscopy, in vitro kinase assay of immunoprecipitated complex Arthritis and rheumatism Medium 13130464
2009 LRRK2 (Parkinson disease-associated kinase) phosphorylates MKK4 in vitro, exhibiting MAPKKK-like activity toward MKK4 and MKK7 as well as MKK3 and MKK6. The pathogenic G2019S and I2020T mutations show increased phosphotransferase activity toward MKK4. In vitro kinase assay with recombinant proteins, disease mutant comparison Journal of neurochemistry Medium 19302196
2012 G2019S-LRRK2 phosphorylates MKK4 at Ser257 with augmented kinase activity in HEK293 cells, and phospho-MKK4(Ser257) is elevated in the substantia nigra of G2019S-LRRK2 transgenic mice. This leads to increased phospho-JNK and phospho-c-Jun, upregulated Bim and FasL, and caspase activation, identifying the LRRK2→MKK4→JNK→c-Jun pathway as a mediator of dopaminergic neuron degeneration. Cell-based kinase assay (HEK293 cells), phosphospecific Western blotting in transgenic mice, epistasis via pathway component measurement Cell death and differentiation Medium 22539006
2010 Filamin A (actin-binding protein 280) binds to both MKK4 and MKK7, connecting them in close proximity. Filamin family members A, B, and C interact with MKK4; the MKK7-binding region on Filamin A is distinct from its MKK4-binding region. Filamin-A-deficient cells show reduced MKK7 activation and impaired synergistic stress-induced JNK activation, establishing Filamin A as a scaffold linking the two MKK upstream kinases. Co-immunoprecipitation, Filamin-A-deficient cell lines, deletion mutant mapping, confocal co-localization, kinase assays The Biochemical journal High 20156194
2009 Cardiac-specific deletion of MKK4 in mice results in exacerbated pathological cardiac hypertrophy and cardiomyocyte apoptosis upon pressure overload or chronic beta-adrenergic stimulation, associated with upregulated NFAT transcriptional activity. Physiological hypertrophy induced by swimming exercise was unaffected. MKK4 expression was reduced in heart failure patients. Conditional cardiac KO (Cre-lox), pressure overload and pharmacologic stress models, NFAT reporter assay, histology Circulation research High 19265040
2006 MKK4 kinase activity is essential for metastasis suppression in ovarian cancer. Expression of MKK6 (a p38-specific activator) suppressed metastatic colonization similarly to MKK4, while MKK7 (JNK-specific) had no effect, placing the p38 pathway downstream of MKK4 as the key pathway for metastasis suppression. Kinase-inactive mutant expression, MKK6/MKK7 substitution, in vivo SCID mouse metastasis model Cancer research High 16489030
2005 In prostate cancer, MKK4 and MKK7 kinase activities are active in the lung (secondary site) but not in the primary tumor, providing a biochemical basis for context-dependent metastasis suppression. MKK7 expression suppresses overt metastases (via JNK), whereas MKK6 had no effect in this model, indicating MKK4 suppresses prostate metastasis through JNK rather than p38. In vivo AT6.1 spontaneous metastasis model, MKK7/MKK6 expression constructs, phospho-specific Western blotting in primary vs. secondary site tissue Cancer research Medium 16322247
2005 POSH scaffold protein co-immunoprecipitates with MLK3, MKK4, and phospho-JNK in the rat hippocampus following cerebral ischemia; interactions are enhanced during reperfusion. Intracerebroventricular POSH antisense oligodeoxynucleotides reduced POSH protein, decreased its interaction with MKK4 and phospho-JNKs, attenuated MLK3-MKK4-JNK activation, and increased neuronal survival. Co-immunoprecipitation from brain tissue, antisense knockdown, immunohistochemistry, histology (neuronal density) Journal of neurochemistry Medium 16248889
2009 MKK4 (Ser80) is phosphorylated by the PI3K/Akt pathway in ovarian cells in response to EGF and TGF-β, and this inactivating phosphorylation is blocked 50-60% by the PI3K/Akt inhibitor wortmannin. The inactivated pSer80 form constitutes 62% of phosphorylated MKK4 in ovarian tumors, providing a mechanism for MKK4 functional inactivation without gene mutation. Western blotting with phosphospecific antibodies, pharmacologic inhibition (wortmannin), growth factor stimulation experiments Gynecologic oncology Medium 17276500
2011 Map2k4 functions as a tumor suppressor in lung adenocarcinoma; conditional bronchial epithelial inactivation in Kras/Tp53-mutant mice accelerated lung neoplasia. MKK4 deficiency increased PPARγ2 expression through noncanonical substrates, and PPARγ2 enhanced tumor cell invasion. Eight of 11 cancer-associated MKK4 mutations reduced protein stability or impaired kinase activity. Conditional KO in Kras/Tp53 mouse model, biochemical characterization of cancer-associated mutants, PPARγ2 epistasis via knockdown Molecular and cellular biology High 21896780
1999 G-protein βγ subunit (Gβγ) activates MKK4 (6-fold) more potently than MKK7 (2-fold), and MKK4 activation by Gβγ is blocked by dominant-negative Rho, Cdc42, and specific tyrosine kinase inhibitors PP2/PP1, while MKK7 activation is blocked by dominant-negative Rac. This demonstrates that Gβγ preferentially signals to JNK through MKK4 via Rho/Cdc42 and tyrosine kinases. Cotransfection with dominant-negative Rho GTPases, pharmacologic kinase inhibitors, kinase assays in HEK293 cells The Journal of biological chemistry Medium 9890951
2009 Delphinidin directly binds MAPKK4 (MKK4) and PI3K in an ATP-competitive manner, as demonstrated by pull-down with delphinidin-Sepharose beads, inhibiting their kinase activities and suppressing UVB-induced COX-2 expression in epidermal cells and mouse skin. Delphinidin-Sepharose pulldown assay (direct binding), in vitro kinase inhibition assay, in vivo mouse skin model Carcinogenesis Medium 19776176
2011 In ESC differentiation, MKK4 is required for p38 activation; Mkk4−/− ESCs display diminished phospho-ATF2 and MEF2C expression, resulting in impaired MHC induction and defective cardiomyocyte differentiation. Exogenous MKK4 expression partially restored cardiomyocyte differentiation. MKK7, by contrast, reduces p38 activation, and Mkk7−/− ESCs have elevated MKK4 and p38 phosphorylation and enhanced cardiomyocyte formation. Gene KO ESC lines, differentiation assays, phospho-specific Western blot, MKK4 rescue transfection The Journal of biological chemistry High 22130668
2007 PKC phosphorylation of JNK augments (but is not sufficient for) JNK activation by MKK4 or MKK7. In vitro kinase assays show that PKC phosphorylation of JNK must precede phosphorylation by MKK4/7 to enhance JNK activity. Inhibiting PKC phosphorylation of JNK affects both early and late phases of UV-induced JNK activation and reduces JNK-mediated apoptosis. In vitro kinase assay, sequential phosphorylation order experiments, pharmacologic PKC inhibition, apoptosis assay The international journal of biochemistry & cell biology Medium 18182317
2006 Different scaffold proteins differentially utilize MKK4 and MKK7 for JNK activation: LMP-1-induced JNK activation depends primarily on MKK4, Axin depends mainly on MKK7, and Dvl depends approximately equally on both. This was demonstrated using MKK4−/− and MKK4−/−/7−/− murine embryonic fibroblasts. Genetic KO MEFs (MKK4−/−, MKK4−/−/7−/−), scaffold protein overexpression, JNK activity assay FEBS letters Medium 17187786
2009 Knockdown of Sec8 enhances binding of JIP4 (JNK-interacting protein 4) to MKK4 and decreases the phosphorylation of MKK4, JNK, and p38, suggesting Sec8 regulates MKK4-JNK signaling by modulating JIP4-MKK4 scaffold interactions. Sec8 siRNA knockdown, co-immunoprecipitation (JIP4-MKK4 binding), phospho-specific Western blot The FEBS journal Low 25244576
2018 MAP3K1 and MAP2K4 loss-of-function mutations confer sensitivity to MEK inhibition by disabling a JNK-JUN feedback loop that normally restores MAPK pathway activity upon MEK inhibition. MEK inhibition activates JNK-JUN signaling through suppression of DUSP4, and cancers lacking MAP2K4 fail to activate this feedback, disabling compensatory pathway re-activation. Loss-of-function mutation analysis in cancer cell lines and PDX models, DUSP4 modulation, JNK-JUN pathway measurements, 168-tumor PDX panel drug response Cell research Medium 29795445
2024 First-in-class small molecule inhibitors of MKK4 (MKK4i) were developed via structure-based design (NMR spectroscopy characterization). MKK4i increased liver regeneration upon hepatectomy in murine and porcine models, allowed pig survival in an 85% hepatectomy model, and showed antisteatotic and antifibrotic effects in liver disease models. A phase I clinical trial with candidate HRX215 showed acceptable safety and pharmacokinetics. Structure-based drug design, NMR spectroscopy characterization, in vivo hepatectomy models (mouse, pig), liver disease mouse models, phase I clinical trial Cell High 38490194
2020 A dual covalent MKK4/7 inhibitor (BSJ-04-122) was developed that targets a conserved cysteine before the DFG motif in both kinases. It exhibits potent cellular target engagement, downstream JNK pathway inhibition, and enhanced antiproliferative activity in triple-negative breast cancer cells when combined with a JNK inhibitor. Covalent inhibitor design, proteomics-based target engagement (mass spectrometry), kinase selectivity profiling, cell viability assays Cell chemical biology Medium 32916088
2009 In the Drosophila JNK pathway, Mkk4 plays a non-redundant role as a MAPKK acting in parallel to Hemipterous/Mkk7 in dTAK1-mediated JNK activation upon Eiger (TNF) and Imd pathway stimulation. Drosophila Mkk4 is dispensable for normal development but required (with Hep/Mkk7) for full JNK activation in the immune context. Dominant suppressor screen, allelic series genetic analysis, biochemical assays in Drosophila cells PloS one Medium 19888449
2018 In retinal ganglion cells, deficiency of Mkk4 or Mkk7 individually reduced JNK signaling after axonal injury (optic nerve crush) and each increased RGC survival. Combined deficiency of both Mkk4 and Mkk7 caused failure of optic nerve formation, irregular axonal trajectories, disrupted retinal lamination, and dendritic fasciculation, demonstrating redundant developmental roles and individual contributions to injury-induced apoptosis. Conditional retina-specific KO, optic nerve crush model, immunohistochemistry, RGC counting Cell death & disease High 30367030
2007 Targeted deletion of MKK4 abrogates TNF-induced NF-κB activation (IKK activation, IκBα phosphorylation/degradation, p65 nuclear translocation) and downregulates NF-κB-regulated anti-apoptotic gene products (survivin, IAP1, XIAP, Bcl-2, Bcl-xL, cFLIP), enhancing TNF-induced apoptosis in MKK4-KO fibroblasts. MKK4 gene-deleted fibroblasts from KO mice, NF-κB DNA binding assays, NF-κB reporter assay, Western blot for pathway components Journal of immunology High 17641059
2019 MAP2K4 interacts with Vimentin (co-immunoprecipitation) and activates the PI3K/AKT signaling pathway in breast cancer cells, promoting proliferation, migration, and invasion through downstream c-JUN activation, G1/S cell cycle progression, and EMT. MAP2K4 knockdown reversed these effects. Co-immunoprecipitation (MAP2K4-Vimentin), KD/OE in breast cancer cell lines, in vivo xenograft, phospho-PI3K/AKT Western blot Aging Low 31761784

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1995 Complementary gradients in expression and binding of ELF-1 and Mek4 in development of the topographic retinotectal projection map. Cell 674 7634327
2002 Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer research 337 12097290
1994 Identification and cloning of ELF-1, a developmentally expressed ligand for the Mek4 and Sek receptor tyrosine kinases. Cell 326 7522971
1997 Targeted disruption of the MKK4 gene causes embryonic death, inhibition of c-Jun NH2-terminal kinase activation, and defects in AP-1 transcriptional activity. Proceedings of the National Academy of Sciences of the United States of America 247 9096336
1998 Induction of cyclooxygenase-2 by the activated MEKK1 --> SEK1/MKK4 --> p38 mitogen-activated protein kinase pathway. The Journal of biological chemistry 226 9582321
2000 MPTP activates c-Jun NH(2)-terminal kinase (JNK) and its upstream regulatory kinase MKK4 in nigrostriatal neurons in vivo. Journal of neurochemistry 204 10936203
1998 JNKK1 organizes a MAP kinase module through specific and sequential interactions with upstream and downstream components mediated by its amino-terminal extension. Genes & development 175 9808624
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
1998 Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene. Cancer research 150 9622070
2009 The Parkinson disease-associated protein kinase LRRK2 exhibits MAPKKK activity and phosphorylates MKK3/6 and MKK4/7, in vitro. Journal of neurochemistry 149 19302196
2006 Physiological roles of MKK4 and MKK7: insights from animal models. Biochimica et biophysica acta 146 17157936
2012 (G2019S) LRRK2 activates MKK4-JNK pathway and causes degeneration of SN dopaminergic neurons in a transgenic mouse model of PD. Cell death and differentiation 145 22539006
2014 EDR1 physically interacts with MKK4/MKK5 and negatively regulates a MAP kinase cascade to modulate plant innate immunity. PLoS genetics 132 24830651
2002 Mitogen-activated protein kinase kinase 4 (MKK4) acts as a metastasis suppressor gene in human ovarian carcinoma. Cancer research 122 12438272
2005 Identification of ASK1, MKK4, JNK, c-Jun, and caspase-3 as a signaling cascade involved in cadmium-induced neuronal cell apoptosis. Biochemical and biophysical research communications 120 15670787
2011 The bottleneck of JNK signaling: molecular and functional characteristics of MKK4 and MKK7. European journal of cell biology 114 21333379
2013 MicroRNA-92a negatively regulates Toll-like receptor (TLR)-triggered inflammatory response in macrophages by targeting MKK4 kinase. The Journal of biological chemistry 113 23355465
2006 The p38 kinases MKK4 and MKK6 suppress metastatic colonization in human ovarian carcinoma. Cancer research 105 16489030
1997 Characterization of the mitogen-activated protein kinase kinase 4 (MKK4)/c-Jun NH2-terminal kinase 1 and MKK3/p38 pathways regulated by MEK kinases 2 and 3. MEK kinase 3 activates MKK3 but does not cause activation of p38 kinase in vivo. The Journal of biological chemistry 105 9162092
1997 Impaired CD28-mediated interleukin 2 production and proliferation in stress kinase SAPK/ERK1 kinase (SEK1)/mitogen-activated protein kinase kinase 4 (MKK4)-deficient T lymphocytes. The Journal of experimental medicine 105 9294148
2018 MAP3K1 and MAP2K4 mutations are associated with sensitivity to MEK inhibitors in multiple cancer models. Cell research 98 29795445
2000 Mitogen-activated protein kinase kinase 4 (MKK4). The international journal of biochemistry & cell biology 95 10785355
2004 Evidence of MKK4 pro-oncogenic activity in breast and pancreatic tumors. Oncogene 92 15184866
2009 MEK4 function, genistein treatment, and invasion of human prostate cancer cells. Journal of the National Cancer Institute 91 19638505
2009 Activated Ask1-MKK4-p38MAPK/JNK stress signaling pathway in human omental fat tissue may link macrophage infiltration to whole-body Insulin sensitivity. The Journal of clinical endocrinology and metabolism 88 19351724
1999 The mixed lineage kinase DLK utilizes MKK7 and not MKK4 as substrate. The Journal of biological chemistry 88 10187804
2014 MicroRNA-27a promotes proliferation, migration and invasion by targeting MAP2K4 in human osteosarcoma cells. Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology 81 24556602
2002 Ubiquitylation of MEKK1 inhibits its phosphorylation of MKK1 and MKK4 and activation of the ERK1/2 and JNK pathways. The Journal of biological chemistry 78 12456688
2019 Cinobufotalin powerfully reversed EBV-miR-BART22-induced cisplatin resistance via stimulating MAP2K4 to antagonize non-muscle myosin heavy chain IIA/glycogen synthase 3β/β-catenin signaling pathway. EBioMedicine 77 31594754
1996 Expression of the Tyro4/Mek4/Cek4 gene specifically marks a subset of embryonic motor neurons and their muscle targets. Molecular and cellular neurosciences 76 8812059
2009 Delphinidin suppresses ultraviolet B-induced cyclooxygenases-2 expression through inhibition of MAPKK4 and PI-3 kinase. Carcinogenesis 75 19776176
2014 Licochalcone A suppresses migration and invasion of human hepatocellular carcinoma cells through downregulation of MKK4/JNK via NF-κB mediated urokinase plasminogen activator expression. PloS one 74 24466137
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
1998 Immunolocalization of the mitogen-activated protein kinases p42MAPK and JNK1, and their regulatory kinases MEK1 and MEK4, in adult rat central nervous system. The Journal of comparative neurology 72 9714150
1997 Activation of p38mapk, MKK3, and MKK4 by TNF-alpha in mouse bone marrow-derived macrophages. Journal of immunology (Baltimore, Md. : 1950) 72 9379049
2014 LPS induced miR-181a promotes pancreatic cancer cell migration via targeting PTEN and MAP2K4. Digestive diseases and sciences 69 24532253
2011 Myricetin attenuated MPP(+)-induced cytotoxicity by anti-oxidation and inhibition of MKK4 and JNK activation in MES23.5 cells. Neuropharmacology 67 21549720
2020 Astrocyte-Derived Exosomal microRNA miR-200a-3p Prevents MPP+-Induced Apoptotic Cell Death Through Down-Regulation of MKK4. Neurochemical research 66 32016794
2009 Cardiac-specific deletion of mkk4 reveals its role in pathological hypertrophic remodeling but not in physiological cardiac growth. Circulation research 66 19265040
2013 Exendin-4 protects pancreatic beta cells from palmitate-induced apoptosis by interfering with GPR40 and the MKK4/7 stress kinase signalling pathway. Diabetologia 62 23995397
2011 Map2k4 functions as a tumor suppressor in lung adenocarcinoma and inhibits tumor cell invasion by decreasing peroxisome proliferator-activated receptor γ2 expression. Molecular and cellular biology 59 21896780
2004 MAP2K4/MKK4 expression in pancreatic cancer: genetic validation of immunohistochemistry and relationship to disease course. Clinical cancer research : an official journal of the American Association for Cancer Research 59 15623633
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
2016 Androgen-induced miR-27A acted as a tumor suppressor by targeting MAP2K4 and mediated prostate cancer progression. The international journal of biochemistry & cell biology 54 27594411
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
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
2009 A non-redundant role for Drosophila Mkk4 and hemipterous/Mkk7 in TAK1-mediated activation of JNK. PloS one 51 19888449
2014 miR-92a inhibits vascular smooth muscle cell apoptosis: role of the MKK4-JNK pathway. Apoptosis : an international journal on programmed cell death 50 24705900
2011 Nonvisual arrestins function as simple scaffolds assembling the MKK4-JNK3α2 signaling complex. Biochemistry 50 22047447
2006 Homozygous deletion of MKK4 in ovarian serous carcinoma. Cancer biology & therapy 49 16627982
2002 Bisindolylmaleimide VIII enhances DR5-mediated apoptosis through the MKK4/JNK/p38 kinase and the mitochondrial pathways. The Journal of biological chemistry 49 12034736
2024 First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure. Cell 48 38490194
2019 MicroRNA-27a-3p Downregulation Inhibits Inflammatory Response and Hippocampal Neuronal Cell Apoptosis by Upregulating Mitogen-Activated Protein Kinase 4 (MAP2K4) Expression in Epilepsy: In Vivo and In Vitro Studies. Medical science monitor : international medical journal of experimental and clinical research 47 31710596
2017 miR-141 promotes colon cancer cell proliferation by inhibiting MAP2K4. Oncology letters 46 28454307
2018 Intronic miR-744 Inhibits Glioblastoma Migration by Functionally Antagonizing Its Host Gene MAP2K4. Cancers 45 30366472
2010 PGE2 inhibits MMP expression by suppressing MKK4-JNK MAP kinase-c-JUN pathway via EP4 in human articular chondrocytes. Journal of cellular biochemistry 45 19998410
2002 Mutation rate of MAP2K4/MKK4 in breast carcinoma. Human mutation 45 11754110
2007 Inhibition of lipopolysaccharide-stimulated NO production by a novel synthetic compound CYL-4d in RAW 264.7 macrophages involving the blockade of MEK4/JNK/AP-1 pathway. Biochemical pharmacology 44 17379190
2002 Vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide inhibit the MEKK1/MEK4/JNK signaling pathway in endotoxin-activated microglia. Biochemical and biophysical research communications 44 12054537
2021 LncRNA CBR3-AS1 regulates of breast cancer drug sensitivity as a competing endogenous RNA through the JNK1/MEK4-mediated MAPK signal pathway. Journal of experimental & clinical cancer research : CR 42 33494806
2019 MAP2K4 interacts with Vimentin to activate the PI3K/AKT pathway and promotes breast cancer pathogenesis. Aging 42 31761784
2010 Cyanidin suppresses ultraviolet B-induced COX-2 expression in epidermal cells by targeting MKK4, MEK1, and Raf-1. Biochemical pharmacology 41 20096264
2014 Mitogen-activated protein kinase kinase 4 (MAP2K4) promotes human prostate cancer metastasis. PloS one 40 25019290
2005 Knock-down of POSH expression is neuroprotective through down-regulating activation of the MLK3-MKK4-JNK pathway following cerebral ischaemia in the rat hippocampal CA1 subfield. Journal of neurochemistry 39 16248889
2017 MicroRNA-802 plays a tumour suppressive role in tongue squamous cell carcinoma through directly targeting MAP2K4. Cell proliferation 38 28319306
2000 Vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide inhibit the MEKK1/MEK4/JNK signaling pathway in LPS-stimulated macrophages. Journal of neuroimmunology 37 11024538
2015 Toll-like receptor 4 signaling promotes invasion of hepatocellular carcinoma cells through MKK4/JNK pathway. Molecular immunology 35 26589455
2017 lncRNA-Map2k4 sequesters miR-199a to promote FGF1 expression and spinal cord neuron growth. Biochemical and biophysical research communications 34 28655615
2010 Diverse physiological functions of MKK4 and MKK7 during early embryogenesis. Journal of biochemistry 34 20801953
2020 Tanshinone IIA prevents platelet activation and down-regulates CD36 and MKK4/JNK2 signaling pathway. BMC cardiovascular disorders 31 32059638
2007 Inhibition of thioredoxin reductase induces apoptosis in neuronal cell lines: role of glutathione and the MKK4/JNK pathway. Biochemical and biophysical research communications 31 17559804
2019 Paeoniflorin inhibits tributyltin chloride-induced apoptosis in hypothalamic neurons via inhibition of MKK4-JNK signaling pathway. Journal of ethnopharmacology 29 30878547
2003 MKK4 and metastasis suppression: a marriage of signal transduction and metastasis research. Clinical & experimental metastasis 29 12650604
2022 Study on the mechanism of Tong-Qiao-Huo-Xue decoction regulating apoptosis via ASK1/MKK4/JNK pathway in MCAO/R rats. Phytomedicine : international journal of phytotherapy and phytopharmacology 28 36099654
2022 Pazopanib alleviates neuroinflammation and protects dopaminergic neurons in LPS-stimulated mouse model by inhibiting MEK4-JNK-AP-1 pathway. Acta pharmacologica Sinica 28 36536076
2020 Saikosaponin D Inhibits Proliferation and Promotes Apoptosis Through Activation of MKK4-JNK Signaling Pathway in Pancreatic Cancer Cells. OncoTargets and therapy 28 33061432
2004 Disruption of MKK4 signaling reveals its tumor-suppressor role in embryonic stem cells. Oncogene 28 15122334
2010 Filamin associates with stress signalling kinases MKK7 and MKK4 and regulates JNK activation. The Biochemical journal 27 20156194
2009 Genetic and molecular alterations in rhabdomyosarcoma: mRNA overexpression of MCL1 and MAP2K4 genes. Histology and histopathology 27 19012245
2007 Requirements for PKC-augmented JNK activation by MKK4/7. The international journal of biochemistry & cell biology 27 18182317
2022 The ARM repeat domain of hemocyanin interacts with MKK4 to modulate antimicrobial peptides expression. iScience 26 35265821
2018 Mkk4 and Mkk7 are important for retinal development and axonal injury-induced retinal ganglion cell death. Cell death & disease 26 30367030
2019 Overexpressed microRNA-136 works as a cancer suppressor in gallbladder cancer through suppression of JNK signaling pathway via inhibition of MAP2K4. American journal of physiology. Gastrointestinal and liver physiology 25 31369289
2017 MKK4 from Litopenaeus vannamei is a regulator of p38 MAPK kinase and involved in anti-bacterial response. Developmental and comparative immunology 25 28939483
2020 Discovery of Covalent MKK4/7 Dual Inhibitor. Cell chemical biology 23 32916088
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
2011 A vaccinia virus-driven interplay between the MKK4/7-JNK1/2 pathway and cytoskeleton reorganization. Journal of virology 23 22031940
2007 Regulation of the metastasis suppressor gene MKK4 in ovarian cancer. Gynecologic oncology 22 17276500
2023 Fluorofenidone protects against acute liver failure in mice by regulating MKK4/JNK pathway. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 21 37224750
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
2007 Targeted deletion of MKK4 gene potentiates TNF-induced apoptosis through the down-regulation of NF-kappa B activation and NF-kappa B-regulated antiapoptotic gene products. Journal of immunology (Baltimore, Md. : 1950) 21 17641059
2023 MKK4 Inhibitors-Recent Development Status and Therapeutic Potential. International journal of molecular sciences 20 37108658
2020 Long noncoding RNA HNF1A-AS1 regulates proliferation and apoptosis of glioma through activation of the JNK signaling pathway via miR-363-3p/MAP2K4. Journal of cellular physiology 20 32779194
2018 Synergistic antimetastatic effect of cotreatment with licochalcone A and sorafenib on human hepatocellular carcinoma cells through the inactivation of MKK4/JNK and uPA expression. Environmental toxicology 20 30187994
2014 Knockdown of Sec8 enhances the binding affinity of c-Jun N-terminal kinase (JNK)-interacting protein 4 for mitogen-activated protein kinase kinase 4 (MKK4) and suppresses the phosphorylation of MKK4, p38, and JNK, thereby inhibiting apoptosis. The FEBS journal 20 25244576
2011 Analysis of the mitogen-activated protein kinase kinase 4 (MAP2K4) tumor suppressor gene in ovarian cancer. BMC cancer 20 21575258
2009 MKK4/SEK1 is negatively regulated through a feedback loop involving the E3 ubiquitin ligase itch. The Journal of biological chemistry 20 19737936
2008 New paradigms for the function of JNKK1/MKK4 in controlling growth of disseminated cancer cells. Cancer letters 20 18572308
2006 Differential requirement of MKK4 and MKK7 in JNK activation by distinct scaffold proteins. FEBS letters 20 17187786

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