Affinage

MAP2K3

Dual specificity mitogen-activated protein kinase kinase 3 · UniProt P46734

Length
347 aa
Mass
39.3 kDa
Annotated
2026-06-10
100 papers in source corpus 41 papers cited in narrative 41 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAP2K3 (MKK3) is a dual-specificity MAPK kinase that occupies a central node in stress- and cytokine-activated p38 MAPK signaling, where it phosphorylates and selectively activates particular p38 isoforms to control inflammatory cytokine production, cell-fate decisions, and tissue remodeling (PMID:9430721, PMID:10097111). It activates p38α and p38γ but not p38β2, and acts as the dominant or sole upstream activator of p38δ in response to UV, hyperosmotic shock, anisomycin, and TNFα, giving the cascade isoform-selective output not redundant with the paralog MKK6 (PMID:9430721, PMID:20004242). MKK3 is itself activated by a tier of MAP3Ks—TAK1, MEKK3, MLK-3, TPL-2/MAP3K8, and LRRK2—through phosphorylation of Ser189 and Thr193 in its activation loop, both of which are required for activation (PMID:8663074, PMID:9162092, PMID:9003778, PMID:27402796). Stimulus specificity is conferred by scaffold assembly: the OSM scaffold links actin, Rac, and MEKK3 to MKK3 during hyperosmotic stress, APPL1 couples TAK1–MKK3 for adiponectin-specific signaling, and RAGE binds MKK3 directly via its C-terminus to nucleate a MEKK3–MKK3–p38 module (PMID:14634666, PMID:20978232, PMID:35080104). Genetic loss of Mkk3 establishes non-redundant roles in TNF- and TGF-β1-driven responses, including inflammatory cytokine and IL-12 induction and selective pro-collagen synthesis, and in oncogene-induced senescence, T-cell apoptosis, myogenic differentiation, and mitochondrial quality control (PMID:10097111, PMID:10202148, PMID:12374793, PMID:11971971, PMID:12151339, PMID:24487387). MKK3 activity is restrained at multiple levels—α4-targeted PP2A dephosphorylates Thr193, while ATF3/HDAC1 and HDAC8/9 repress Map2k3 transcription through promoter histone deacetylation (PMID:17438131, PMID:28249877, PMID:34021025). Beyond its canonical p38 axis, MKK3 directly phosphorylates JNK to drive migration in a conserved pathway demonstrated in Drosophila with human MKK3 rescue (PMID:30770795).

Mechanistic history

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

    Established MKK3 as a kinase positioned within a defined stress cascade, answering whether it both activates p38 and is itself activated by an upstream MAP3K.

    Evidence In vitro kinase assays and cell co-expression reconstituting TAK1→MKK3→p38

    PMID:8663074 PMID:9003778

    Open questions at the time
    • Did not define which p38 isoforms are preferentially activated
    • Physiological stimulus context not established
  2. 1997 High

    Identified the activation-loop phosphoacceptor sites and additional upstream MAP3Ks, defining the molecular switch that turns MKK3 on.

    Evidence In vitro kinase assays with MEKK3, site-directed mutagenesis of Ser189/Thr193 in COS-7 cells; macrophage activation assays

    PMID:9162092 PMID:9379049

    Open questions at the time
    • Relative contribution of each MAP3K in vivo unresolved
    • Substrate spectrum beyond p38 not addressed
  3. 1998 High

    Defined isoform-selective coupling, answering whether MKK3 and MKK6 are functionally redundant toward the p38 family.

    Evidence In vitro kinase assays and cotransfection comparing p38α, p38β2, p38γ activation by MKK3 vs MKK6, with cloning of p38β2

    PMID:9430721

    Open questions at the time
    • Structural basis of isoform discrimination not determined
    • Stimulus dependence of selectivity not tested in cells
  4. 1999 High

    Genetic loss-of-function established non-redundant physiological roles in inflammatory cytokine signaling, moving MKK3 from in vitro kinase to required pathway component.

    Evidence Mkk3-/- mice and primary cells; TNF cytokine and IL-12 p40 promoter/mRNA assays

    PMID:10097111 PMID:10202148

    Open questions at the time
    • Did not resolve which downstream p38 effectors mediate cytokine transcription
    • MKK6 compensation not fully delineated
  5. 2002 High

    Demonstrated context-specific, non-redundant MKK3 functions across senescence, differentiation, apoptosis, and TGF-β1 fibrogenesis, showing the same kinase yields divergent cell-fate outputs.

    Evidence Dominant-active/negative MKK3 constructs and Mkk3-/- cells in fibroblasts, C2C12 myoblasts, T cells, and mesangial cells with selective phenotypic readouts

    PMID:11971971 PMID:12151339 PMID:12374793 PMID:12444016

    Open questions at the time
    • How a single kinase achieves divergent outputs in different cells not mechanistically resolved
    • p38 isoform attribution incomplete in some contexts
  6. 2003 High

    Identified scaffold-based assembly as the mechanism for stimulus-specific MKK3 activation, answering how a shared kinase achieves signal specificity.

    Evidence RNAi, FRET, co-IP, and live imaging of the OSM-MEKK3-MKK3 complex during hyperosmotic shock

    PMID:14634666

    Open questions at the time
    • Whether other stimuli use distinct scaffolds was unaddressed at the time
    • Stoichiometry and assembly kinetics not quantified
  7. 2004 Medium

    Linked MKK3 spatial control to the cytoskeleton, showing microtubule/dynactin association is required for stimulus-induced activation.

    Evidence Yeast two-hybrid, siRNA of p150Glued, direct microtubule binding, and phospho-Western in endothelial cells

    PMID:15375157 PMID:15516490

    Open questions at the time
    • Direct microtubule binding region of MKK3 not mapped
    • Single lab for p150Glued interaction
  8. 2007 High

    Defined negative regulation of MKK3 at the post-translational level via site-specific dephosphorylation, completing the on/off cycle of the activation loop.

    Evidence FLAG co-IP, in vitro phosphatase assay, and α4 siRNA showing PP2A selectively dephosphorylates Thr193; TAK1/TAB1 dominant-negative studies in mesangial cells

    PMID:17299140 PMID:17438131

    Open questions at the time
    • Why Thr193 but not Ser189 is targeted is unexplained
    • Other phosphatases acting on MKK3 not identified
  9. 2009 Medium

    Systematically resolved MKK3 vs MKK6 division of labor across all p38 isoforms and stress stimuli, and identified LRRK2 as a disease-relevant upstream kinase.

    Evidence Single and double MKK3/MKK6 KO fibroblasts with isoform-specific assays; in vitro LRRK2 kinase assay with G2019S/I2020T variants

    PMID:19302196 PMID:20004242

    Open questions at the time
    • LRRK2→MKK3 lacks cellular validation
    • Disease relevance of LRRK2-MKK3 axis untested in vivo
  10. 2012 High

    Established transcriptional and post-transcriptional control of MAP2K3 abundance as a regulatory layer distinct from kinase activation.

    Evidence ATF3/HDAC1 ChIP and genetic rescue in cardiac fibroblasts; miR-20a 3'-UTR luciferase reporter and siRNA phenocopy in endothelial cells

    PMID:22696064 PMID:28249877

    Open questions at the time
    • Interplay between transcriptional repression and kinase activation not integrated
    • Tissue-specificity of these regulators not broadly mapped
  11. 2014 Medium

    Extended MKK3 function beyond cytokine signaling to mitochondrial quality control, broadening its physiological role.

    Evidence Mkk3-/- mice in LPS sepsis with mitochondrial biogenesis/mitophagy readouts via Sirt1/Pink1/Parkin

    PMID:24487387

    Open questions at the time
    • Pathway placement to Sirt1/Pink1/Parkin is associative, not direct
    • Whether p38 mediates the mitochondrial phenotype unclear
  12. 2016 High

    Refined the upstream activator hierarchy by placing TPL-2 downstream of TAK1 as a direct MKK3/6 activation-loop kinase in TLR/TNF signaling.

    Evidence Quantitative phosphoproteomics and Map3k8(D270A) catalytic-dead knockin macrophages

    PMID:27402796

    Open questions at the time
    • Direct vs indirect phosphorylation of MKK3 by TPL-2 not fully distinguished
    • Selectivity over MKK4 mechanism unexplained
  13. 2019 Medium

    Revealed a non-canonical MKK3→JNK pathway driving cell migration, challenging the view that MKK3 signals exclusively through p38.

    Evidence Drosophila genetic epistasis with lic/mkk3 and ask1, phospho-JNK Western, and human MKK3 rescue

    PMID:30770795 PMID:31554796

    Open questions at the time
    • MKK3→JNK phosphorylation not validated in mammalian cells
    • Conditions favoring JNK over p38 substrate choice unknown
  14. 2021 High

    Identified chromatin-level control of MAP2K3 via histone deacetylation and the factors enabling its transcriptional elongation.

    Evidence HDAC8/9 siRNA, H3K9ac/H3K27ac ChIP, proteomic identification of SSRP1/SUPT16H, and conditional KO mice in keratinocytes

    PMID:34021025

    Open questions at the time
    • How epigenetic repression integrates with acute signaling unresolved
    • Generality across cell types not established
  15. 2022 High

    Demonstrated that scaffold/stabilizing partners and paralog compensation tune MKK3 output toward specific p38 isoforms and disease phenotypes.

    Evidence RAGE C-terminal binding mutagenesis and in vivo rescue; SNCG co-IP and degradation protection; MKK6 KO mice with compensatory MKK3-p38γ/δ-mTOR hypertrophy and rapamycin rescue

    PMID:35080104 PMID:35637967 PMID:35971771

    Open questions at the time
    • Whether MKK3 stabilization by SNCG is direct vs indirect not fully resolved
    • Therapeutic targeting of compensatory MKK3 axis untested clinically

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MKK3 selects among p38 isoforms versus JNK at the structural and substrate-docking level, and how the multiple scaffolds, phosphatases, and transcriptional repressors are coordinated in real time, remains unresolved.
  • No structural model of MKK3 substrate discrimination
  • MKK3→JNK pathway awaits mammalian validation
  • Integration of transcriptional, epigenetic, and post-translational control not reconstituted

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016740 transferase activity 3 GO:0140657 ATP-dependent activity 2
Localization
GO:0005856 cytoskeleton 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-168256 Immune System 3 R-HSA-8953897 Cellular responses to stimuli 3
Partners
APPL1LRRK2MAP3K8MEKK3MLK-3RAGESNCGTAK1
Complex memberships
APPL1-TAK1-MKK3OSM-MEKK3-MKK3RAGE-MEKK3-MKK3

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 MKK3 selectively activates p38α and p38γ MAP kinase isoforms, but not p38β2, whereas MKK6 activates p38α, p38β2, and p38γ. This establishes isoform-selective coupling between upstream kinases and p38 family members. In vitro kinase assays, cotransfection, molecular cloning of p38β2 The Journal of biological chemistry High 9430721
1996 MKK3 phosphorylates and activates the p38/MPK2 subgroup of MAP kinases and is itself phosphorylated and activated in vitro by TAK1 (a MAPKKK), establishing a TAK1→MKK3→p38 kinase cascade. In vitro kinase assay, co-expression in cultured cells The Journal of biological chemistry High 8663074
1997 MEKK3 (but not MEKK2) directly activates MKK3 in vitro and in cells; activating phosphorylation of MKK3 occurs at Ser189 and Thr193 within kinase subdomains VII and VIII. Substitution of either site with Ala abolished MKK3 autophosphorylation and activation. In vitro kinase assay with recombinant kinases, site-directed mutagenesis (Ser189Ala, Thr193Ala), cotransfection in COS-7 cells The Journal of biological chemistry High 9162092
1996 MLK-3 directly phosphorylates MKK3 at sites required for activation (in vitro), co-precipitates with MKK6, and activates the p38 pathway through MKK3/6, placing MLK-3 upstream of MKK3 in the stress MAPK cascade. In vitro kinase assay (immunoprecipitated MLK-3 phosphorylating SEK1/MKK3), co-precipitation, co-transfection The EMBO journal Medium 9003778
1997 In TNF-α-stimulated mouse bone marrow-derived macrophages, MKK3 is activated (assessed by in vitro kinase assay using kinase-inactive p38 as substrate) and capable of phosphorylating p38 MAPK, establishing MKK3 as an upstream activator of p38 in TNF-α signaling in macrophages. In vitro kinase assay, immunoprecipitation, phospho-specific detection Journal of immunology Medium 9379049
1997 MKK3b, an N-terminally extended isoform of MKK3 encoded by an alternative exon, is more abundantly expressed than MKK3 and more efficient at activating p38 downstream signaling. cDNA cloning, Northern blotting, functional p38 activation assay FEBS letters Medium 9038352
1999 Targeted disruption of Mkk3 in mice causes selective defect in p38 activation and TNF-induced cytokine expression in fibroblasts, demonstrating that MKK3 is a critical, non-redundant component of the TNF→p38 signaling pathway for inflammatory cytokine induction. Homologous recombination knockout mice, cytokine expression assays, p38 activation assays in primary cells Proceedings of the National Academy of Sciences of the United States of America High 10097111
1999 Mkk3-/- mice show defective IL-12 production by macrophages and dendritic cells, with reduced IL-12 p40 promoter activity and mRNA, demonstrating that MKK3-activated p38 MAPK regulates IL-12 transcription in antigen-presenting cells. Homologous recombination knockout mice, IL-12 ELISA, promoter-reporter assays, cytokine mRNA analysis The EMBO journal High 10202148
1999 Anthrax lethal factor (LF), a zinc-endopeptidase, cleaves MKK3 in macrophages; sublytic doses of LF reduce NO and TNFα production induced by LPS/IFNγ, linking MKK3 cleavage to suppression of inflammatory response. Western blot cleavage assay in macrophages, NO/TNFα production assays FEBS letters Medium 10580119
2001 In Gq-signaling, Gαq activates MKK3 via a Rac/Cdc42- and phospholipase C/c-Src-dependent mechanism, while Gβγ activates MKK3 via Rac/Cdc42 and a non-Src tyrosine kinase; both activate MKK3 in parallel, leading to p38 activation. Dominant-negative kinase mutant transfections, kinase activity assays in HEK293 cells The Journal of biological chemistry Medium 11304531
2002 MKK3 deficiency in mouse mesangial cells abolishes TGF-β1-induced phosphorylation of both MKK3 and p38 (specifically p38α and p38δ isoforms), and selectively abrogates TGF-β1-stimulated pro-α1(I) collagen (but not fibronectin or PAI-1) expression, placing MKK3 as an essential and specific mediator of TGF-β1→p38α/δ→collagen signaling. Mkk3-/- mouse-derived mesangial cells, Western blotting, collagen/fibronectin/PAI-1 expression assays The Journal of biological chemistry High 12374793
2002 Oncogenic Ras sequentially activates MEK-ERK and then MKK3/6-p38 pathways in primary human fibroblasts; constitutive activation of p38 by active MKK3 induces premature senescence, and inhibiting p38 prevents Ras-induced senescence. Dominant-active MKK3/MKK6 constructs, p38 inhibitor (SB203580), senescence assays in primary human fibroblasts Molecular and cellular biology High 11971971
2002 A dominant-negative form of MKK3 expressed stably in C2C12 cells abolishes p38 activation and prevents terminal muscle differentiation, with inhibition of p21, p27, MyoD, troponin T and disorganization of cytoskeleton; demonstrating that the MKK3/p38α pathway is required for myogenic terminal differentiation. Stable transfection of dominant-negative MKK3 in C2C12 cells, Western blotting, differentiation markers American journal of physiology. Cell physiology Medium 12444016
2002 In T cells, MKK3 (induced upon stimulation) mediates activation-induced cell death and cytokine-withdrawal apoptosis in peripheral CD4+ T cells, whereas MKK6 (downregulated upon stimulation) mediates deletion of double-positive thymocytes; demonstrating differential, non-redundant roles for MKK3 vs MKK6 in T cell apoptosis. Mkk3-/- and Mkk6-/- mice, in vivo thymocyte deletion assays, T cell apoptosis assays EMBO reports High 12151339
2002 αv integrin ligation activates Rac1, which selectively signals through MKK3 (not MKK6) to activate p38 MAPK, leading to stabilization of uPA mRNA via the MAPKAPK2 pathway acting on AU-rich elements in the uPA 3'-UTR. Dominant-negative Rac1, constitutively active MKK3/MKK6, dominant-negative MKK3, β-globin reporter with uPA 3'-UTR, p38/MAPKAPK2 activity assays The Journal of biological chemistry Medium 12377770
2002 MKK3 co-immunoprecipitates with Mirk/Dyrk1B kinase; MKK3 enhances Mirk kinase activity and Mirk-dependent transcriptional activation of HNF1α, indicating that MKK3 acts as an upstream activator of Mirk/Dyrk1B in stress signaling. Co-immunoprecipitation, GST pull-down, kinase activity assay, transcriptional reporter assay The Journal of biological chemistry Medium 11980910
2003 A scaffold protein OSM (osmosensing scaffold for MEKK3) binds actin, Rac, MEKK3, and MKK3, forming a complex that is required for p38 activation during hyperosmotic shock; FRET demonstrates cytoplasmic assembly of the complex that is recruited to dynamic actin/membrane ruffles in response to sorbitol. RNAi knockdown, FRET, co-immunoprecipitation, confocal microscopy, sorbitol-induced stress assays Nature cell biology High 14634666
2003 MKK3/p38β pathway mediates cytoprotective effects of carbon monoxide against oxidant-induced lung injury; dominant-negative MKK3 mutants and Mkk3-/- mice abolish CO-dependent protection. Dominant-negative MKK3 constructs, Mkk3-/- mice, hyperoxic lung injury model The American journal of pathology Medium 14633627
2004 p150Glued (dynactin subunit) specifically interacts with MKK6 and its close homologue MKK3; siRNA silencing of p150Glued reduces stimulus-induced phosphorylation of MKK3/6 and p38. MKK3/6 directly associate with microtubules, and microtubule disruption specifically inhibits stimulus-induced MKK3/6 and p38 phosphorylation. Yeast two-hybrid, siRNA knockdown, direct microtubule binding assay, phospho-Western blotting The Journal of biological chemistry Medium 15375157
2004 siRNA knockdown of MKK3 and MKK6 individually or in combination shows that both kinases are required for p38 phosphorylation following neutrophil adherence in pulmonary microvascular endothelial cells, leading to HSP27 phosphorylation, cytoskeletal changes, and neutrophil migration. siRNA knockdown, confocal microscopy, p38/HSP27 phosphorylation assays American journal of physiology. Lung cellular and molecular physiology Medium 15516490
2005 H-Ras specifically activates the Rac→MKK3/6→p38 pathway (not activated by N-Ras), leading to MMP-2 upregulation and invasive/migratory phenotype in MCF10A breast epithelial cells; dominant-negative MKK3 blocks αv-integrin-mediated p38 activation and invasion. Stable H-Ras/N-Ras expression in MCF10A cells, dominant-negative MKK3, invasion/migration assays, MMP-2/9 expression The Journal of biological chemistry Medium 15677464
2005 Caveolin-1 modulates LPS-induced cytokine production via the MKK3/p38 MAPK pathway; peritoneal macrophages from MKK3-null mice do not show cytokine modulation by caveolin-1, demonstrating that MKK3 is required for caveolin-1's anti-inflammatory immunomodulatory function. siRNA knockdown of caveolin-1, overexpression, Mkk3-/- macrophages, EMSA, cytokine ELISA American journal of respiratory cell and molecular biology Medium 16357362
2007 TAK1 and its binding protein TAB1 function as upstream activators of the MKK3→p38 cascade in TGF-β1 signaling in mesangial cells; dominant-negative TAK1 suppresses TGF-β1-induced MKK3 and p38 activation and reduces steady-state protein levels of MKK3 and p38. Overexpression and dominant-negative TAK1/TAB1 constructs, endogenous TAK1 kinase activity assay, Western blotting in mouse mesangial cells American journal of physiology. Renal physiology Medium 17299140
2007 α4 regulatory subunit targets protein phosphatase 2A (PP2A) to MEK3/MKK3, selectively dephosphorylating Thr193 (but not Ser189) in the activation loop, thereby suppressing p38 MAPK activation by TNF-α and IL-1β and protecting against apoptosis. FLAG co-immunoprecipitation, in vitro phosphatase assay, siRNA knockdown of α4, dominant-negative α4 domain overexpression Molecular and cellular biology High 17438131
2009 MKK3 is phosphorylated in its activation loop by LRRK2 in vitro; disease-associated LRRK2 G2019S and I2020T mutations show increased phosphotransferase activity toward MKK3, identifying MKK3 as a substrate of LRRK2 MAPKKK activity. In vitro kinase assay with purified LRRK2 variants and MKK3 as substrate Journal of neurochemistry Medium 19302196
2009 MKK3 and MKK6 are both essential for activation of p38γ and p38β by environmental stress; p38δ activation by UV, hyperosmotic shock, anisomycin, or TNFα is mediated specifically by MKK3; MKK6 is the major p38γ activator in response to TNFα. MKK3-/-, MKK6-/-, and double-KO fibroblasts, p38 isoform-specific activation assays, multiple stress stimuli Cellular signalling High 20004242
2010 APPL1 scaffolds the TAK1-MKK3 complex: TAK1 and MKK3 bind to different regions of APPL1, as shown by in vitro affinity binding and co-immunoprecipitation; APPL1 knockdown/overexpression selectively modulates adiponectin-stimulated (but not TNFα-stimulated) p38 MAPK activation via MKK3. In vitro affinity binding, co-immunoprecipitation, siRNA knockdown and overexpression of APPL1 in C2C12 cells American journal of physiology. Endocrinology and metabolism Medium 20978232
2010 LFA-1 engagement in human T cells activates Rac1/2 via Vav-1, which activates MKK3 and p38, leading to HuR translocation from nucleus to cytoplasm and stabilization of ARE-containing mRNAs (IFN-γ, TNF-α); MKK3-/- T cells lose this LFA-1-induced mRNA stabilization. Mkk3-/- mice T cells, siRNA knockdown of Rac1/Rac2, Vav-1-deficient Jurkat cells, mRNA stability assays, HuR localization PloS one Medium 21206905
2012 ATF3 binds the Map2k3 promoter, recruiting HDAC1, causing histone deacetylation at the Map2k3 locus and suppressing Map2k3 gene expression; genetic knockdown of Map2k3 rescues the profibrotic/hypertrophic phenotype caused by ATF3 knockout in cardiac fibroblasts. ChIP-seq, chromatin immunoprecipitation, siRNA knockdown, ATF3 KO and transgenic mice, cardiac fibroblast functional assays Circulation High 28249877
2014 MKK3 regulates mitochondrial biogenesis and mitophagy in sepsis-induced lung injury; MKK3 deficiency simultaneously increases mitochondrial biogenesis and mitophagy through Sirt1, Pink1, and Parkin, providing protection against sepsis. Mkk3-/- mice, LPS sepsis models, mitochondrial function assays, ROS measurement, Western blotting for Sirt1/Pink1/Parkin American journal of physiology. Lung cellular and molecular physiology Medium 24487387
2014 MKK3 (Drosophila licorne) activates JNK signaling by directly phosphorylating JNK, upregulating MMP1 and integrin to drive EMT-like cell migration; human MKK3 expressed in Drosophila rescues lic loss-of-function and initiates JNK-mediated cell migration, demonstrating a conserved MKK3→JNK pathway distinct from the established MKK3→p38 pathway. Drosophila genetic screen, epistasis (loss-of-function and ectopic expression), phospho-JNK Western blot, MMP1/integrin assays; human MKK3 rescue experiment Cell death & disease Medium 30770795
2016 TPL-2 kinase (MAP3K8) catalytic activity is required for phosphorylation of MKK3/6 activation loops (but not MKK4) following TLR4 (LPS) or TNF stimulation in macrophages; this requires IKK-mediated phosphorylation of NF-κB1 p105, placing TPL-2 downstream of TAK1 as an activator of MKK3/6. Quantitative mass spectrometry phosphoproteomics, Map3k8(D270A) catalytic-inactive knockin mice, macrophage stimulation assays The Biochemical journal High 27402796
2021 HDAC8 and HDAC9 suppress MAP2K3 expression by controlling acetylation at H3K9 and H3K27 marks in the MAP2K3 promoter; SSRP1 and SUPT16H associate with HDAC8/9 and are responsible for transcriptional elongation of MAP2K3. Silencing MAP2K3 blocks the capacity of HDAC8/9 to influence cytokine responses in keratinocytes. siRNA knockdown of HDAC8/9 and MAP2K3, ChIP (H3K9ac, H3K27ac), proteomic analysis of HDAC8/9-associated proteins, keratinocyte functional assays, HDAC8/9 conditional KO mice Science immunology High 34021025
2022 MKK6 deficiency causes compensatory MKK3-p38γ/δ hyperphosphorylation and increased mTOR signaling, leading to cardiac hypertrophy; knockdown of p38γ or p38δ, or rapamycin treatment, reverts hypertrophy. This demonstrates that MKK3 specifically drives p38γ/δ-mTOR-dependent cardiac hypertrophy when MKK6 is absent. MKK6 KO mice (longitudinal cardiac phenotyping), p38γ/δ KO rescue, rapamycin treatment, Western blotting eLife High 35971771
2022 RAGE binds directly to MKK3 via its C-terminal amino acids 2-5 (ctRAGE AAs 2-5), and this binding is required for assembly of the MEKK3-MKK3-p38 signaling module; RAGE R2A-K3A-R4A-Q5A mutation suppresses p38/NF-κB activation and neuronal damage in diabetic mice. Immunoprecipitation, GST pull-down, site-directed mutagenesis of RAGE C-terminus, electrophysiology, behavioral tests in db/db mice Aging cell Medium 35080104
2020 PRSS23 forms a complex with MKK3; tipranavir treatment suppresses PRSS23 expression, releasing MKK3 from the PRSS23/MKK3 complex, which activates p38 MAPK and subsequently the IL24-mediated Bax/Bak mitochondrial apoptotic pathway in gastric cancer stem cells. Co-immunoprecipitation, Western blotting, siRNA knockdown of PRSS23, p38 activity assays, xenograft mouse model Acta pharmacologica Sinica Medium 37814123
2022 Gamma synuclein (SNCG) interacts with MKK3/6 and prevents their degradation, promoting TGF-β-induced MKK3/6 and p38 phosphorylation; SNCG knockdown decreases TGF-β-induced MKK3/6 phosphorylation, MMP-9 expression, and cancer cell invasion. Co-immunoprecipitation, Western blotting, siRNA knockdown of SNCG, invasion assays, xenograft lung metastasis model International journal of biological sciences Medium 35637967
2019 In Drosophila midgut, the kinase Ask1 and MKK3 (Licorne) are required upstream of p38 for activation of p38 signaling in enterocytes in response to infection, oxidative stress, detergent exposure, and wounding; Nox-derived ROS are required for this Ask1-MKK3-p38 activation. Drosophila genetic null mutants (ask1, lic/mkk3), RNAi knockdown, p38 phosphorylation assays, intestinal stem cell activation assays Nature communications Medium 31554796
2013 HERC1 ubiquitin ligase ubiquitylates C-RAF targeting it for proteasomal degradation; C-RAF (and RAF proteins broadly) regulates MKK3 mRNA levels; HERC1 knockdown causes C-RAF stabilization and subsequent RAF-dependent MKK3 upregulation and p38 activation, regulating cell migration. siRNA knockdown of HERC1, Western blotting, MKK3 mRNA quantification, cell migration assays, ubiquitylation assay Scientific reports Medium 31965002
2012 miR-20a specifically binds the 3'-UTR of MKK3 mRNA (validated by luciferase reporter) and reduces MKK3 protein expression, thereby inhibiting VEGF-induced p38 activation, actin remodeling, and endothelial cell migration. Luciferase 3'-UTR reporter assay, qPCR, Western blotting, lentiviral miR-20a overexpression, antagomir, siRNA knockdown of MKK3 Angiogenesis Medium 22696064
2013 HDAC inhibition by trichostatin A (TSA) increases MKK3 phosphorylation and acetylation in myocardium; disruption of either Akt-1 or MKK3 abolishes TSA-induced cardioprotection; Akt-1 disruption abolishes both acetylation and phosphorylation of MKK3, placing Akt-1 upstream of MKK3 post-translational modification in this context. MKK3-/- and Akt-1-/- mice, Langendorff heart ischemia/reperfusion model, co-immunoprecipitation, phospho/acetyl-MKK3 Western blotting PloS one Medium 23762381

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 A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. The Journal of biological chemistry 406 8663074
2002 Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Molecular and cellular biology 328 11971971
2003 Rac-MEKK3-MKK3 scaffolding for p38 MAPK activation during hyperosmotic shock. Nature cell biology 320 14634666
1999 Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. The EMBO journal 304 10202148
1996 MLK-3 activates the SAPK/JNK and p38/RK pathways via SEK1 and MKK3/6. The EMBO journal 281 9003778
2001 Activation of NF-kappa B by nontypeable Hemophilus influenzae is mediated by toll-like receptor 2-TAK1-dependent NIK-IKK alpha /beta-I kappa B alpha and MKK3/6-p38 MAP kinase signaling pathways in epithelial cells. Proceedings of the National Academy of Sciences of the United States of America 228 11438700
1999 Anthrax lethal factor cleaves MKK3 in macrophages and inhibits the LPS/IFNgamma-induced release of NO and TNFalpha. FEBS letters 228 10580119
2003 MKK3 mitogen-activated protein kinase pathway mediates carbon monoxide-induced protection against oxidant-induced lung injury. The American journal of pathology 164 14633627
2005 H-Ras-specific activation of Rac-MKK3/6-p38 pathway: its critical role in invasion and migration of breast epithelial cells. The Journal of biological chemistry 159 15677464
2009 The Parkinson disease-associated protein kinase LRRK2 exhibits MAPKKK activity and phosphorylates MKK3/6 and MKK4/7, in vitro. Journal of neurochemistry 149 19302196
2017 Cardiac Fibroblast-Specific Activating Transcription Factor 3 Protects Against Heart Failure by Suppressing MAP2K3-p38 Signaling. Circulation 145 28249877
1998 Regulation of human involucrin promoter activity by a protein kinase C, Ras, MEKK1, MEK3, p38/RK, AP1 signal transduction pathway. The Journal of biological chemistry 144 9733728
2005 Caveolin-1 confers antiinflammatory effects in murine macrophages via the MKK3/p38 MAPK pathway. American journal of respiratory cell and molecular biology 137 16357362
1999 Requirement of mitogen-activated protein kinase kinase 3 (MKK3) for tumor necrosis factor-induced cytokine expression. Proceedings of the National Academy of Sciences of the United States of America 129 10097111
2009 Differential activation of p38MAPK isoforms by MKK6 and MKK3. Cellular signalling 120 20004242
2007 TGF-beta-activated kinase 1 and TAK1-binding protein 1 cooperate to mediate TGF-beta1-induced MKK3-p38 MAPK activation and stimulation of type I collagen. American journal of physiology. Renal physiology 107 17299140
1997 Characterization of the mitogen-activated protein kinase kinase 4 (MKK4)/c-Jun NH2-terminal kinase 1 and MKK3/p38 pathways regulated by MEK kinases 2 and 3. MEK kinase 3 activates MKK3 but does not cause activation of p38 kinase in vivo. The Journal of biological chemistry 105 9162092
2008 Role of MKK3-p38 MAPK signalling in the development of type 2 diabetes and renal injury in obese db/db mice. Diabetologia 101 19066844
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
2014 MKK3 regulates mitochondrial biogenesis and mitophagy in sepsis-induced lung injury. American journal of physiology. Lung cellular and molecular physiology 83 24487387
2002 Requirement of mitogen-activated protein kinase kinase 3 (MKK3) for activation of p38alpha and p38delta MAPK isoforms by TGF-beta 1 in murine mesangial cells. The Journal of biological chemistry 83 12374793
2002 Regulation of C2C12 myogenic terminal differentiation by MKK3/p38alpha pathway. American journal of physiology. Cell physiology 76 12444016
2002 Rac1-MKK3-p38-MAPKAPK2 pathway promotes urokinase plasminogen activator mRNA stability in invasive breast cancer cells. The Journal of biological chemistry 74 12377770
2010 Pomegranate extract inhibits the interleukin-1β-induced activation of MKK-3, p38α-MAPK and transcription factor RUNX-2 in human osteoarthritis chondrocytes. Arthritis research & therapy 72 20955562
1997 Activation of p38mapk, MKK3, and MKK4 by TNF-alpha in mouse bone marrow-derived macrophages. Journal of immunology (Baltimore, Md. : 1950) 72 9379049
2010 APPL1 mediates adiponectin-stimulated p38 MAPK activation by scaffolding the TAK1-MKK3-p38 MAPK pathway. American journal of physiology. Endocrinology and metabolism 71 20978232
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
2001 BetaPix-enhanced p38 activation by Cdc42/Rac/PAK/MKK3/6-mediated pathway. Implication in the regulation of membrane ruffling. The Journal of biological chemistry 66 11309380
2019 Damage sensing by a Nox-Ask1-MKK3-p38 signaling pathway mediates regeneration in the adult Drosophila midgut. Nature communications 65 31554796
2002 Mirk protein kinase is activated by MKK3 and functions as a transcriptional activator of HNF1alpha. The Journal of biological chemistry 62 11980910
2006 MKK3/6-p38 MAPK signaling is required for IL-1beta and TNF-alpha-induced RANKL expression in bone marrow stromal cells. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 60 17032166
1997 Identification and characterization of a predominant isoform of human MKK3. FEBS letters 59 9038352
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
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
2012 miR-20a represses endothelial cell migration by targeting MKK3 and inhibiting p38 MAP kinase activation in response to VEGF. Angiogenesis 48 22696064
2007 Cytokine activation of p38 mitogen-activated protein kinase and apoptosis is opposed by alpha-4 targeting of protein phosphatase 2A for site-specific dephosphorylation of MEK3. Molecular and cellular biology 48 17438131
2019 The protective role of microRNA-21 against coxsackievirus B3 infection through targeting the MAP2K3/P38 MAPK signaling pathway. Journal of translational medicine 46 31585536
2015 Targeting MKK3 as a novel anticancer strategy: molecular mechanisms and therapeutical implications. Cell death & disease 45 25633290
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
2003 Comparative studies of a new subfamily of human Ste20-like kinases: homodimerization, subcellular localization, and selective activation of MKK3 and p38. Oncogene 45 13679851
2007 Phosphatidylinositol ether lipid analogues that inhibit AKT also independently activate the stress kinase, p38alpha, through MKK3/6-independent and -dependent mechanisms. The Journal of biological chemistry 44 17631503
2021 Cutaneous innate immune tolerance is mediated by epigenetic control of MAP2K3 by HDAC8/9. Science immunology 42 34021025
2016 Exendin-4 induces myocardial protection through MKK3 and Akt-1 in infarcted hearts. American journal of physiology. Cell physiology 41 26739490
2009 Molecular characterisation of MEK1/2- and MKK3/6-like mitogen-activated protein kinase kinases (MAPKK) from the fox tapeworm Echinococcus multilocularis. International journal for parasitology 41 19887070
2007 MKK3-p38 signaling promotes apoptosis and the early inflammatory response in the obstructed mouse kidney. American journal of physiology. Renal physiology 41 17686961
1999 Mitogen-activated protein kinase cascade and transcription factors: the opposite role of MKK3/6-p38K and MKK1-MAPK. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 41 10048449
2010 GADD45beta enhances Col10a1 transcription via the MTK1/MKK3/6/p38 axis and activation of C/EBPbeta-TAD4 in terminally differentiating chondrocytes. The Journal of biological chemistry 40 20048163
2020 Sulforaphene inhibits esophageal cancer progression via suppressing SCD and CDH3 expression, and activating the GADD45B-MAP2K3-p38-p53 feedback loop. Cell death & disease 39 32873775
2018 Gossypetin is a novel MKK3 and MKK6 inhibitor that suppresses esophageal cancer growth in vitro and in vivo. Cancer letters 39 30391783
2016 MiR-21a-5p suppresses bisphenol A-induced pre-adipocyte differentiation by targeting map2k3 through MKK3/p38/MAPK. Biochemical and biophysical research communications 39 26996129
2018 PKCα in colon cancer cells promotes M1 macrophage polarization via MKK3/6-P38 MAPK pathway. Molecular carcinogenesis 38 29637628
2012 Endothelial MKK3 is a critical mediator of lethal murine endotoxemia and acute lung injury. Journal of immunology (Baltimore, Md. : 1950) 37 23275604
2009 Phenotype-assisted transcriptome analysis identifies FOXM1 downstream from Ras-MKK3-p38 to regulate in vitro cellular invasion. Oncogene 37 20023695
2015 Elevation of miR-21, through targeting MKK3, may be involved in ischemia pretreatment protection from ischemia-reperfusion induced kidney injury. Journal of nephrology 36 26149640
2001 Parallel regulation of mitogen-activated protein kinase kinase 3 (MKK3) and MKK6 in Gq-signaling cascade. The Journal of biological chemistry 36 11304531
2019 MKK3 modulates JNK-dependent cell migration and invasion. Cell death & disease 35 30770795
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
2011 Balance between MKK6 and MKK3 mediates p38 MAPK associated resistance to cisplatin in NSCLC. PloS one 34 22164285
2021 The miR-19b-3p-MAP2K3-STAT3 feedback loop regulates cell proliferation and invasion in esophageal squamous cell carcinoma. Molecular oncology 33 33660414
2019 The MKKK62-MKK3-MAPK7/14 module negatively regulates seed dormancy in rice. Rice (New York, N.Y.) 32 30671680
2017 Matrine-Type Alkaloids Inhibit Advanced Glycation End Products Induced Reactive Oxygen Species-Mediated Apoptosis of Aortic Endothelial Cells In Vivo and In Vitro by Targeting MKK3 and p38MAPK Signaling. Journal of the American Heart Association 32 29197828
2020 Heme induces rapid endothelial barrier dysfunction via the MKK3/p38MAPK axis. Blood 29 32548640
2013 HDAC inhibition elicits myocardial protective effect through modulation of MKK3/Akt-1. PloS one 29 23762381
2004 p150(Glued), Dynein, and microtubules are specifically required for activation of MKK3/6 and p38 MAPKs. The Journal of biological chemistry 29 15375157
2014 Differential roles of MAPK kinases MKK3 and MKK6 in osteoclastogenesis and bone loss. PloS one 28 24400116
2014 MLK3-MKK3/6-P38MAPK cascades following N-methyl-D-aspartate receptor activation contributes to amyloid-β peptide-induced apoptosis in SH-SY5Y cells. Journal of neuroscience research 28 24482239
2009 MKK3, an upstream activator of p38, contributes to formalin phase 2 and late allodynia in mice. Neuroscience 28 19427893
2022 MKK6 deficiency promotes cardiac dysfunction through MKK3-p38γ/δ-mTOR hyperactivation. eLife 27 35971771
2021 MTA2 silencing attenuates the metastatic potential of cervical cancer cells by inhibiting AP1-mediated MMP12 expression via the ASK1/MEK3/p38/YB1 axis. Cell death & disease 27 33958583
2016 Convergence of Multiple MAP3Ks on MKK3 Identifies a Set of Novel Stress MAPK Modules. Frontiers in plant science 27 28066492
2018 Associations of MAP2K3 Gene Variants With Superior Memory in SuperAgers. Frontiers in aging neuroscience 26 29896098
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
2010 Proteome profiling of immortalization-to-senescence transition of human breast epithelial cells identified MAP2K3 as a senescence-promoting protein which is downregulated in human breast cancer. Proteomics. Clinical applications 26 21137025
2016 SIRT1 increases YAP- and MKK3-dependent p38 phosphorylation in mouse liver and human hepatocellular carcinoma. Oncotarget 25 26824501
2016 MKK3 influences mitophagy and is involved in cigarette smoke-induced inflammation. Free radical biology & medicine 25 27717867
2013 MAP2K3 is associated with body mass index in American Indians and Caucasians and may mediate hypothalamic inflammation. Human molecular genetics 25 23825110
2013 Eupatilin, a major flavonoid of Artemisia, attenuates aortic smooth muscle cell proliferation and migration by inhibiting PI3K, MKK3/6, and MKK4 activities. Planta medica 25 23877919
2019 MKK3 sustains cell proliferation and survival through p38DELTA MAPK activation in colorectal cancer. Cell death & disease 24 31695024
2010 Transcription activation of myostatin by trichostatin A in differentiated C2C12 myocytes via ASK1-MKK3/4/6-JNK and p38 mitogen-activated protein kinase pathways. Journal of cellular biochemistry 24 20568119
2010 T cell LFA-1 engagement induces HuR-dependent cytokine mRNA stabilization through a Vav-1, Rac1/2, p38MAPK and MKK3 signaling cascade. PloS one 24 21206905
2006 Role of MKK3 and p38 MAPK in cytokine-induced death of insulin-producing cells. The Biochemical journal 24 16097952
2021 p47phox-Dependent Oxidant Signalling through ASK1, MKK3/6 and MAPKs in Angiotensin II-Induced Cardiac Hypertrophy and Apoptosis. Antioxidants (Basel, Switzerland) 23 34572995
2020 Therapeutic potential of targeting MKK3-p38 axis with Capsaicin for Nasopharyngeal Carcinoma. Theranostics 22 32685028
2015 Fragment-based drug discovery of potent and selective MKK3/6 inhibitors. Bioorganic & medicinal chemistry letters 22 26704264
2022 HADHA alleviates hepatic steatosis and oxidative stress in NAFLD via inactivation of the MKK3/MAPK pathway. Molecular biology reports 21 36376538
2004 MKK3 and -6-dependent activation of p38alpha MAP kinase is required for cytoskeletal changes in pulmonary microvascular endothelial cells induced by ICAM-1 ligation. American journal of physiology. Lung cellular and molecular physiology 21 15516490
2023 Targeting PRSS23 with tipranavir induces gastric cancer stem cell apoptosis and inhibits growth of gastric cancer via the MKK3/p38 MAPK-IL24 pathway. Acta pharmacologica Sinica 20 37814123
2020 The ubiquitin ligase HERC1 regulates cell migration via RAF-dependent regulation of MKK3/p38 signaling. Scientific reports 20 31965002
2019 Incremental load training improves renal fibrosis by regulating the TGF‑β1/TAK1/MKK3/p38MAPK signaling pathway and inducing the activation of autophagy in aged mice. International journal of molecular medicine 20 31545406
2019 miR-214 down-regulates MKK3 and suppresses malignant phenotypes of cervical cancer cells. Gene 20 31634561
2017 Modulation of adenylate cyclase signaling in association with MKK3/6 stabilization under combination of SAC and berberine to reduce HepG2 cell survivability. Apoptosis : an international journal on programmed cell death 20 28836036
2013 Modulation of the ASK1-MKK3/6-p38/MAPK signalling pathway mediates sildenafil protection against chemical hypoxia caused by malonate. British journal of pharmacology 20 23186227
2024 The MKK3 MAPK cascade integrates temperature and after-ripening signals to modulate seed germination. Proceedings of the National Academy of Sciences of the United States of America 19 38968100
2022 Receptor for advanced glycation end products aggravates cognitive deficits in type 2 diabetes through binding of C-terminal AAs 2-5 to mitogen-activated protein kinase kinase 3 (MKK3) and facilitation of MEKK3-MKK3-p38 module assembly. Aging cell 19 35080104
2022 Gamma synuclein promotes cancer metastasis through the MKK3/6-p38MAPK cascade. International journal of biological sciences 19 35637967
2020 MiR-92b-3p ameliorates inflammation and autophagy by targeting TRAF3 and suppressing MKK3-p38 pathway in caerulein-induced AR42J cells. International immunopharmacology 19 32822908
2016 Genetic Analyses Reveal Functions for MAP2K3 and MAP2K6 in Mouse Testis Determination. Biology of reproduction 18 27009039
2015 MKK3 mediates inflammatory response through modulation of mitochondrial function. Free radical biology & medicine 18 25697779

Missed literature

Know a paper Affinage missed for MAP2K3? Flag it for the maintainers and the community.

No submissions yet.