Affinage

MAP2K6

Dual specificity mitogen-activated protein kinase kinase 6 · UniProt P52564

Length
334 aa
Mass
37.5 kDa
Annotated
2026-04-28
100 papers in source corpus 48 papers cited in narrative 47 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAP2K6 (MKK6) is a dual-specificity MAP kinase kinase that serves as the primary upstream activator of all four p38 MAPK isoforms (α, β, γ, δ), phosphorylating their TGY activation loop motif in response to diverse stresses, cytokines, and receptor signals relayed through MAP3Ks including MEKK3, ASK1, TAK1, TPL-2, and PKR (PMID:8621675, PMID:9430721, PMID:10347227, PMID:20364819, PMID:15229216, PMID:27402796). Structural studies reveal that unphosphorylated MKK6 adopts an autoinhibited dimeric conformation with unique activation-loop α-helices that prevent premature activation, while the cryo-EM structure of the MKK6–p38α complex demonstrates a dynamic multistep dual-phosphorylation mechanism in which MKK6's disordered N-terminus determines pathway specificity (PMID:19141286, PMID:22383536, PMID:37708276). MKK6 activity is negatively regulated by p38α-mediated destabilization of its own mRNA, FBXO31-directed K48-linked ubiquitination and proteasomal degradation, and PPM1G-catalyzed dephosphorylation, while TRIM9s-mediated K63-linked ubiquitination at Lys82 stabilizes MKK6 in a positive feedback loop (PMID:12482988, PMID:24936062, PMID:36349938, PMID:29669288). Beyond canonical p38 signaling, MKK6 phosphorylates non-p38 substrates including Gatad2b to promote chromatin remodeling during somatic cell reprogramming, directly interacts with Rac1 to modulate GTPase activity, and exerts p38-independent inhibition of ERK signaling, underpinning its roles in inflammation, apoptosis, G2 arrest, thymocyte negative selection, adipogenesis, osteoclastogenesis, chondrogenesis, and cardiac homeostasis (PMID:34815549, PMID:17854274, PMID:32371393, PMID:12151339, PMID:10585441, PMID:35971771).

Mechanistic history

Synthesis pass · year-by-year structured walk · 20 steps
  1. 1996 High

    Identification of MKK6 as a selective p38 MAPK activator resolved the question of which MAP2K relays stress/cytokine signals specifically to p38 rather than ERK or JNK, establishing the specificity principle of MAPK cascades.

    Evidence cDNA cloning, co-transfection, and direct in vitro kinase assays in multiple labs; biochemical purification from rabbit skeletal muscle

    PMID:8621675 PMID:8626699 PMID:8861944

    Open questions at the time
    • Relative contributions of MKK6 vs MKK3 to p38 activation in specific tissues were not resolved
    • Upstream MAP3Ks for MKK6 were unknown
  2. 1997 High

    Demonstration that MKK6 activates p38γ and p38δ (in addition to p38α/β) while MKK3 cannot activate p38β2 established MKK6 as the broadest-spectrum p38 activator and defined isoform-specific coupling rules.

    Evidence In vitro kinase assays and co-transfection in COS cells with all four p38 isoforms

    PMID:9029150 PMID:9218798 PMID:9430721

    Open questions at the time
    • Whether isoform selectivity held in vivo with endogenous expression levels was untested
    • Structural basis for broader substrate range of MKK6 vs MKK3 was unknown
  3. 1998 Medium

    Placement of MKK6 downstream of specific receptor systems—Fas, TCR, TNF/RIP/TRAF2, and Gq-coupled receptors—and demonstration that constitutively active MKK6(Glu) confers p38-dependent anti-apoptotic or pro-inflammatory effects established MKK6 as a critical signaling node in immune and cardiac cell biology.

    Evidence Dominant-negative MKK6 epistasis, constitutively active MKK6(Glu) gain-of-function, reporter assays, and pharmacological inhibition in T cells, monocytes, endothelial cells, and cardiac myocytes

    PMID:9362518 PMID:9525929 PMID:9575191 PMID:9712898

    Open questions at the time
    • Direct MAP3K→MKK6 phosphorylation was not reconstituted
    • Endogenous protein-level validation was limited in most systems
  4. 1999 High

    Identification of MEKK3 as a MAP3K that directly phosphorylates and activates MKK6 in vitro filled the gap between upstream signals and MKK6 activation, completing a three-tier MEKK3→MKK6→p38 cascade.

    Evidence In vitro kinase assay with immunoprecipitated MEKK3 and recombinant MKK6, cascade reconstitution to MAPKAPK2 in COS-7 cells

    PMID:10347227

    Open questions at the time
    • Physiological contexts requiring MEKK3 vs other MAP3Ks for MKK6 activation were unclear
    • Other MAP3Ks capable of activating MKK6 had not been systematically identified
  5. 2000 High

    Discovery that MKK6–p38γ mediates ATM-dependent G2 arrest after γ-irradiation and that MKK6–p38/MAPKAPK2 phosphorylates αB-crystallin for cytoprotection expanded MKK6 function beyond inflammation to DNA damage response and proteostasis.

    Evidence Dominant-negative alleles for MKK6 and p38γ, cell cycle analysis after irradiation, epistasis with ATM; constitutively active MKK6(Glu) in cardiac myocytes with phospho-site mapping

    PMID:10816593 PMID:10848581

    Open questions at the time
    • Direct ATM→MKK6 phosphorylation was not shown
    • Whether p38γ-selective G2 arrest generalizes beyond HeLa cells was untested
  6. 2002 High

    Generation of Mkk6 knockout mice revealed a non-redundant requirement for MKK6 in thymocyte negative selection, distinct from MKK3's role in peripheral T cell apoptosis, establishing in vivo isoform specificity.

    Evidence Mkk6−/− and Mkk3−/− mice, thymocyte deletion assays, peripheral T cell death assays

    PMID:12151339

    Open questions at the time
    • Molecular basis for MKK6's exclusive role in thymic deletion vs MKK3 in peripheral apoptosis was unknown
    • Compensatory mechanisms in double-knockout mice were not examined
  7. 2003 High

    Identification of a p38α-mediated negative feedback loop that destabilizes MKK6 mRNA via its 3′UTR revealed autoregulation of MAPK cascade amplitude and explained elevated MKK6 in p38α-null cells.

    Evidence p38α−/− MEFs, mRNA stability assays, 3′UTR luciferase reporters, rescue by p38α re-expression

    PMID:12482988

    Open questions at the time
    • RNA-binding protein(s) mediating p38α-dependent MKK6 mRNA decay were not identified
    • Whether this feedback operates in all tissues was unknown
  8. 2004 High

    Demonstration that PKR directly phosphorylates MKK6 (but not MKK3/4) upon dsRNA stimulation identified a unique MAP3K-like activator linking innate antiviral sensing to p38 signaling.

    Evidence In vitro kinase assay, coupled kinase cascade, PKR−/− cells, kinase-inactive PKR dominant-negative

    PMID:15229216

    Open questions at the time
    • Phosphorylation sites on MKK6 targeted by PKR were not mapped
    • Contribution of PKR–MKK6 axis relative to conventional MAP3Ks in vivo was unclear
  9. 2005 High

    Structural analysis of p38α inhibitors showed that DFG-out conformation stabilizers block MKK6-dependent p38α activation by displacing the activation loop, providing mechanistic insight into how substrate conformation gates upstream kinase access.

    Evidence Crystal structures of seven p38α-inhibitor complexes, cell-free MKK6-dependent p38α activation assay, cellular TNFα inhibition

    PMID:16342939

    Open questions at the time
    • No co-crystal of MKK6 with p38α was available at this time
    • Whether DFG-out inhibitors affect MKK6 interaction with other p38 isoforms was not tested
  10. 2007 Medium

    MKK6 was found to interact directly with Rac1 and modulate its GTPase activity, and to recruit SWI/SNF chromatin remodelers to muscle gene promoters via p38, expanding MKK6's roles beyond canonical MAPK signaling to include GTPase regulation and chromatin remodeling.

    Evidence Co-IP of MKK6–Rac1, Y219F mutagenesis, NADPH oxidase assays in MKK6−/− tissue; ChIP for SWI/SNF complex on muscle gene promoters with p38 pathway perturbation

    PMID:17854274 PMID:17964260

    Open questions at the time
    • Whether MKK6 phosphorylates Rac1 directly was not established
    • Whether SWI/SNF recruitment requires direct p38-mediated phosphorylation of SWI/SNF subunits was untested
  11. 2009 High

    The crystal structure of the MKK6 kinase domain revealed an autoinhibited elongated dimer whose interface occludes the activation loop, explaining how MKK6 prevents spurious activation and providing the first atomic model of a MAP2K autoinhibitory mechanism.

    Evidence X-ray crystallography at 2.3 Å (phosphomimetic DD mutant), SAXS confirmation of dimer in solution

    PMID:19141286

    Open questions at the time
    • How MAP3K binding disrupts the autoinhibitory dimer was unknown
    • Whether the dimer exists under physiological concentrations in cells was not shown
  12. 2010 High

    Quantitative kinetics of ASK1-mediated MKK6 phosphorylation showed that oxidative stress increases ASK1's catalytic efficiency for MKK6 ~4000-fold (primarily by decreasing Km ~1000-fold), revealing a stress-regulated substrate recruitment mechanism within the ASK1 signalosome.

    Evidence In vitro kinetic analysis, immunoprecipitation, high-MW signalosome purification from H2O2-treated cells

    PMID:20364819

    Open questions at the time
    • Identity of adaptor proteins mediating stress-dependent Km reduction was unknown
    • Whether similar kinetic regulation applies to other MAP3K–MKK6 pairs was untested
  13. 2012 High

    A second MKK6 crystal structure (non-phosphorylated, ATP-analogue-bound) revealed three unique activation-loop α-helices (AH1–AH3) that enforce autoinhibition by displacing αC-helix and sequestering the ATP γ-phosphate, establishing a distinct autoinhibitory mechanism from other MAP2Ks.

    Evidence X-ray crystallography at 2.6 Å, structural comparison with MAP2K1 and MAP2K4

    PMID:22383536

    Open questions at the time
    • How upstream phosphorylation unfolds the AH1–AH3 helices was not resolved
    • No structure of MAP3K-bound MKK6 existed
  14. 2014 Medium

    Identification of FBXO31-mediated K48-linked polyubiquitination as a degradation pathway for MKK6 established ubiquitin-proteasome regulation as a mechanism controlling MKK6 protein levels during genotoxic stress.

    Evidence Co-IP, K48-specific ubiquitination assay, proteasome inhibitor rescue, functional assays in cancer cells

    PMID:24936062

    Open questions at the time
    • Specific lysine residue(s) ubiquitinated by FBXO31 were not mapped
    • In vivo validation in knockout models was lacking
  15. 2017 High

    Mkk6 deletion in mice increased white adipose tissue thermogenesis and UCP1 expression, protecting against diet-induced obesity, revealing MKK6 as a negative regulator of adaptive thermogenesis—an unexpected role given its canonical p38-activating function.

    Evidence MKK6 knockout mice, metabolic phenotyping, UCP1 expression analysis, pathway dissection showing p38 activation via alternative AMPK–TAK–TAB pathway in WAT

    PMID:29021624

    Open questions at the time
    • Whether MKK6's thermogenic suppression is cell-autonomous in adipocytes vs systemic was not fully resolved
    • Direct mechanism by which MKK6 suppresses UCP1 was not identified
  16. 2018 High

    Discovery that TRIM9s stabilizes MKK6 via K63-linked ubiquitination at Lys82, competing with degradative K48-linked ubiquitination at the same residue, while MKK6/p38 reciprocally stabilizes TRIM9s, revealed a positive feedback circuit controlling p38 pathway amplitude.

    Evidence Co-IP, K48 vs K63 linkage-specific ubiquitination assays, Lys82 mutagenesis, phospho-site mapping (Ser76/80) on TRIM9s

    PMID:29669288

    Open questions at the time
    • Whether this feedback operates in all tissues or is context-specific was unknown
    • Other E3 ligases mediating K48 ubiquitination at Lys82 beyond FBXO31 were not identified
  17. 2020 High

    Optogenetic activation of MKK6 demonstrated that MKK6 inhibits ERK signaling with equal potency regardless of p38 inhibition, establishing a p38-independent cross-regulatory function of MKK6 between the p38 and ERK MAPK pathways.

    Evidence Light-activated (caged lysine) MKK6, pharmacological inhibition of all p38 isoforms, ERK phosphorylation readout, apoptosis assay

    PMID:32371393

    Open questions at the time
    • Direct molecular target through which MKK6 inhibits ERK was not identified
    • Whether this cross-regulation occurs at a MAP3K, RAF, or MEK1/2 level was unknown
  18. 2021 Medium

    Identification of Gatad2b as a direct, p38-independent MKK6 substrate linked MKK6 kinase activity to chromatin remodeling (H3K9 acetylation, heterochromatin loosening) during somatic cell reprogramming, expanding MKK6's substrate repertoire beyond p38.

    Evidence Kinase assays, ATAC-seq, ChIP for H3K9ac, iPSC reprogramming efficiency with MKK6 overexpression/knockdown

    PMID:34815549

    Open questions at the time
    • Phosphorylation sites on Gatad2b targeted by MKK6 were not fully mapped
    • Independent replication of Gatad2b as a direct substrate is needed
  19. 2022 High

    MKK6 deficiency in mice caused compensatory MKK3–p38γ/δ hyperactivation and mTOR-dependent cardiac hypertrophy reversible by rapamycin, revealing that the MKK6/MKK3 balance controls p38 isoform signaling output with pathological consequences for the heart.

    Evidence MKK6 knockout mice, longitudinal echocardiography, p38γ/δ double-knockout rescue, rapamycin treatment

    PMID:35971771

    Open questions at the time
    • How MKK6 loss causes MKK3–p38γ/δ hyperactivation mechanistically was not determined
    • Whether cardiac hypertrophy depends on cardiomyocyte-autonomous MKK6 loss was not tested with conditional knockouts
  20. 2023 High

    The cryo-EM structure of the MKK6–p38α complex, combined with HDX-MS and MD simulations, revealed a dynamic multistep dual-phosphorylation mechanism and showed that MKK6's disordered N-terminus determines pathway specificity, providing the first high-resolution view of a MAP2K–MAPK catalytic complex.

    Evidence Cryo-EM, molecular dynamics simulation, hydrogen-deuterium exchange mass spectrometry, cell-based assays

    PMID:37708276

    Open questions at the time
    • Structures of MKK6 complexed with p38β/γ/δ are not available
    • Mechanism by which the N-terminus discriminates p38 from ERK/JNK substrates at atomic resolution is incompletely resolved
    • No structure of an activated MAP3K–MKK6 complex exists

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include: the molecular target through which MKK6 inhibits ERK signaling independently of p38; whether MKK6's autoinhibitory dimer is disrupted by MAP3K binding or other mechanisms in cells; the full scope of non-p38 MKK6 substrates; and the structural basis for MKK6 vs MKK3 isoform selectivity toward p38 family members.
  • Direct p38-independent MKK6 target in ERK pathway not identified
  • No MAP3K–MKK6 co-structure available
  • Comprehensive substrate profiling not performed

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 8 GO:0016740 transferase activity 4
Localization
GO:0005829 cytosol 2
Pathway
R-HSA-162582 Signal Transduction 7 R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-1266738 Developmental Biology 2 R-HSA-4839726 Chromatin organization 2
Partners
FBXO31MAP3K3MAP3K5MAPK11MAPK12MAPK14RAC1TRIM9
Complex memberships
ASK1 signalosome

Evidence

Reading pass · 47 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 MKK6 (MAP2K6) was identified as a novel MAP kinase kinase that selectively phosphorylates and activates p38 MAPK, but not ERK or JNK family members, as demonstrated by direct kinase assays and co-transfection studies. Two human splice isoforms (278 and 334 aa) and one murine isoform were cloned. cDNA cloning, co-transfection assays, direct in vitro kinase assays The Journal of biological chemistry High 8621675 8626699
1996 SAPKK3/MKK6 was purified from rabbit skeletal muscle as the major activator of RK/p38 in stress- and cytokine-stimulated monocytes and epithelial cells; it activates p38 but not JNK/SAPK in vitro. Protein purification to near homogeneity, tryptic peptide sequencing, cDNA cloning, in vitro kinase assay The EMBO journal High 8861944
1997 MKK6 (SAPKK3) selectively activates SAPK3/p38gamma and SAPK4/p38delta in response to cytokines and cellular stresses, and is the only activator of these isoforms induced by IL-1 or stress in KB cells. MKK6 mediates phosphorylation of ATF2, Elk-1 and SAP-1 through these downstream kinases. In vitro kinase assay, co-transfection in COS cells, immunoprecipitation kinase assay The EMBO journal High 9029150 9218798
1998 MKK6 is identified as a common activator of p38α, p38β2, and p38γ isoforms, while MKK3 activates only p38α and p38γ, defining selective coupling between upstream kinases and p38 isoforms. Molecular cloning, co-transfection assays, in vitro kinase assays The Journal of biological chemistry High 9430721
1998 In Fas signaling, MKK6 is the major upstream activator of p38, acting independently of CPP32-like proteases; MKK7 (not MKK4/SEK1) activates JNK in the same pathway, establishing pathway-specific MKK usage downstream of Fas. Immunoprecipitation kinase assay, peptide inhibitor experiments, co-transfection The Journal of cell biology Medium 9362518
1998 MKK6 (constitutively active MKK6(Glu)) selectively activates p38 in cardiac myocytes, protecting them from apoptosis in a p38-dependent manner and activating NF-κB transcription; anti-apoptotic effect is blocked by SB203580. Overexpression of constitutively active MKK6(Glu) in primary neonatal rat ventricular myocytes, SB203580 inhibition, NF-κB reporter assay, cell death assays The Journal of biological chemistry High 9525929
1998 MKK6 is activated by T cell receptor signaling and is required for p38-dependent IL-2 promoter transcriptional activation; dominant-negative MKK6 suppresses IL-2 promoter activity; both MKK6-p38 and MKK7-JNK pathways are inhibited by cyclosporin A. Dominant-negative mutant expression, luciferase reporter assay, kinase assay in T lymphocytes The Journal of biological chemistry Medium 9575191
1998 In TNF signaling, RIP (receptor interacting protein) associates with an endogenous MAPKKK that activates MKK6 and the p38 pathway in vitro; TRAF2 activation of p38 requires RIP, placing RIP upstream of MKK6. In vivo binding assays, in vitro kinase cascade assay, co-expression studies The Journal of biological chemistry Medium 9712898
1999 MEKK3 (and MEKK2) directly phosphorylate and activate MKK6 in vitro, identifying MEKK3 as a MAP3K upstream of MKK6 in the p38 pathway; immunoprecipitated MEKK3 directly activated recombinant MKK6 in cell-free assays. Co-expression in COS-7 cells, in vitro kinase assay with immunoprecipitated MEKK3/MKK6, MAPKAPK2 phosphorylation assay The Journal of biological chemistry High 10347227
1999 The MKK6/p38 pathway is required for TNF-α-induced MCP-1 expression in endothelial cells; dominant-negative MKK6 strongly inhibits MCP-1, and constitutively active MKK6 enhances it, as shown by flow cytometry, Northern blot, and luciferase reporter assays. Dominant-negative and constitutively active MKK6 expression, flow cytometry, Northern blot, luciferase reporter assay Blood Medium 9920834
1999 Constitutively active MKK6 (MKK6(Glu)) is sufficient to drive spontaneous adipogenesis of 3T3-L1 fibroblasts in the absence of hormonal inducers, demonstrating that p38 activation via MKK6 is sufficient for the adipogenic differentiation program. Inducible expression system for MKK6(Glu), Oil Red O staining, morphological analysis in 3T3-L1 and NIH-3T3 cells The Journal of biological chemistry Medium 10585441
2000 Activation of the MKK6-p38γ cascade, but not other p38 isoforms, is required and sufficient for γ-irradiation-induced G2 cell cycle arrest; dominant-negative MKK6 or p38γ abrogates the DNA damage-induced G2 delay; MKK6 activation is ATM-dependent and leads to Cds1/Chk2 activation. Dominant-negative allele expression, gamma-irradiation, cell cycle analysis, epistasis with ATM Molecular and cellular biology High 10848581
2000 MKK6(Glu) induces p38-dependent transcriptional upregulation and phosphorylation of αB-crystallin on serine-59 (via MAPKAP-K2) in cardiac myocytes, providing cytoprotection against stress-induced apoptosis. Constitutively active MKK6(Glu) overexpression, Northern/Western blot, in vitro kinase assay, apoptosis assay in cardiac myocytes The Journal of biological chemistry Medium 10816593
2000 IL-12 activates p38 which, together with MKK6, phosphorylates STAT4 on serine 721 to drive full STAT4 transcriptional activity; mutation of Ser721 abrogates IL-12-induced transcription, establishing an MKK6/p38α/STAT4 signaling axis. Co-transfection, in vitro kinase assay, site-directed mutagenesis (S721A), luciferase reporter, dominant-negative MKK6 Blood High 10961885
2001 G protein Gαq activates MKK6 in a Rho-dependent manner, while Gβγ activates MKK6 via Rho-, Rac-, and Cdc42-dependent pathways; kinase-deficient MKK6 blocks p38 activation by Gαq and Gβγ, placing MKK6 downstream of Gq-coupled receptors. Kinase-deficient mutant expression in HEK293 cells, p38 activity assay, GTPase dependency studies The Journal of biological chemistry Medium 11304531
2001 MKK6/MKK3-p38 MAPK pathway activation by constitutively active MKK6 upregulates GLUT1 and downregulates GLUT4 expression in adipocytes and myotubes, increasing basal glucose transport while reducing insulin-stimulated uptake; p38 activation is not required for insulin-induced glucose uptake itself. Adenovirus-mediated expression of constitutively active/dominant-negative MKK6 and MKK3, glucose uptake assay, Western blot in 3T3-L1 adipocytes and L6 myotubes The Journal of biological chemistry Medium 11279172
2002 MKK6 is specifically required for deletion of double-positive thymocytes in vivo (negative selection), while MKK3 (not MKK6) is required for activation-induced cell death and cytokine withdrawal-induced apoptosis of peripheral CD4+ T cells; established using Mkk6-/- and Mkk3-/- mice. Mkk6 knockout mouse generation, thymocyte deletion assay, T cell apoptosis assays EMBO reports High 12151339
2003 p38α negatively regulates MKK6 mRNA stability via the 3'UTR of MKK6 mRNA, forming a negative feedback loop; p38α-/- cells have elevated MKK6 mRNA and protein; reintroduction of p38α normalizes MKK6 levels. p38α knockout MEFs, pharmacological p38α inhibition, mRNA stability assay, 3'UTR reporter assay Molecular and cellular biology High 12482988
2003 MKK6-p38 MAPK pathway activation prolongs cardiac contractile calcium transients by downregulating SERCA2 expression, increasing diastolic [Ca2+]i and activating NF-AT; SERCA2 overexpression reverses these effects. MKK6(Glu) overexpression in neonatal rat ventricular myocytes, indo-1 calcium imaging, Northern/Western blot, SERCA2 reporter assay, NF-AT reporter Cardiovascular research Medium 12829175
2004 PKR (double-stranded RNA-activated protein kinase) interacts with and directly phosphorylates MKK6 (but not MKK3 or MKK4) following dsRNA stimulation, providing a mechanism for p38 activation in the dsRNA response. Co-immunoprecipitation, in vitro kinase assay, coupled kinase assay, kinase-inactive PKR dominant-negative, PKR-null cells The Journal of biological chemistry High 15229216
2005 MEKK3 activates MKK6 and p38 in the p38 pathway in intact cells; anisomycin, sorbitol, or MEKK3 expression all activate MAPKAPK2 in a p38/SB203580-sensitive manner, confirming MEKK3→MKK6→p38 as a physiologically relevant cascade. Co-expression in COS-7 and HEK293 cells, in vitro kinase assay, SB203580 inhibition The Journal of biological chemistry Medium 10347227
2005 Selectivity pocket inhibitors of p38α (e.g., BIRB796) that stabilize a DFG-out conformation prevent MKK6-dependent phosphorylation/activation of p38α, while purine-site-only inhibitors do not; crystal structures of seven inhibitor complexes were solved, showing the activation loop displacement that blocks MKK6 recognition. Kinetic analysis, novel cell-free MKK6-dependent p38α activation assay, crystal structures (4 new), cellular TNFα inhibition assay Biochemistry High 16342939
2005 Type I interferons (IFNα/β) activate both MKK3 and MKK6, which are required for downstream p38 activation and for IFN-dependent gene transcription (Isg15, Irf-9) via a STAT-independent mechanism, as shown using MKK3-/-/MKK6-/- double-knockout MEFs. Double-knockout MEFs, luciferase reporter assay, kinase assay, qPCR The Journal of biological chemistry High 15644321
2006 TAK1 and MKK6 (but not MKK3) are required for RANKL-induced NFATc1 induction and NF-κB transactivation (via p65 Ser-536 phosphorylation) during osteoclast differentiation; dominant-negative TAK1 and MKK6 both impair osteoclastogenesis. Retroviral transduction of dominant-negative kinases, RANKL-stimulated primary bone marrow cells, NFATc1 and NF-κB reporter assays, Western blot Cell death and differentiation Medium 16498455
2007 MKK6-p38 signaling in inflammation-activated muscle progenitors recruits the SWI/SNF chromatin-remodeling complex to muscle gene promoters; MKK6/p38 and IGF1/PI3K/AKT pathways converge on chromatin of muscle genes to regulate distinct components of the myogenic transcriptosome. Chromatin immunoprecipitation, genetic and pharmacological inhibition of p38 and AKT, MEF2-SWI/SNF complex assembly assays Molecular cell High 17964260
2007 TNF-α stabilizes SOCS3 mRNA via activation of the MKK6/p38MAPK/MK2 cascade; in MK2-deficient fibroblasts and macrophages, basal SOCS3 expression is reduced and TNF-α-induced SOCS3 mRNA stabilization is impaired. The 3'UTR AUUUA/U-rich region (positions 2422–2541) of SOCS3 is identified as the regulatory target. MK2 knockout cells, mRNA stability assay, 3'UTR mapping, dominant-negative MKK6 expression Journal of immunology High 17312125
2007 Constitutively active MKK6 in chondrocytes in vivo (transgenic mice) reduces chondrocyte proliferation, inhibits hypertrophic differentiation, delays ossification, and increases Sox9 transcriptional activity; p38 signaling increases Sox9 transactivation in transfected cells, suggesting Sox9 is a downstream target of MKK6-p38 in endochondral ossification. Transgenic mouse generation, in situ hybridization, histology, co-transfection reporter assay for Sox9 Proceedings of the National Academy of Sciences of the United States of America High 16387856
2007 MKK6 phosphorylation (especially Tyr219) enhances Rac GTPase activity; constitutively active MKK6 directly interacts with Rac1 in vitro and inhibits PMA-induced NADPH oxidase activation in RAW cells; MKK6 deficiency leads to increased Rac1-GTP levels in brain tissue. Co-immunoprecipitation under redox stress, in vitro kinase assay, site-directed mutagenesis (Y219F), NADPH oxidase activity assay, MKK6 knockout brain tissue Antioxidants & redox signaling Medium 17854274
2009 The crystal structure of the MEK6/MAP2K6 kinase domain (phosphomimetic DD mutant, 2.3 Å) reveals an autoinhibited elongated dimer; the interface includes the phosphate-binding ribbon, activation loop, and an arginine stack; the dimer conformation prevents activation loop phosphorylation by inappropriate kinases. Solution SAXS confirms the dimer. X-ray crystallography (2.3 Å), gel filtration, SAXS Structure High 19141286
2009 Using MKK3-/-, MKK6-/-, and double-knockout cells, MKK3 and MKK6 are both required for stress-induced p38γ and p38β activation, while MKK6 is the major p38γ activator in response to TNFα; p38δ activation by UV, osmotic shock, anisomycin, and TNFα is mediated selectively by MKK3. MKK knockout fibroblasts, kinase activity assays, phosphorylation of downstream substrate hDlg Cellular signalling High 20004242
2010 ASK1 phosphorylates MKK6 in response to oxidative stress (H2O2); H2O2 treatment increases ASK1 catalytic efficiency for MKK6 ~4000-fold primarily by decreasing Km(MKK6) ~1000-fold; MKK6 co-purifies within the ASK1 signalosome in a transient, stress-regulated manner. In vitro kinetic analysis, immunoprecipitation, high-molecular mass complex purification from intact cells Biochemistry High 20364819
2010 LRRK2 (Parkinson's disease kinase) binds to MKK6 and phosphorylates MKK6 in vitro; co-expression of LRRK2 and MKK6 increases steady-state levels of each protein and increases MKK6 membrane localization; disease-linked LRRK2 mutations (G2019S, R1441C, I2020T) enhance binding to MKK6. Co-immunoprecipitation, in vitro kinase assay, subcellular fractionation, C. elegans RNAi epistasis Journal of neurochemistry Medium 20067578
2010 Constitutively active MKK6 in melanocytes induces dendrite elongation via upregulation of Cdc42 and Rac1 (Rho family GTPases), identifying MKK6 as an upstream regulator of dendricity through this GTPase pathway. Adenovirus-mediated constitutively active MKK6 overexpression, morphometric analysis, Western blot in SK-mel-24 melanoma and primary human melanocytes Journal of dermatological science Low 20869211
2012 Crystal structure of non-phosphorylated human MAP2K6 complexed with an ATP analogue (2.6 Å) reveals three activation-loop α-helices (AH1, AH2, AH3) that enforce auto-inhibition: AH1 displaces the αC-helix and AH1/AH2 enclose the ATP γ-phosphate, representing a unique auto-inhibition mechanism distinct from MAP2K1 and MAP2K4. X-ray crystallography (2.6 Å), structural comparison Journal of biochemistry High 22383536
2013 β-Amyloid activates MKK6 (phosphorylation at Ser207), which then directly phosphorylates p66shc at Ser36; MKK6 physically associates with p66shc (co-IP), and this MKK6-p66shc complex mediates β-amyloid-evoked ROS production and apoptotic cell death. Co-immunoprecipitation, site-directed mutagenesis, MKK6 knockdown, ROS assay, apoptosis assay Neuromolecular medicine Medium 24085465
2014 FBXO31, a component of SCF E3 ubiquitin ligase, binds MKK6 and mediates its Lys48-linked polyubiquitination and proteasomal degradation, functioning as a negative regulator of MKK6-p38 signaling upon genotoxic stress. Co-immunoprecipitation, ubiquitination assay (K48-specific), proteasome inhibitor studies, loss-of-function in cancer cells The Journal of biological chemistry Medium 24936062
2016 TPL-2 (MAP3K8) kinase activity is required for TLR4 and TNF receptor activation of MKK3/6 phosphorylation in macrophages, downstream of IKK-mediated phosphorylation of NF-κB1 p105; established by quantitative mass spectrometry comparing wild-type and kinase-inactive TPL-2 knock-in macrophages. Quantitative phosphoproteomics (mass spectrometry), kinase-inactive knock-in mice, macrophage stimulation assays The Biochemical journal High 27402796
2016 miR-625-3p directly targets MAP2K6 mRNA (validated by luciferase reporter), reducing MAP2K6-p38 signaling and inducing oxaliplatin resistance in colorectal cancer cells; resistance is reversed by anti-miR-625-3p treatment or ectopic expression of a miR-625-3p-insensitive MAP2K6 variant. Luciferase reporter assay, siRNA, dominant-negative MAP2K6, transcriptome/proteome/phosphoproteome profiling, functional rescue Nature communications High 27526785
2017 MKK6 is elevated in white adipose tissue of obese individuals; Mkk6 deletion in mice increases thermogenic capacity and UCP1 expression in WAT via T3 stimulation, protecting against diet-induced obesity; mechanistically, p38 is activated in WAT through an alternative pathway involving AMPK-TAK-TAB rather than MKK6. MKK6 knockout mice, shRNA knockdown, UCP1 expression assay, metabolic phenotyping, pathway dissection with specific inhibitors Nature communications High 29021624
2018 TRIM9 short isoform (TRIM9s) stabilizes MKK6 by promoting K63-linked ubiquitination at Lys82, thereby blocking competing degradative K48-linked ubiquitination at the same lysine; MKK6 in turn stabilizes TRIM9s via p38-dependent phosphorylation at Ser76/80, forming a positive feedback loop that enhances p38 signaling. Co-immunoprecipitation, ubiquitination assay (K48 vs K63 linkage), mutagenesis (Lys82, Ser76/80), phosphorylation assay Cell reports High 29669288
2018 Gossypetin directly inhibits MKK3 and MKK6 protein kinase activity in vitro; Arg61 in MKK6 is critical for gossypetin binding as shown by mutagenesis; inhibition is dependent on MKK3/6 expression in cells. In vitro kinase assay, computational docking, site-directed mutagenesis (R61), cell growth assays Cancer letters Medium 30391783
2020 Optical activation (uncaging) of MKK6 in fibroblasts is sufficient to trigger p38-dependent apoptosis and potently inhibits ERK/pro-proliferative signaling; the ERK pathway inhibition by MKK6 is equally robust even when all p38 isoforms are pharmacologically inhibited, revealing a p38-independent negative cross-regulatory function of MKK6. Caged lysine light-activatable kinase expression, p38 inhibition, ERK pathway readout, apoptosis assay The Journal of biological chemistry High 32371393
2021 MKK6 phosphorylates Gatad2b as a novel substrate (independent of p38), promoting K9 histone acetylation and heterochromatin loosening to facilitate somatic cell reprogramming; this requires MKK6 kinase activity but not its canonical p38 target. Overexpression/knockdown during iPSC reprogramming, kinase activity assays, ATAC-seq, ChIP, identification of Gatad2b as MKK6 substrate Cell death and differentiation Medium 34815549
2021 NMR spectroscopy and ITC define the binding interface between full-length MKK6 and p38: MKK6 engages p38 via the hydrophobic docking groove and influences helix αF; the conserved docking (CD) site of p38 is much less affected by MKK6 than by phosphatases; MKK6 binding is independent of its activation state. NMR spectroscopy, isothermal titration calorimetry (ITC) Protein science High 33554397
2022 MKK6 deficiency in mice blunts p38α activation while causing MKK3-p38γ/δ hyperphosphorylation and elevated mTOR signaling, leading to cardiac hypertrophy that progresses to dilatation and fibrosis; cardiac hypertrophy is reversed by p38γ or p38δ knockout or rapamycin treatment, identifying MKK3/6-p38γ/δ-mTOR as a cardiac hypertrophy pathway. MKK6 knockout mice, longitudinal cardiac function analysis, p38γ/p38δ double knockout rescue, rapamycin treatment, kinase assays eLife High 35971771
2022 PPM1G phosphatase directly dephosphorylates MEK6 (phospho-MEK6 identified as direct PPM1G substrate), reducing p38 activation and promoting lung adenocarcinoma proliferation and metastasis. Phosphoproteomics, in vitro dephosphorylation assay, co-immunoprecipitation, loss-of-function in cancer cells Carcinogenesis Medium 36349938
2023 Cryo-EM structure of the MKK6-p38α complex combined with molecular dynamics simulations, HDX-MS, and cell experiments reveals a dynamic multistep dual-phosphorylation mechanism; MKK6's disordered N-terminus determines pathway specificity; catalytically relevant interaction interfaces were identified. Cryo-electron microscopy, molecular dynamics simulation, hydrogen-deuterium exchange mass spectrometry, cell-based assays Science High 37708276

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1998 Selective activation of p38 mitogen-activated protein (MAP) kinase isoforms by the MAP kinase kinases MKK3 and MKK6. The Journal of biological chemistry 477 9430721
1996 Characterization of the structure and function of a novel MAP kinase kinase (MKK6). The Journal of biological chemistry 477 8621675
1997 Activation of the novel stress-activated protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6); comparison of its substrate specificity with that of other SAP kinases. The EMBO journal 351 9218798
1997 Activation of stress-activated protein kinase-3 (SAPK3) by cytokines and cellular stresses is mediated via SAPKK3 (MKK6); comparison of the specificities of SAPK3 and SAPK2 (RK/p38). The EMBO journal 327 9029150
2000 Involvement of the MKK6-p38gamma cascade in gamma-radiation-induced cell cycle arrest. Molecular and cellular biology 228 10848581
1998 Tumor necrosis factor signaling to stress-activated protein kinase (SAPK)/Jun NH2-terminal kinase (JNK) and p38. Germinal center kinase couples TRAF2 to mitogen-activated protein kinase/ERK kinase kinase 1 and SAPK while receptor interacting protein associates with a mitogen-activated protein kinase kinase kinase upstream of MKK6 and p38. The Journal of biological chemistry 227 9712898
1998 MKK6 activates myocardial cell NF-kappaB and inhibits apoptosis in a p38 mitogen-activated protein kinase-dependent manner. The Journal of biological chemistry 199 9525929
2007 Functional interdependence at the chromatin level between the MKK6/p38 and IGF1/PI3K/AKT pathways during muscle differentiation. Molecular cell 177 17964260
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 177 9575191
1996 Cloning and characterization of MEK6, a novel member of the mitogen-activated protein kinase kinase cascade. The Journal of biological chemistry 165 8626699
2000 alpha B-crystallin gene induction and phosphorylation by MKK6-activated p38. A potential role for alpha B-crystallin as a target of the p38 branch of the cardiac stress response. The Journal of biological chemistry 138 10816593
1999 The MKK6/p38 stress kinase cascade is critical for tumor necrosis factor-alpha-induced expression of monocyte-chemoattractant protein-1 in endothelial cells. Blood 138 9920834
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
2010 HINKEL kinesin, ANP MAPKKKs and MKK6/ANQ MAPKK, which phosphorylates and activates MPK4 MAPK, constitute a pathway that is required for cytokinesis in Arabidopsis thaliana. Plant & cell physiology 133 20802223
2006 Osteoclast differentiation requires TAK1 and MKK6 for NFATc1 induction and NF-kappaB transactivation by RANKL. Cell death and differentiation 128 16498455
2001 Activation of MKK6, an upstream activator of p38, in Alzheimer's disease. Journal of neurochemistry 126 11677259
2009 Differential activation of p38MAPK isoforms by MKK6 and MKK3. Cellular signalling 119 20004242
1996 Purification and cDNA cloning of SAPKK3, the major activator of RK/p38 in stress- and cytokine-stimulated monocytes and epithelial cells. The EMBO journal 117 8861944
2000 Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity. Blood 107 10961885
2006 The p38 kinases MKK4 and MKK6 suppress metastatic colonization in human ovarian carcinoma. Cancer research 105 16489030
2001 MKK6/3 and p38 MAPK pathway activation is not necessary for insulin-induced glucose uptake but regulates glucose transporter expression. The Journal of biological chemistry 104 11279172
1999 Constitutively active mitogen-activated protein kinase kinase 6 (MKK6) or salicylate induces spontaneous 3T3-L1 adipogenesis. The Journal of biological chemistry 103 10585441
2006 The role of the MKK6/p38 MAPK pathway in Wip1-dependent regulation of ErbB2-driven mammary gland tumorigenesis. Oncogene 92 17016428
2007 Regulation of suppressor of cytokine signaling 3 (SOCS3) mRNA stability by TNF-alpha involves activation of the MKK6/p38MAPK/MK2 cascade. Journal of immunology (Baltimore, Md. : 1950) 89 17312125
2002 Differential involvement of p38 mitogen-activated protein kinase kinases MKK3 and MKK6 in T-cell apoptosis. EMBO reports 89 12151339
2018 Insights of Crosstalk between p53 Protein and the MKK3/MKK6/p38 MAPK Signaling Pathway in Cancer. Cancers 88 29751559
2005 Constitutive activation of MKK6 in chondrocytes of transgenic mice inhibits proliferation and delays endochondral bone formation. Proceedings of the National Academy of Sciences of the United States of America 84 16387856
2010 MKK6 binds and regulates expression of Parkinson's disease-related protein LRRK2. Journal of neurochemistry 83 20067578
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
2005 Prevention of MKK6-dependent activation by binding to p38alpha MAP kinase. Biochemistry 80 16342939
2004 Protein kinase R (PKR) interacts with and activates mitogen-activated protein kinase kinase 6 (MKK6) in response to double-stranded RNA stimulation. The Journal of biological chemistry 79 15229216
2016 miR-625-3p regulates oxaliplatin resistance by targeting MAP2K6-p38 signalling in human colorectal adenocarcinoma cells. Nature communications 77 27526785
2003 Negative feedback regulation of MKK6 mRNA stability by p38alpha mitogen-activated protein kinase. Molecular and cellular biology 70 12482988
2012 Antiinflammatory functions of p38 in mouse models of rheumatoid arthritis: advantages of targeting upstream kinases MKK-3 or MKK-6. Arthritis and rheumatism 66 22488549
2021 A novel tumour suppressor protein encoded by circMAPK14 inhibits progression and metastasis of colorectal cancer by competitively binding to MKK6. Clinical and translational medicine 58 34709743
2010 PKC-delta and -eta, MEKK-1, MEK-6, MEK-3, and p38-delta are essential mediators of the response of normal human epidermal keratinocytes to differentiating agents. The Journal of investigative dermatology 58 20445555
2017 MKK6 controls T3-mediated browning of white adipose tissue. Nature communications 57 29021624
2016 TLR and TNF-R1 activation of the MKK3/MKK6-p38α axis in macrophages is mediated by TPL-2 kinase. The Biochemical journal 52 27402796
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
2018 Long noncoding RNA CRCMSL suppresses tumor invasive and metastasis in colorectal carcinoma through nucleocytoplasmic shuttling of HMGB2. Oncogene 47 30575817
2014 F-box only protein 31 (FBXO31) negatively regulates p38 mitogen-activated protein kinase (MAPK) signaling by mediating lysine 48-linked ubiquitination and degradation of mitogen-activated protein kinase kinase 6 (MKK6). The Journal of biological chemistry 47 24936062
2005 15S-Lipoxygenase-2 mediates arachidonic acid-stimulated adhesion of human breast carcinoma cells through the activation of TAK1, MKK6, and p38 MAPK. The Journal of biological chemistry 47 16000313
2010 ß-Elemene inhibits proliferation of human glioblastoma cells and causes cell-cycle G0/G1 arrest via mutually compensatory activation of MKK3 and MKK6. International journal of oncology 45 21132268
2019 Induction of Pluripotent Stem Cells from Mouse Embryonic Fibroblasts by Jdp2-Jhdm1b-Mkk6-Glis1-Nanog-Essrb-Sall4. Cell reports 43 31216469
2017 Negative regulation of TGF-β1-induced MKK6-p38 and MEK-ERK signalling and epithelial-mesenchymal transition by Rac1b. Scientific reports 42 29229918
2018 Gossypetin is a novel MKK3 and MKK6 inhibitor that suppresses esophageal cancer growth in vitro and in vivo. Cancer letters 39 30391783
2018 MKK6 Functions in Two Parallel MAP Kinase Cascades in Immune Signaling. Plant physiology 37 30185442
2014 Monocytic cell differentiation from band-stage neutrophils under inflammatory conditions via MKK6 activation. Blood 36 25214442
2001 Parallel regulation of mitogen-activated protein kinase kinase 3 (MKK3) and MKK6 in Gq-signaling cascade. The Journal of biological chemistry 36 11304531
2020 CircASPH promotes KGN cells proliferation through miR-375/MAP2K6 axis in Polycystic Ovary Syndrome. Journal of cellular and molecular medicine 35 33372369
2019 Circ_016719 plays a critical role in neuron cell apoptosis induced by I/R via targeting miR-29c/Map2k6. Molecular and cellular probes 35 31698040
2006 Effects of sodium ferulate on amyloid-beta-induced MKK3/MKK6-p38 MAPK-Hsp27 signal pathway and apoptosis in rat hippocampus. Acta pharmacologica Sinica 35 17007737
2005 Activation of mitogen-activated protein kinase kinase (MKK) 3 and MKK6 by type I interferons. The Journal of biological chemistry 35 15644321
2020 Quercetin inhibits caerulein-induced acute pancreatitis through regulating miR-216b by targeting MAP2K6 and NEAT1. Inflammopharmacology 34 33051781
2011 Balance between MKK6 and MKK3 mediates p38 MAPK associated resistance to cisplatin in NSCLC. PloS one 34 22164285
2019 Scaffold protein GhMORG1 enhances the resistance of cotton to Fusarium oxysporum by facilitating the MKK6-MPK4 cascade. Plant biotechnology journal 33 31794094
2008 ASK1 and MAP2K6 as modifiers of age at onset in Huntington's disease. Journal of molecular medicine (Berlin, Germany) 33 18327563
2023 Architecture of the MKK6-p38α complex defines the basis of MAPK specificity and activation. Science (New York, N.Y.) 32 37708276
2022 MiR-1298-5p level downregulation induced by Helicobacter pylori infection inhibits autophagy and promotes gastric cancer development by targeting MAP2K6. Cellular signalling 31 35192930
2009 The structure of the MAP2K MEK6 reveals an autoinhibitory dimer. Structure (London, England : 1993) 30 19141286
2018 Mutual Stabilization between TRIM9 Short Isoform and MKK6 Potentiates p38 Signaling to Synergistically Suppress Glioblastoma Progression. Cell reports 29 29669288
2015 MKK6 from pacific white shrimp Litopenaeus vannamei is responsive to bacterial and WSSV infection. Molecular immunology 29 26745320
2007 Tissue inhibitor of metalloproteinase-1 promotes hematopoietic differentiation via caspase-3 upstream the MEKK1/MEK6/p38alpha pathway. Leukemia 29 17301822
2006 Human Langerhans-cell activation triggered in vitro by conditionally expressed MKK6 is counterregulated by the downstream effector RelB. Blood 29 16960152
2000 Identification of a nuclear export signal in MKK6, an activator of the carp p38 mitogen-activated protein kinases. European journal of biochemistry 29 10880959
2017 Biogenesis of Pro-senescent Microparticles by Endothelial Colony Forming Cells from Premature Neonates is driven by SIRT1-Dependent Epigenetic Regulation of MKK6. Scientific reports 28 28811647
2014 Differential roles of MAPK kinases MKK3 and MKK6 in osteoclastogenesis and bone loss. PloS one 28 24400116
2003 The MKK6-p38 MAPK pathway prolongs the cardiac contractile calcium transient, downregulates SERCA2, and activates NF-AT. Cardiovascular research 28 12829175
2018 Pharmacological targeting of p38 MAP-Kinase 6 (MAP2K6) inhibits the growth of esophageal adenocarcinoma. Cellular signalling 27 30102978
2011 Role of C/EBP-β, p38 MAPK, and MKK6 in IL-1β-mediated C3 gene regulation in astrocytes. Journal of cellular biochemistry 27 21308746
2016 MEK2 controls the activation of MKK3/MKK6-p38 axis involved in the MDA-MB-231 breast cancer cell survival: Correlation with cyclin D1 expression. Cellular signalling 26 27181679
2022 MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation. eLife 25 35971771
2012 Crystal structure of non-phosphorylated MAP2K6 in a putative auto-inhibition state. Journal of biochemistry 24 22383536
2013 β-Amyloid-evoked apoptotic cell death is mediated through MKK6-p66shc pathway. Neuromolecular medicine 23 24085465
2007 MKK6-p38 MAPK signaling pathway enhances survival but not bone-resorbing activity of osteoclasts. Biochemical and biophysical research communications 23 17983595
2014 MKK6 is upregulated in human esophageal, stomach, and colon cancers. Cancer investigation 20 25019214
2018 MiR-422a targets MAPKK6 and regulates cell growth and apoptosis in colorectal cancer cells. Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie 19 29566993
2020 Optical control of MAP kinase kinase 6 (MKK6) reveals that it has divergent roles in pro-apoptotic and anti-proliferative signaling. The Journal of biological chemistry 18 32371393
2016 Genetic Analyses Reveal Functions for MAP2K3 and MAP2K6 in Mouse Testis Determination. Biology of reproduction 18 27009039
2010 MKK6 increases the melanocyte dendricity through the regulation of Rho family GTPases. Journal of dermatological science 18 20869211
2018 Quantitative proteome analysis identifies MAP2K6 as potential regulator of LIFR-induced radioresistance in nasopharyngeal carcinoma cells. Biochemical and biophysical research communications 17 30245131
2021 The interaction of p38 with its upstream kinase MKK6. Protein science : a publication of the Protein Society 16 33554397
2020 MicroRNA‑375 prevents TGF‑β‑dependent transdifferentiation of lung fibroblasts via the MAP2K6/P38 pathway. Molecular medicine reports 15 32582987
2020 Elevated miR-10a-5p facilitates cell cycle and restrains adipogenic differentiation via targeting Map2k6 and Fasn, respectively. Acta biochimica et biophysica Sinica 15 33128541
2023 Microcystin-LR-Exposure-Induced Kidney Damage by Inhibiting MKK6-Mediated Mitophagy in Mice. Toxins 14 37368704
2014 Involvement of potato (Solanum tuberosum L.) MKK6 in response to potato virus Y. PloS one 14 25111695
2010 Mechanism of oxidative stress-induced ASK1-catalyzed MKK6 phosphorylation. Biochemistry 14 20364819
2024 Inhibitory Impact of Prenatal Exposure to Nano-Polystyrene Particles on the MAP2K6/p38 MAPK Axis Inducing Embryonic Developmental Abnormalities in Mice. Toxics 11 38787149
2021 CircRNA-MSR Regulates LPS-Induced C28/I2 Chondrocyte Injury through miR-643/MAP2K6 Signaling Pathway. Cartilage 11 34581623
2017 MAP2K6-FP Enhances the Sensitiveness of Paclitaxel for Ovarian Cancer via Inducing Autophagy. International journal of gynecological cancer : official journal of the International Gynecological Cancer Society 11 28604448
2021 MAP2K6 remodels chromatin and facilitates reprogramming by activating Gatad2b-phosphorylation dependent heterochromatin loosening. Cell death and differentiation 10 34815549
2015 A de novo 1.58 Mb deletion, including MAP2K6 and mapping 1.28 Mb upstream to SOX9, identified in a patient with Pierre Robin sequence and osteopenia with multiple fractures. American journal of medical genetics. Part A 10 26059046
2022 Circ_0005925 Promotes Granulosa Cell Growth by Targeting MiR-324-3p to Upregulate MAP2K6 in Polycystic Ovary Syndrome. Biochemical genetics 9 35689709
2012 Catenarin Prevents Type 1 Diabetes in Nonobese Diabetic Mice via Inhibition of Leukocyte Migration Involving the MEK6/p38 and MEK7/JNK Pathways. Evidence-based complementary and alternative medicine : eCAM 9 22454693
2011 A novel DC therapy with manipulation of MKK6 gene on nickel allergy in mice. PloS one 9 21544193
2010 Activin A induction of erythroid differentiation through MKK6-p38alpha/p38beta pathway is inhibited by follistatin. Journal of cellular physiology 9 20162623
2007 MKK6 phosphorylation regulates production of superoxide by enhancing Rac GTPase activity. Antioxidants & redox signaling 9 17854274
2023 PPM1G promotes the progression of lung adenocarcinoma by inhibiting p38 activation via dephosphorylation of MEK6. Carcinogenesis 8 36349938
2022 APEX1 promotes the oncogenicity of hepatocellular carcinoma via regulation of MAP2K6. Aging 8 36205565
2021 MEK6 Overexpression Exacerbates Fat Accumulation and Inflammatory Cytokines in High-Fat Diet-Induced Obesity. International journal of molecular sciences 8 34948353