Affinage

MAP2K6

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

Length
334 aa
Mass
37.5 kDa
Annotated
2026-06-10
100 papers in source corpus 52 papers cited in narrative 50 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAP2K6 (MKK6) is a dual-specificity MAP kinase kinase that functions as a principal upstream activator of the p38 MAPK stress-signaling module, selectively phosphorylating and activating p38 isoforms but not JNK or ERK in response to cellular stress and pro-inflammatory cytokines (PMID:8621675, PMID:8626699, PMID:8861944). It is a common activator of p38α, p38β, and p38γ (PMID:9430721, PMID:20004242) and, together with MKK3, is required for stress- and cytokine-induced activation of p38γ/p38δ (PMID:9218798, PMID:9029150, PMID:20004242). MKK6 sits downstream of multiple MAP3Ks and stress inputs: MEKK3/MEKK2 directly phosphorylate it (PMID:10347227), ASK1 phosphorylates it within the H2O2-responsive ASK1 signalosome with oxidative stress dramatically lowering KM for MKK6 (PMID:20364819), and TLR4/TNF-R1 signaling activates it through TPL-2 and IKK-dependent NF-κB1 p105 phosphorylation (PMID:27402796); PKR links it to dsRNA responses (PMID:15229216). MKK6 abundance and activity are tightly controlled by an autoregulatory negative feedback in which p38α destabilizes MKK6 mRNA via its 3'UTR (PMID:12482988), by opposing ubiquitin signals (TRIM9s-mediated stabilizing K63 ubiquitination at Lys82 versus FBXO31-mediated degradative K48 ubiquitination) (PMID:29669288, PMID:24936062), and by PPM1G-mediated dephosphorylation (PMID:36349938). Through p38, MKK6 controls inflammation and cytokine gene expression (PMID:9920834, PMID:22488549), stress-induced and Fas-induced apoptosis (PMID:9362518, PMID:32371393), ATM-dependent G2/M cell cycle arrest via p38γ and Chk2 (PMID:10848581), cardiac calcium homeostasis and cytoprotection (PMID:12829175, PMID:10816593), and muscle differentiation by recruiting the SWI/SNF chromatin-remodeling complex (PMID:17964260). MKK6 also exerts p38-independent functions, directly phosphorylating Gatad2b to loosen heterochromatin during reprogramming (PMID:34815549) and inhibiting the ERK pathway (PMID:32371393). Genetic loss of MKK6 in mice shortens lifespan and causes cardiac hypertrophy progressing to dilatation through blunted p38α activation, MKK3-p38γ/δ hyperphosphorylation, and elevated mTOR signaling (PMID:35971771). Structurally, unphosphorylated MKK6 adopts an autoinhibited dimer (PMID:19141286, PMID:22383536), and a cryo-EM structure of the MKK6-p38α complex defines a dynamic multi-step phosphorylation mechanism in which the disordered MKK6 N-terminus determines MAPK pathway specificity (PMID:37708276).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1996 High

    Established the core identity of MKK6 as a p38-selective MAP kinase kinase, distinguishing it from JNK and ERK activators and defining the substrate specificity that anchors all later biology.

    Evidence cDNA cloning, in vitro kinase and co-transfection assays, plus protein purification from skeletal muscle

    PMID:8621675 PMID:8626699 PMID:8861944

    Open questions at the time
    • Did not resolve which p38 isoforms are differentially engaged
    • Upstream activating kinases unidentified at this stage
  2. 1998 High

    Defined the isoform selectivity of the MKK6-p38 branch relative to MKK3, showing MKK6 activates p38α, p38β, and p38γ and (with later work) p38δ, mapping overlapping but distinct signaling arms.

    Evidence co-transfection and in vitro kinase assays, later confirmed with knockout fibroblast panels

    PMID:20004242 PMID:9029150 PMID:9218798 PMID:9430721

    Open questions at the time
    • Physiological stimuli driving each isoform branch not fully separated
    • Redundancy with MKK3 in vivo unresolved at this time
  3. 1999 High

    Placed MKK6 in a defined kinase cascade by identifying MEKK3/MEKK2 as direct upstream MAP3Ks and connecting it to TNF-receptor signaling through RIP, answering how stress signals reach MKK6.

    Evidence in vitro reconstitution with immunoprecipitated MEKK3 activating recombinant MKK6, co-IP, cell-based assays

    PMID:10347227 PMID:9712898

    Open questions at the time
    • Full set of physiological MAP3Ks not enumerated
    • Stimulus-specific MAP3K usage not defined
  4. 2002 High

    Genetic knockout revealed non-redundant in vivo roles, showing MKK6 is required for thymocyte negative selection while MKK3 governs peripheral T-cell death, demonstrating that the two activators are functionally distinct despite shared substrate.

    Evidence Mkk6-/- mice with parallel Mkk3-/- comparison and thymocyte apoptosis assays

    PMID:12151339

    Open questions at the time
    • Molecular basis of MKK6 vs MKK3 selectivity in vivo not defined
    • p38 isoform mediating negative selection not pinned down
  5. 2003 High

    Uncovered a negative feedback loop in which p38α destabilizes MKK6 mRNA via its 3'UTR, establishing the first mechanism for pathway self-limitation at the level of MKK6 abundance.

    Evidence p38α knockout cells with rescue, pharmacological inhibition, and 3'UTR mRNA stability reporter assays

    PMID:12482988

    Open questions at the time
    • RNA-binding factors mediating destabilization not identified
    • Quantitative contribution to pathway dynamics not modeled
  6. 2005 High

    Extended the upstream input map to innate/antiviral signaling, showing MKK3/MKK6 are activated by Type I interferons and dsRNA (via PKR) to drive p38-dependent gene transcription independent of STAT phosphorylation.

    Evidence double-knockout MEFs, kinase and reporter assays, plus PKR-null cells and coupled kinase assays

    PMID:15229216 PMID:15644321

    Open questions at the time
    • How PKR selectively activates MKK6 but not MKK3 structurally unexplained
    • Interferon-induced gene set incompletely mapped
  7. 2009 High

    Provided the first structural basis for autoregulation, showing unphosphorylated MKK6 forms an autoinhibited elongated dimer, later refined to an activation-loop helix mechanism occluding the active site.

    Evidence X-ray crystallography of phosphomimetic and non-phosphorylated MEK6, SAXS, and gel filtration

    PMID:19141286 PMID:22383536

    Open questions at the time
    • Conformational transition to active state not captured
    • Dimer relevance to cellular activation not directly tested
  8. 2010 High

    Revealed post-translational control by oxidative stress and disease-linked kinases, with ASK1 acquiring ~4000-fold greater catalytic efficiency for MKK6 upon H2O2, and LRRK2 binding/phosphorylating MKK6 with PD mutations enhancing the interaction.

    Evidence in vitro kinetics with native ASK1 signalosome co-purification, plus LRRK2 co-IP, in vitro kinase assay, and C. elegans sek-1 genetics

    PMID:20067578 PMID:20364819

    Open questions at the time
    • Physiological consequence of LRRK2-MKK6 phosphorylation in human neurons not established
    • ASK1-to-MKK6 signalosome assembly dynamics partly resolved
  9. 2014 High

    Defined opposing ubiquitin-dependent control of MKK6 stability, identifying FBXO31 as a K48 degradative ligase, complemented by TRIM9s as a K63 stabilizing modifier at the same Lys82, establishing a ubiquitin switch governing MKK6 levels.

    Evidence co-IP, linkage-specific ubiquitination assays, site-directed mutagenesis of Lys82, and proteasome inhibition

    PMID:24936062 PMID:29669288

    Open questions at the time
    • Signals dictating K48 vs K63 choice at Lys82 not defined
    • Deubiquitinases counteracting these marks unknown
  10. 2016 High

    Demonstrated MKK6 as a clinically relevant node whose suppression alters drug response, with miR-625-3p targeting MAP2K6 to abrogate p38 signaling and confer oxaliplatin resistance in colorectal cancer.

    Evidence luciferase target validation, rescue with a miR-insensitive MAP2K6 variant, and multi-omic profiling

    PMID:27526785

    Open questions at the time
    • Downstream p38 effectors mediating drug sensitivity not fully mapped
    • Generality across other chemotherapies untested
  11. 2021 Medium

    Expanded MKK6 function beyond p38 by identifying Gatad2b as a direct, p38-independent substrate that loosens heterochromatin during reprogramming, indicating MKK6 has chromatin-remodeling activity of its own.

    Evidence kinase-dead mutant, substrate identification, ATAC-seq and ChIP in a reprogramming model

    PMID:34815549

    Open questions at the time
    • Phosphosite on Gatad2b and structural basis not defined
    • Breadth of p38-independent MKK6 substrates unknown
  12. 2022 High

    Established the physiological cost of MKK6 loss, showing knockout mice develop cardiac hypertrophy and reduced lifespan via blunted p38α, compensatory MKK3-p38γ/δ hyperphosphorylation, and elevated mTOR.

    Evidence longitudinal MKK6 knockout mice with p38γ-KO, p38δ-KO, and rapamycin rescue experiments

    PMID:35971771

    Open questions at the time
    • Molecular mechanism coupling MKK3-p38γ/δ to mTOR not detailed
    • Translation to human cardiac disease unestablished
  13. 2023 High

    Resolved the mechanism of how MKK6 phosphorylates its target kinase, with a cryo-EM MKK6-p38α complex revealing a multi-step phosphorylation cycle and the disordered N-terminus as the determinant of MAPK pathway specificity, complemented by phosphatase (PPM1G) regulation.

    Evidence cryo-EM, molecular dynamics, HDX-MS and cell experiments, plus NMR/ITC interface mapping and PPM1G phosphatase substrate identification

    PMID:33554397 PMID:36349938 PMID:37708276

    Open questions at the time
    • Structural basis of isoform discrimination among p38β/γ/δ not solved
    • How disordered N-terminus is read by the system mechanistically incomplete

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MKK6's distinct upstream MAP3Ks, ubiquitin/phosphatase regulators, and p38-independent substrates are integrated to produce context-specific cell fate decisions remains unresolved.
  • No unified model linking input identity to MKK6 output selectivity
  • p38-independent substrate repertoire largely uncharacterized
  • Stimulus-specific MAP3K-to-MKK6 coupling rules not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 6 GO:0016740 transferase activity 4 GO:0140657 ATP-dependent activity 2
Localization
GO:0005829 cytosol 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 4 R-HSA-5357801 Programmed Cell Death 3 R-HSA-8953897 Cellular responses to stimuli 3 R-HSA-4839726 Chromatin organization 2 R-HSA-1640170 Cell Cycle 1
Partners
ASK1FBXO31LRRK2MAPK14MEKK3PKRPPM1GTRIM9
Complex memberships
ASK1 signalosomeMKK6-p38α complex

Evidence

Reading pass · 50 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1996 MKK6 (MEK6) was identified as a novel MAP kinase kinase that selectively phosphorylates and activates p38 MAPK but not JNK or ERK family members, as demonstrated by direct kinase assays and co-transfection assays. Two splice isoforms (278 and 334 amino acids) were identified in humans. cDNA cloning, in vitro kinase assay, co-transfection assay The Journal of biological chemistry High 8621675 8626699
1996 SAPKK3 (MKK6) was purified from rabbit skeletal muscle and identified as the major activator of RK/p38 (not JNK) in stress- or cytokine-stimulated epithelial cells and monocytes; human SAPKK3 comprises 334 amino acids and is 78% identical to MKK3. Protein purification, tryptic peptide sequencing, cDNA cloning, in vitro kinase assay The EMBO journal High 8861944
1998 MKK6 is a common activator of p38α, p38β2, and p38γ MAP kinase isoforms, whereas MKK3 activates only p38α and p38γ, defining distinct but overlapping signaling branches. Co-transfection, in vitro kinase assay, molecular cloning The Journal of biological chemistry High 20004242 9430721
1997 MKK6 (SAPKK3) is the upstream activator of SAPK3 (p38γ) and SAPK4 (p38δ) in response to cellular stresses and pro-inflammatory cytokines (IL-1, TNF); co-transfection with MKK6 induced SAPK3/4 activity and enhanced activation in response to osmotic shock. Co-transfection, in vitro kinase assay, cell stimulation assays The EMBO journal High 9029150 9218798
1998 MKK6 is the major activator of p38 during Fas-induced apoptosis in Jurkat and KB cells; MKK7 (not SEK1/MKK4) activates JNK/SAPK in the same pathway. Both pathways operate independently of CPP32-like proteases. Immunoprecipitation kinase assay, peptide inhibitor dissection, cell stimulation The Journal of cell biology Medium 9362518
1998 In cardiac myocytes, constitutively active MKK6 (MKK6-Glu) selectively activates p38 and protects cells from apoptosis; this anti-apoptotic effect is blocked by the p38 inhibitor SB203580. MKK6-Glu also activates NF-κB transcription in a p38-dependent manner, though NF-κB is not the principal anti-apoptotic mechanism. Adenoviral overexpression, pharmacological inhibition (SB203580), reporter gene assay, primary cardiomyocyte culture The Journal of biological chemistry Medium 9525929
1998 Receptor-interacting protein (RIP) associates in vivo with an endogenous MAPKKK that can activate the p38 pathway via MKK6; activation of p38 by TRAF2 requires RIP, placing RIP upstream of MKK6 in TNF receptor signaling. Co-immunoprecipitation, in vitro kinase assay, co-transfection in mammalian cells The Journal of biological chemistry Medium 9712898
1999 MEKK3 (and MEKK2) directly phosphorylates and activates MKK6 in vitro and in cells, identifying MEKK3 as an upstream MAP3K for the MKK6-p38 pathway; immunoprecipitates of MEKK3 directly activated recombinant MKK6 in vitro. In vitro kinase assay, co-transfection, immunoprecipitation kinase assay in COS-7 and HEK293 cells The Journal of biological chemistry High 10347227
1999 The MKK6/p38 cascade is required for TNF-α-induced MCP-1 expression in human endothelial cells; dominant-negative MKK6 strongly inhibited MCP-1, while constitutively active MKK6 enhanced it, as shown by flow cytometry, Northern blot, and luciferase reporter assays. Dominant-negative/constitutively active mutant overexpression, pharmacological inhibition, flow cytometry, Northern blot, luciferase reporter Blood Medium 9920834
2000 Activation of the MKK6-p38γ cascade is required and sufficient for γ-irradiation-induced G2 cell cycle arrest; p38γ activation is dependent on ATM and leads to activation of Chk2 (Cds1). Dominant-negative MKK6 or p38γ allows cells to escape DNA damage-induced G2 delay. Dominant-negative mutant expression, gamma irradiation, cell cycle analysis, epistasis with ATM Molecular and cellular biology Medium 10848581
2000 MKK6-activated p38 induces αB-crystallin gene expression and phosphorylates αB-crystallin on serine-59 via MAPKAP-K2, contributing to cytoprotection in cardiac myocytes; this pathway is blocked by p38 inhibitor SB203580. Constitutively active MKK6 overexpression, SB203580 inhibition, Northern/Western blot, phosphospecific antibodies The Journal of biological chemistry Medium 10816593
2000 MKK6 and p38α phosphorylate STAT4 on serine 721, and are required for STAT4 full transcriptional activity induced by IL-12, establishing the MKK6/p38α/STAT4 axis as a mediator of IL-12 signaling in T and NK cells. In vitro kinase assay, dominant-negative mutant expression, reporter gene assay, mutagenesis (STAT4-S721 mutation) Blood Medium 10961885
2001 MKK6 activates p38 MAPK downstream of Gαq and Gβγ subunits; Gαq activates MKK6 through a Rho-dependent mechanism requiring phospholipase C and c-Src, while Gβγ activates MKK6 via Rho, Rac, and Cdc42. This was established by kinase-deficient mutant block and direct MKK6 activity assays. Kinase-deficient dominant-negative mutants, in vitro kinase assay, inhibitor studies in HEK293 cells The Journal of biological chemistry Medium 11304531
2001 MKK6/3-p38 MAPK activation is not necessary for insulin-stimulated glucose uptake; instead, constitutively active MKK6 up-regulates GLUT1 and down-regulates GLUT4 expression, increasing basal glucose transport while diminishing insulin-stimulated transport, acting through p38. Adenoviral overexpression of constitutively active and dominant-negative MKK6/MKK3, glucose uptake assay, GLUT1/GLUT4 expression analysis The Journal of biological chemistry Medium 11279172
2002 MKK6 is required for negative selection (deletion of double-positive thymocytes) in vivo, while MKK3 mediates activation-induced cell death and cytokine-withdrawal apoptosis in peripheral CD4+ T cells; MKK3/MKK6 thus have differential roles in T-cell apoptosis via p38 MAPK. Mkk6-/- knockout mice generation, thymocyte apoptosis assays, comparison with Mkk3-/- mice EMBO reports High 12151339
2003 p38α negatively regulates MKK6 mRNA stability via its 3' UTR, forming a negative feedback loop; p38α-/- cells show elevated MKK6 mRNA and protein due to increased mRNA stability, while reintroduction of p38α reduces MKK6 to normal levels. p38α knockout cells, pharmacological p38 inhibition, mRNA stability assays, 3'UTR reporter assay Molecular and cellular biology High 12482988
2003 The MKK6-p38 pathway prolongs the cardiac contractile calcium transient by downregulating SERCA2 expression and its promoter activity, increasing diastolic Ca2+ and activating NF-AT in cardiac myocytes; SERCA2 overexpression rescues these effects. MKK6(Glu) overexpression in neonatal cardiomyocytes, calcium transient measurement (indo-1), Northern/Western blot, reporter gene assay Cardiovascular research Medium 12829175
2004 PKR (dsRNA-activated protein kinase) directly interacts with and phosphorylates MKK6 (but not MKK3) in response to poly(rI:rC) stimulation; this interaction provides a mechanism for p38 activation by dsRNA. Kinase-inactive PKR blocks MKK6 activation but not MKK3. Co-immunoprecipitation, in vitro kinase assay, coupled kinase assay, PKR-null cells, kinase-inactive PKR expression The Journal of biological chemistry Medium 15229216
2005 MKK3 and MKK6 are both activated by Type I interferons (IFNα/β); double knockout of Mkk3 and Mkk6 abolishes IFN-dependent p38 and MAPKAPK-2/3 activation and impairs IFN-inducible gene transcription (ISG15, IRF-9) independently of STAT protein phosphorylation. MKK3-/-/MKK6-/- double knockout MEFs, kinase assays, luciferase reporter, qPCR, Western blot The Journal of biological chemistry High 15644321
2005 Selectivity-pocket p38α inhibitors (e.g. BIRB796) that stabilize the DFG-out conformation prevent MKK6-dependent activation of p38α (in addition to inhibiting catalysis), whereas purine-site-only inhibitors do not prevent MKK6-dependent activation. Crystal structures of seven inhibitor complexes were determined. Crystal structure determination, kinetic analysis, cellular TNFα assay, novel Kd assay for non-activated p38α Biochemistry High 16342939
2005 Constitutive MKK6 activation in chondrocytes in vivo inhibits proliferation and delays endochondral bone formation; p38 signaling increases Sox9 transcriptional activity, and transgenic mice expressing active MKK6 in chondrocytes phenocopy SOX9-overexpressing mice. Transgenic mice with chondrocyte-specific constitutively active MKK6, histology, in situ hybridization, reporter assay for Sox9 activity Proceedings of the National Academy of Sciences of the United States of America High 16387856
2006 TAK1 and MKK6 (but not MKK3) are required for RANKL-induced NFATc1 induction and NF-κB transactivation (via p65-Ser536 phosphorylation) during osteoclast differentiation from bone marrow cells; dominant-negative MKK6 reduces osteoclastogenesis. Retroviral transduction of dominant-negative forms, RANKL stimulation, Western blot, reporter assays Cell death and differentiation Medium 16498455
2006 MKK6 suppresses metastatic colonization in ovarian carcinoma through p38 signaling; MKK6 expression suppressed metastasis while MKK7 (the JNK activator) had no effect, showing the p38 pathway is the functional effector of MKK4-mediated metastasis suppression. In vivo metastasis colonization assay, kinase-inactive mutant, specific pathway activators (MKK6 vs MKK7) Cancer research Medium 16489030
2006 MKK6 activation in Langerhans cells is sufficient to induce upregulation of costimulatory molecules and enhanced T-cell stimulatory capacity; this simultaneously induces alternative NF-κB member RelB, which acts as a counterregulatory brake on LC maturation. Conditional inducible dominant-active MKK6 expression in primary Langerhans cells, flow cytometry, T-cell stimulation assay Blood Medium 16960152
2007 MKK6-p38 and IGF1/PI3K/AKT pathways converge on chromatin of muscle genes: p38α/β kinases recruit the SWI/SNF chromatin-remodeling complex, while AKT promotes MyoD association with p300/PCAF acetyltransferases. Blockade of either pathway produces distinct reversible chromatin assembly defects. Pharmacological and genetic interference, chromatin immunoprecipitation, co-immunoprecipitation, primary myoblast differentiation Molecular cell High 17964260
2007 TNF-α stabilizes SOCS3 mRNA via activation of the MKK6/p38MAPK/MK2 cascade; in MK2-deficient fibroblasts and macrophages, TNF-α-induced SOCS3 mRNA stabilization is impaired. The relevant destabilizing region maps to a 3'UTR AUUUA/U-rich element between positions 2422-2541. MK2-/- fibroblasts/macrophages, mRNA stability assays, Western blot, luciferase reporter for 3'UTR function Journal of immunology Medium 17312125
2007 MKK6-p38 signaling in osteoclasts enhances osteoclast survival but does not increase bone-resorbing (dentine resorption) activity; established using adenoviral delivery of constitutively active MKK6 into mature osteoclasts. Adenoviral gene transfer of constitutively active MKK6, osteoclast survival assay, dentine resorption assay Biochemical and biophysical research communications Medium 17983595
2007 MKK6 phosphorylates MKK6 on tyrosine 219 to enhance its interaction with Rac1, and constitutively active MKK6 enhances Rac GTPase activity in vitro; overexpression of MKK6 inhibits PMA-induced NADPH oxidase activation, while a Y219F mutant partially loses this activity. Co-immunoprecipitation, in vitro Rac-GTPase assay, NADPH oxidase activation assay, Y219F mutagenesis, MKK6-deficient tissue analysis Antioxidants & redox signaling Medium 17854274
2009 Crystal structure of the MEK6 kinase domain with phosphomimetic mutations (MEK6/ΔN/DD) at 2.3 Å reveals an autoinhibited elongated ellipsoidal dimer; the dimer interface involves the phosphate-binding ribbon, activation loop, and an 'arginine stack'. Solution-phase dimerization confirmed by gel filtration and SAXS. X-ray crystallography (2.3 Å), gel filtration, small-angle X-ray scattering (SAXS) Structure High 19141286
2009 MKK3 and MKK6 are both essential for stress-induced p38γ and p38β activation, while p38δ activation by UV, hyperosmotic shock, anisomycin, or TNFα is mediated predominantly by MKK3; MKK6 is the major p38γ activator in response to TNFα. In osmotic stress, MKK3 and MKK6 regulate phosphorylation of the p38γ substrate hDlg. MKK3-/-, MKK6-/-, and double MKK3-/-/MKK6-/- knockout fibroblasts, kinase assays, substrate phosphorylation assays Cellular signalling High 20004242
2010 LRRK2 (Parkinson's disease kinase) physically 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 LRRK2-MKK6 binding. RNAi of the C. elegans MKK6 ortholog sek-1 abolishes LRRK2-mediated protection against mitochondrial stress. Co-immunoprecipitation, in vitro kinase assay, subcellular fractionation, C. elegans RNAi/deletion genetics Journal of neurochemistry Medium 20067578
2010 ASK1 phosphorylates MKK6 within the ASK1 signalosome in response to H2O2; oxidative stress increases ASK1 catalytic efficiency for MKK6 ~4000-fold by dramatically decreasing KM(MKK6) (~1000-fold), while KM(ATP) is unchanged. Endogenous MKK6 co-purifies with the ASK1 signalosome transiently after H2O2 treatment. In vitro kinase assay with kinetic parameter measurement, native complex purification, co-immunoprecipitation Biochemistry High 20364819
2010 MKK6 overexpression in melanocytes increases dendrite length through upregulation of Rho family GTPases Cdc42 and Rac1; constitutively active MKK6 adenovirus produced dendrite elongation in both melanoma cells and normal human epidermal melanocytes. Adenoviral constitutively active MKK6 overexpression, morphological analysis, Rho GTPase expression analysis Journal of dermatological science Low 20869211
2012 Crystal structure of non-phosphorylated human MAP2K6 complexed with an ATP analogue at 2.6 Å resolution reveals an autoinhibitory state; three activation-loop α-helices (AH1, AH2, AH3) mediate auto-inhibition: AH1 displaces the αC-helix and AH1/AH2 enclose the γ-phosphate of ATP. X-ray crystallography (2.6 Å), structural comparison with MEK1 and MEK4 Journal of biochemistry High 22383536
2012 In rheumatoid arthritis models, MKK6-deficient bone marrow-derived macrophages show suppressed LPS-mediated IL-6 expression but normal IL-10 production and MAPK phosphorylation; chimeric mice with MKK6-deficient bone marrow show markedly decreased passive K/BxN arthritis severity. MKK6-/- bone marrow chimeras, K/BxN serum-transfer arthritis model, qPCR, Western blot, ELISA Arthritis and rheumatism Medium 22488549
2013 MKK6 directly binds p66shc and phosphorylates p66shc at serine 36; MKK6 knockdown reduces Ser36 phosphorylation of p66shc. Physical association between p66shc and wild-type MKK6 (but not catalytic mutants) was demonstrated by co-immunoprecipitation. The MKK6-p66shc complex mediates β-amyloid-induced ROS production and apoptosis. Co-immunoprecipitation, siRNA knockdown, ROS measurement, cell death assay, mutagenesis Neuromolecular medicine Medium 24085465
2014 FBXO31 (an SCF E3 ligase component) binds MKK6 and mediates its K48-linked polyubiquitination and proteasomal degradation, thereby negatively regulating MKK6-p38 signaling upon genotoxic stress. Co-immunoprecipitation, ubiquitination assay (K48-linkage-specific), proteasome inhibitor treatment, FBXO31 overexpression/knockdown The Journal of biological chemistry Medium 24936062
2014 MKK3 (not MKK6) directly mediates osteoclastogenesis in vitro, regulating NFATc1 and osteoclast-specific gene expression; however, both MKK3 and MKK6 deficiency partially protect against ovariectomy-induced bone loss in vivo, with MKK6 likely contributing via pro-inflammatory cytokine production rather than direct osteoclast differentiation. MKK3-/- and MKK6-/- mice, in vitro osteoclast differentiation from bone marrow, micro-CT analysis, NFATc1 expression analysis PloS one Medium 24400116
2014 MKK6-p38MAPK signaling induces a monocyte differentiation program in band-stage neutrophils under inflammatory conditions; MKK6-p38MAPK signaling leads to diminishment of C/EBPα transcription factor, enabling the monocyte differentiation program. MKK6 pathway activation in G-CSF-dependent neutrophils, adoptive transfer experiments, gene expression profiling, C/EBPα protein analysis Blood Medium 25214442
2016 miR-625-3p directly targets MAP2K6 mRNA, and MAP2K6 downregulation abrogates p38 signaling to induce oxaliplatin resistance in colorectal cancer; resistance is reversed by ectopic expression of a miR-625-3p-insensitive MAP2K6 variant or anti-miR-625-3p treatment. miRNA target validation (luciferase reporter), ectopic MAP2K6 expression, anti-miR treatment, transcriptome/proteome/phosphoproteome profiling Nature communications High 27526785
2016 TLR4 and TNF-R1 stimulation activates MKK3/MKK6 via TPL-2 kinase activity and IKK-dependent phosphorylation of NF-κB1 p105 in macrophages; TPL-2 catalytic inactivity (D270A) abolishes MKK3/6 activation loop phosphorylation but not MKK4. TNF activation of p38α is substantially reduced in TPL-2 catalytic-inactive macrophages. Quantitative phosphoproteomics, Map3k8-D270A/D270A knock-in mice, LPS/TNF stimulation of macrophages The Biochemical journal High 27402796
2017 MKK6 expression is elevated in white adipose tissue of obese individuals; Mkk6 deletion increases T3-stimulated UCP1 expression in adipocytes and increases thermogenic capacity; in white adipose tissue, p38 is activated by an alternative pathway involving AMPK, TAK, and TAB rather than through MKK6. Mkk6 knockout mice, shRNA knockdown, diet-induced obesity model, UCP1 expression analysis, AMPK/TAK pathway dissection Nature communications High 29021624
2018 TRIM9 short isoform (TRIM9s) stabilizes MKK6 by promoting K63-linked ubiquitination of MKK6 at Lys82, which inhibits the degradative K48-linked ubiquitination at the same lysine; reciprocally, MKK6 stabilizes TRIM9s by promoting p38-mediated phosphorylation of TRIM9s at Ser76/80, blocking its proteasomal degradation. Co-immunoprecipitation, ubiquitination assay (K48/K63 linkage-specific), site-directed mutagenesis (Lys82), phosphorylation mapping (Ser76/80), proteasome inhibitor treatment Cell reports High 29669288
2018 Gossypetin directly inhibits MKK3 and MKK6 kinase activity in vitro; arginine-61 in MKK6 is critical for gossypetin binding, established by mutagenesis. In vitro kinase assay, kinase screening panel, Arg61 mutagenesis, cell growth inhibition assays Cancer letters Medium 30391783
2020 Optical activation of MKK6 via caged-lysine decaging is sufficient to trigger apoptosis in fibroblasts in a p38-dependent manner; MKK6 activation also rapidly and potently inhibits the ERK pathway through a mechanism that is independent of p38 isoforms, positioning MKK6 as a pleiotropic signal transducer. Caged kinase optical activation, p38 inhibitor SB203580, ERK pathway readouts, time-lapse imaging The Journal of biological chemistry Medium 32371393
2021 NMR spectroscopy and isothermal titration calorimetry define the MKK6-p38 binding interface: p38 engages MKK6 via its hydrophobic docking groove and also influences helix αF; the p38 conserved docking (CD) site is much less engaged by MKK6 than by MAPK phosphatases; interactions are conserved regardless of MKK6 activation state. NMR spectroscopy, isothermal titration calorimetry (ITC), full-length protein interaction mapping Protein science High 33554397
2021 MKK6 phosphorylates Gatad2b as a novel substrate (independent of p38) to elevate histone acetylation levels and loosen heterochromatin, facilitating reprogramming and Sox2/Klf4 binding to targets; this chromatin-remodeling function requires MKK6 kinase activity. Kinase activity-dead mutant, substrate identification, ATAC-seq, ChIP, chromatin accessibility assays in reprogramming model Cell death and differentiation Medium 34815549
2022 MKK6 deficiency in mice reduces lifespan and leads to cardiac hypertrophy progressing to dilatation and fibrosis; mechanistically, loss of MKK6 blunts p38α activation while causing MKK3-p38γ/δ hyperphosphorylation and increased mTOR signaling. Cardiac hypertrophy is reverted by p38γ or p38δ knockout or rapamycin. MKK6 knockout mice (longitudinal study), cardiac function measurements, MKK3/p38γ/p38δ additional knockouts, rapamycin treatment, Western blot for mTOR pathway eLife High 35971771
2023 Cryo-EM structure of the MKK6-p38α complex plus molecular dynamics, HDX-MS, and cell experiments reveals a dynamic multi-step phosphorylation mechanism; MKK6 disordered N-terminus determines MAPK pathway specificity; the complex captures the fundamental step of a kinase phosphorylating its downstream target kinase. Cryo-electron microscopy, molecular dynamics simulations, hydrogen-deuterium exchange mass spectrometry, cell-based experiments Science High 37708276
2023 PPM1G (a metal-dependent phosphatase) directly dephosphorylates phospho-MEK6 as a substrate, thereby reducing p38 phosphorylation and promoting lung adenocarcinoma proliferation/invasion; PPM1G was identified as a negative regulator of MKK6-p38 signaling. Phosphatase substrate identification, siRNA knockdown, Western blot, in vitro phosphatase assay Carcinogenesis Medium 36349938

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1996 Characterization of the structure and function of a novel MAP kinase kinase (MKK6). The Journal of biological chemistry 478 8621675
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
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
1998 T lymphocyte activation signals for interleukin-2 production involve activation of MKK6-p38 and MKK7-SAPK/JNK signaling pathways sensitive to cyclosporin A. The Journal of biological chemistry 178 9575191
2007 Functional interdependence at the chromatin level between the MKK6/p38 and IGF1/PI3K/AKT pathways during muscle differentiation. Molecular cell 177 17964260
1996 Cloning and characterization of MEK6, a novel member of the mitogen-activated protein kinase kinase cascade. The Journal of biological chemistry 167 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
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 120 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 108 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
2002 Differential involvement of p38 mitogen-activated protein kinase kinases MKK3 and MKK6 in T-cell apoptosis. EMBO reports 90 12151339
2018 Insights of Crosstalk between p53 Protein and the MKK3/MKK6/p38 MAPK Signaling Pathway in Cancer. Cancers 89 29751559
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
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 71 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 59 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
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 48 16000313
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
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 44 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 38 30185442
2014 Monocytic cell differentiation from band-stage neutrophils under inflammatory conditions via MKK6 activation. Blood 37 25214442
2019 Circ_016719 plays a critical role in neuron cell apoptosis induced by I/R via targeting miR-29c/Map2k6. Molecular and cellular probes 36 31698040
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 Quercetin inhibits caerulein-induced acute pancreatitis through regulating miR-216b by targeting MAP2K6 and NEAT1. Inflammopharmacology 35 33051781
2020 CircASPH promotes KGN cells proliferation through miR-375/MAP2K6 axis in Polycystic Ovary Syndrome. Journal of cellular and molecular medicine 35 33372369
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
2011 Balance between MKK6 and MKK3 mediates p38 MAPK associated resistance to cisplatin in NSCLC. PloS one 34 22164285
2008 ASK1 and MAP2K6 as modifiers of age at onset in Huntington's disease. Journal of molecular medicine (Berlin, Germany) 34 18327563
2023 Architecture of the MKK6-p38α complex defines the basis of MAPK specificity and activation. Science (New York, N.Y.) 33 37708276
2019 Scaffold protein GhMORG1 enhances the resistance of cotton to Fusarium oxysporum by facilitating the MKK6-MPK4 cascade. Plant biotechnology journal 33 31794094
2022 MiR-1298-5p level downregulation induced by Helicobacter pylori infection inhibits autophagy and promotes gastric cancer development by targeting MAP2K6. Cellular signalling 32 35192930
2009 The structure of the MAP2K MEK6 reveals an autoinhibitory dimer. Structure (London, England : 1993) 31 19141286
2018 Mutual Stabilization between TRIM9 Short Isoform and MKK6 Potentiates p38 Signaling to Synergistically Suppress Glioblastoma Progression. Cell reports 30 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
2018 Pharmacological targeting of p38 MAP-Kinase 6 (MAP2K6) inhibits the growth of esophageal adenocarcinoma. Cellular signalling 28 30102978
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
2022 MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation. eLife 27 35971771
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
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 16 32582987
2023 Microcystin-LR-Exposure-Induced Kidney Damage by Inhibiting MKK6-Mediated Mitophagy in Mice. Toxins 15 37368704
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
2010 Mechanism of oxidative stress-induced ASK1-catalyzed MKK6 phosphorylation. Biochemistry 15 20364819
2014 Involvement of potato (Solanum tuberosum L.) MKK6 in response to potato virus Y. PloS one 14 25111695
2024 Inhibitory Impact of Prenatal Exposure to Nano-Polystyrene Particles on the MAP2K6/p38 MAPK Axis Inducing Embryonic Developmental Abnormalities in Mice. Toxics 13 38787149
2021 CircRNA-MSR Regulates LPS-Induced C28/I2 Chondrocyte Injury through miR-643/MAP2K6 Signaling Pathway. Cartilage 11 34581623
2021 MAP2K6 remodels chromatin and facilitates reprogramming by activating Gatad2b-phosphorylation dependent heterochromatin loosening. Cell death and differentiation 11 34815549
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
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
2010 Activin A induction of erythroid differentiation through MKK6-p38alpha/p38beta pathway is inhibited by follistatin. Journal of cellular physiology 10 20162623
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
2007 MKK6 phosphorylation regulates production of superoxide by enhancing Rac GTPase activity. Antioxidants & redox signaling 9 17854274
2025 LncRNA CRCMSL interferes in phospholipid unsaturation to suppress colorectal cancer progression via reducing membrane fluidity. Journal of advanced research 8 39921055
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

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