Affinage

MAP3K3

Mitogen-activated protein kinase kinase kinase 3 · UniProt Q99759

Length
626 aa
Mass
70.9 kDa
Annotated
2026-06-10
100 papers in source corpus 53 papers cited in narrative 53 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

MAP3K3 (MEKK3) is a serine/threonine MAP kinase kinase kinase that functions as a central signaling hub coupling inflammatory, mechanosensory, developmental, and stress inputs to NF-κB and MAPK output cascades (PMID:11429546, PMID:14661019, PMID:10700190). In receptor-proximal inflammatory signaling, MEKK3 is recruited specifically to the TNF-R1 complex by RIP, where it phosphorylates and activates the IKK complex to drive NF-κB (PMID:11429546, PMID:15572679), and downstream of IL-1R/TLR it is brought into TRAF6-containing complexes via PB1-domain scaffolds including p62 and NBR1 to mediate a TAK1-independent branch of NF-κB and JNK/p38 activation marked by IKKγ phosphorylation (PMID:14661019, PMID:17197697, PMID:16737960, PMID:19903815, PMID:25043814). Through PB1–PB1 heterodimerization with MEK5 it activates the ERK5 cascade (PMID:10593883, PMID:12912994, PMID:17985933), and it nucleates a Rac–OSM–MEKK3–MKK3 scaffold to drive p38 activation in response to osmotic and other stresses (PMID:14634666, PMID:16684924). MEKK3 kinase activity is gated by activation-loop phosphorylation at Ser526 and at Thr516/Ser520, by inhibitory Thr294 phosphorylation that recruits 14-3-3, and by PP2A-mediated dephosphorylation, with Hsp90 maintaining protein stability (PMID:16407301, PMID:18308725, PMID:20448038, PMID:20068038, PMID:19560753). A defining regulatory axis is physical restraint by the CCM complex: CCM2 directly binds the MEKK3 N-terminus through its harmonin homology domain and, together with CCM2L and recruited STK24/25, suppresses constitutive MEKK3 activity, so that CCM loss releases MEKK3 to elevate KLF2/KLF4 and ADAMTS expression and drive cerebral cavernous malformation and cardiovascular defects (PMID:26235885, PMID:27027284, PMID:25625206, PMID:26540726, PMID:36692953, PMID:27513872). Endothelial MEKK3 thereby integrates hemodynamic and inflammatory cues—via PIEZO1/CaMKII upstream input—to control vascular remodeling and endothelial-to-hematopoietic transition (PMID:30732528, PMID:35883633, PMID:34911761, PMID:35245372). MEKK3 is genetically required for embryonic blood vessel development (PMID:10700190), and additional direct substrates extend its reach into Hippo/YAP signaling (LATS1/2, YAP Ser405/Ser405) (PMID:33571521, PMID:38622197), Hedgehog signaling (GLI1) (PMID:29662197), and myeloid ROS production (p47phox Ser208) (PMID:33910977).

Mechanistic history

Synthesis pass · year-by-year structured walk · 17 steps
  1. 1999 High

    Established MEKK3 as a direct upstream activator of the ERK5 cascade, defining its first concrete MAPK output.

    Evidence Yeast two-hybrid, co-IP, dominant-active overexpression, and kinase assays linking MEKK3 to MEK5/ERK5

    PMID:10593883

    Open questions at the time
    • Did not define the interaction interface
    • Physiological stimulus context unresolved at this stage
  2. 2000 High

    Genetic knockout placed MEKK3 as essential for embryonic angiogenesis, linking the kinase to p38-MEF2C cardiovascular development.

    Evidence Map3k3-/- mouse embryos with vascular phenotyping and pathway analysis

    PMID:10700190

    Open questions at the time
    • Cell-type-autonomous requirement not separated from systemic effect
    • Did not identify upstream receptors driving the developmental signal
  3. 2001 High

    Defined MEKK3 as a required transducer of TNF-induced IKK/NF-κB signaling downstream of RIP, establishing its inflammatory role.

    Evidence MEKK3-deficient fibroblasts, co-IP with RIP, in vitro IKK phosphorylation

    PMID:11429546

    Open questions at the time
    • Mechanism of RIP-MEKK3 recruitment specificity not yet resolved
    • Relationship to TAK1 in the same pathway unclear
  4. 2003 High

    Mapped the structural and scaffolding basis of MEKK3 output: PB1-domain heterodimerization with MEK5 for ERK5, and a Rac-OSM-MKK3 actin-associated scaffold for stress-induced p38.

    Evidence PB1 binding/mutagenesis, RNAi epistasis, FRET, and live-cell imaging across two studies

    PMID:12912994 PMID:14634666

    Open questions at the time
    • Did not establish how scaffold assembly is regulated by stimulus
    • Stoichiometry of the multi-protein complexes not defined
  5. 2003 High

    Placed MEKK3 downstream of MyD88-IRAK-TRAF6 in IL-1R/TLR signaling, broadening its receptor repertoire beyond TNF.

    Evidence MEKK3-deficient MEFs, co-IP with TRAF6, pathway-specific NF-κB/JNK/p38 readouts

    PMID:14661019

    Open questions at the time
    • Did not resolve the TRAF6-MEKK3 connection at domain resolution
    • ERK independence noted but mechanism unexplained
  6. 2004 High

    Demonstrated receptor-recruitment specificity: RIP recruits MEKK3 (not MEKK2 or NEMO) to TNF-R1, explaining the kinase's selective requirement.

    Evidence Reconstitution of RIP-deficient Jurkat cells with MEKK3-DD fusion vs. controls

    PMID:15572679

    Open questions at the time
    • Did not define structural basis of RIP-MEKK3 specificity
    • TRAF7 interaction context (parallel finding) not integrated
  7. 2006 High

    Resolved a TAK1-independent branch of NF-κB signaling driven by MEKK3, characterized by IKKγ phosphorylation and non-degradative IκBα modification, distinguishing two parallel inflammatory routes.

    Evidence IRAK mutation reconstitution, TAK1-/- and MEKK3-/- MEFs, IKK subunit-specific readouts, TLR8 stimulation

    PMID:16737960 PMID:17197697

    Open questions at the time
    • Physiological discrimination of TAK1 vs MEKK3 branch usage incomplete
    • Biochemical basis of IKKγ-targeted activation not fully defined
  8. 2006 High

    Defined activation-loop autophosphorylation at Ser526 as essential for kinase activity and identified PP2A and 14-3-3 as opposing regulators, establishing the core activity switch.

    Evidence Mutagenesis, phospho-specific antibody, in vitro kinase assay, PP2A inhibitor studies

    PMID:16407301

    Open questions at the time
    • Did not place Ser526 control within a receptor-proximal kinetic scheme
    • Other activation-loop sites (Thr516/Ser520) not yet known
  9. 2010 High

    Completed the activation-loop model by showing Thr516/Ser520 phosphorylation is required for IKKβ/NF-κB activation and is reversed by PP2Acβ to terminate signaling.

    Evidence Alanine/aspartate mutagenesis, IKKβ phosphorylation assays, PP2Ac co-IP and knockdown

    PMID:20068038 PMID:20448038

    Open questions at the time
    • Interplay between Ser526 and Thr516/Ser520 control not unified
    • Stimulus-specific phosphatase recruitment not detailed
  10. 2008 Medium

    Identified inhibitory Thr294 phosphorylation/14-3-3 binding as a brake released by TNFα/LPS, and characterized TAK1-MEKK3 mutual regulation maintaining basal NF-κB tone.

    Evidence Phospho-specific antibody and T294A mutagenesis; TAP-MS, FRET, and reporter assays for TAK1-MEKK3 complex

    PMID:16260783 PMID:18206350 PMID:18308725

    Open questions at the time
    • TAK1-MEKK3 regulatory model rests on single-lab data
    • Phosphatase responsible for Thr294 dephosphorylation not identified
  11. 2009 High

    Connected MEKK3 to PB1-scaffold adaptors and chaperone-dependent stability, and extended its role to GPCR (LPA) inflammatory signaling.

    Evidence p62 PB1 binding/co-localization, Hsp90 co-IP/geldanamycin half-life assays, MEKK3-/- vs TAK1-/- MEFs for LPA-IKK

    PMID:19465115 PMID:19560753 PMID:19903815

    Open questions at the time
    • Hsp90 dependence shown pharmacologically; the cognate E3 ligase unidentified
    • GPCR-to-MEKK3 coupling mechanism not resolved
  12. 2015 High

    Revealed the structural basis of CCM-mediated restraint: CCM2's HHD directly contacts the MEKK3 N-terminus, and disrupting this interaction phenocopies endothelial MEKK3 loss, defining the CCM-MEKK3 axis.

    Evidence 2.35 Å co-crystal structure, inducible endothelial Mekk3 KO, Rho-ROCK analysis, and CCM2/CCM2L binding/MEK5 phosphorylation assays with zebrafish rescue

    PMID:26235885 PMID:26540726

    Open questions at the time
    • Did not establish how upstream signals trigger MEKK3 release from CCM restraint
    • Quantitative kinetics of the restraint not defined
  13. 2016 High

    Established gain of MEKK3 signaling as causal for CCM disease, with KLF2/KLF4 as the key downstream effectors, validated genetically and in human tissue.

    Evidence Neonatal CCM mouse models, endothelial conditional KO, human CCM tissue, Mekk3 heterozygosity rescue by micro-CT

    PMID:25625206 PMID:27027284 PMID:27513872

    Open questions at the time
    • Full transcriptional program downstream of KLF2/4 incompletely mapped
    • Therapeutic targeting of the axis not addressed
  14. 2022 High

    Identified upstream mechanosensory inputs (PIEZO1/CaMKII and CDC42) and integrated inflammatory cues that feed the endothelial MEKK3-ERK5-KLF2/4 axis, and extended it to hemogenic endothelium specification.

    Evidence Endothelial Piezo1 and Cdc42 conditional KOs with epistasis, CaMKII-MEKK3 co-IP, Mekk3 KO with RUNX1+ EHT readouts

    PMID:30732528 PMID:35245372 PMID:35883633

    Open questions at the time
    • Direct CaMKII phosphorylation site on MEKK3 not mapped
    • How distinct upstream cues converge on the same output unclear
  15. 2021 High

    Expanded the MEKK3 substrate landscape into Hippo/YAP, Hedgehog/GLI1, type I IFN (IRF7), myeloid ROS (p47phox), and arterial remodeling via TGFβ crosstalk.

    Evidence Direct in vitro phosphorylation assays, MS phosphosite mapping, conditional/knock-in mouse models across multiple studies

    PMID:29662197 PMID:33571521 PMID:33812250 PMID:33910977 PMID:34911761

    Open questions at the time
    • Several substrate links rest on single-lab evidence
    • Context-dependence determining which substrate is engaged not resolved
  16. 2023 High

    Defined STK24/25 as CCM2-recruited kinases that limit constitutive MEKK3 activity, completing the molecular logic of CCM-complex restraint.

    Evidence Endothelial STK24/25 conditional KO and zebrafish domain-swap rescue with hybrid STK-CCM2 protein

    PMID:36692953

    Open questions at the time
    • How STK24/25 kinase activity acts on MEKK3 mechanistically not defined
    • Single-lab in vivo system
  17. 2024 Medium

    Established a Hippo-independent YAP stabilization route in which MAP3K3 phosphorylates YAP Ser405 to block FBXW7 binding and lysosomal degradation, linking the kinase to cancer drug resistance.

    Evidence Phosphoproteomics, MAP3K3 depletion, in vitro phosphorylation, FBXW7 co-IP, lysosomal degradation assays

    PMID:38622197

    Open questions at the time
    • Single-lab mechanism awaiting independent confirmation
    • Reconciliation with MEKK3's reported LATS-activating role unresolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • How upstream stimuli select among MEKK3's many output cascades and substrates—and how the CCM/STRIPAK restraint is dynamically released in vivo—remains the central open question.
  • No unified model of stimulus-to-substrate routing
  • Dynamics of CCM/STRIPAK release in physiological settings undefined
  • Structural basis of activation-loop control in full-length kinase unknown

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 5 GO:0060089 molecular transducer activity 3 GO:0140110 transcription regulator activity 2
Localization
GO:0005829 cytosol 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-1266738 Developmental Biology 6 R-HSA-168256 Immune System 6 R-HSA-162582 Signal Transduction 4 R-HSA-9612973 Autophagy 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
CCM2MAP2K5NBR1RIPK1SQSTM1STK24TAK1TRAF6
Complex memberships
CCM (KRIT1/CCM2/CCM2L/PDCD10) complexMEKK3-MEK5 PB1 heterodimerRac-OSM-MEKK3-MKK3 scaffoldSTRIPAK complex

Evidence

Reading pass · 53 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2001 MEKK3 is required for TNF-induced IKK activation and NF-κB signaling; MEKK3 physically interacts with RIP and directly phosphorylates IKK, placing MEKK3 downstream of RIP and TRAF2 in the TNF receptor pathway. MEKK3-deficient fibroblasts, co-immunoprecipitation, in vitro kinase assay Nature immunology High 11429546
2003 MEKK3 forms a scaffold complex with the GTPase Rac, the adaptor protein OSM (osmosensing scaffold for MEKK3), and MKK3 on actin structures; this Rac-OSM-MEKK3-MKK3 complex is required for p38 MAPK activation in response to sorbitol-induced hyperosmolarity. RNAi knockdown, FRET, co-immunoprecipitation, live-cell imaging Nature cell biology High 14634666
2003 MEKK3 is an essential signal transducer downstream of the MyD88-IRAK-TRAF6 complex in IL-1R and TLR4 signaling; MEKK3 forms a complex with TRAF6 upon IL-1 or LPS stimulation and is required for NF-κB and JNK-p38 (but not ERK) activation. MEKK3-deficient MEFs, co-immunoprecipitation, cytokine measurement Nature immunology High 14661019
1999 MEKK3 physically interacts with MEK5 and directly activates MEK5 to stimulate BMK1/ERK5 activity; a dominant-active MEKK3 is sufficient to activate ERK5 through MEK5, and MEKK3 kinase activity is required for growth-factor-mediated ERK5 activation. Yeast two-hybrid, co-immunoprecipitation, dominant-active overexpression, kinase activity assay The Journal of biological chemistry High 10593883
2000 MEKK3 is essential for embryonic blood vessel development; Map3k3-/- mice die ~E11 with angiogenesis defects, and MEKK3 activates MEF2C through the p38 MAPK cascade to drive cardiovascular development. Gene knockout in mice, embryo phenotyping, signaling pathway analysis Nature genetics High 10700190
2015 CCM2 directly binds MEKK3 via its harmonin homology domain (HHD) interacting with the N-terminus of MEKK3; a co-crystal structure at 2.35 Å was determined. MEKK3 deficiency in endothelial cells causes intracranial hemorrhage partially dependent on Rho-ROCK signaling, and disruption of MEKK3:CCM2 interaction phenocopies this neurovascular leakage. Co-crystal structure (2.35 Å), inducible endothelial-specific Mekk3 knockout mice, Rho-ROCK pathway analysis Nature communications High 26235885
2016 Gain of MEKK3 signaling in endothelial cells is causal for CCM disease; endothelial loss of KRIT1/CCM2/PDCD10 increases MEKK3 activity leading to elevated KLF2/KLF4 expression and Rho/ADAMTS activity. Endothelial-specific loss of Map3k3 or Klf2/Klf4 prevents lesion formation. A disease-causing CCM2 mutation abrogates the MEKK3 interaction without disrupting CCM complex formation. Neonatal mouse CCM model, endothelial-specific conditional knockout, human CCM tissue analysis, signaling pathway readouts Nature High 27027284
2015 Loss of CCM signaling in endocardial cells increases MEKK3 activity, which is both necessary and sufficient for elevated Klf2/Klf4 and Adamts4/5 expression causing cardiac jelly degradation; partial loss of MEKK3 rescues cardiac defects in CCM-deficient embryos. Conditional knockout mice, genetic epistasis (partial Mekk3 loss rescuing CCM deficiency), gene expression analysis Developmental cell High 25625206
2003 The PB1 domains of MEKK3 (and MEKK2) interact with the PB1 domain of MEK5 to form heterodimers required for ERK5 pathway activation; deletion or mutation of the MEKK3 PB1 domain abolishes MEKK3-MEK5 complex formation and ERK5 activation. In vitro PB1 domain binding assay, co-immunoprecipitation, dominant-negative PB1 domain expression The Journal of biological chemistry High 12912994
2006 Two IL-1-mediated NF-κB activation pathways bifurcate at IRAK modification: a TAK1-dependent pathway activating IKKα/β and a MEKK3-dependent (TAK1-independent) pathway that involves IKKγ phosphorylation and IKKα activation, resulting in IκBα phosphorylation without degradation. IRAK mutation analysis in reconstituted cells, TAK1-/- and MEKK3-/- MEFs, IKK subunit-specific readouts The Journal of biological chemistry High 17197697
2006 TLR8-mediated NF-κB and JNK activation are completely abolished in MEKK3-/- MEFs but only moderately reduced in TAK1-/- MEFs; TLR8 signals through a MEKK3-dependent pathway involving IKKγ phosphorylation rather than IKKα/β phosphorylation. MEKK3-/- and TAK1-/- MEFs, IKK complex phosphorylation analysis The Journal of biological chemistry High 16737960
2006 Phosphorylation of MEKK3 at Ser526 within the T-loop activation loop is required for MEKK3 kinase activity (NF-κB, ERK, JNK, p38 activation); Ser526 is autophosphorylated, regulated by protein phosphatase 2A (PP2A), and association with 14-3-3 at pSer526 prevents dephosphorylation. Alanine/phosphomimetic mutagenesis, phospho-specific antibody, in vitro kinase assay with MKK6, PP2A inhibitor studies The Journal of biological chemistry High 16407301
2009 The rear-end acidic cluster of the p62/sequestosome-1 PB1 domain binds the front-end basic region of the MEKK3 PB1 domain; the p62-MEKK3 complex co-localizes in cytoplasmic speckles, recruits TRAF6, and is required for TRAF6-regulated NF-κB activation downstream of IL-1. PB1 domain binding assays, co-localization microscopy, shRNA knockdown, NF-κB reporter assays The Journal of biological chemistry High 19903815
2004 TRAF7 specifically interacts with MEKK3 and potentiates MEKK3-mediated AP1 and CHOP activation; depletion of TRAF7 by antisense RNA inhibits MEKK3-mediated AP1 and CHOP activation. Co-immunoprecipitation, antisense RNA knockdown, reporter gene assays, domain mapping The Journal of biological chemistry Medium 15001576
2005 TAK1 is recruited to the TNF-R1 complex in a RIP-dependent manner and forms a functional complex with MEKK3; TAK1 regulates autophosphorylation of MEKK3 in a TAK1-kinase-activity-dependent manner, requiring TAB1 for TAK1 activation and subsequent MEKK3 phosphorylation. Co-immunoprecipitation, receptor complex isolation, dominant-negative TAK1, TAB1 co-expression The Journal of biological chemistry Medium 16260783
2008 MEKK3 and TAK1 form a complex containing non-phosphorylated forms of both kinases; non-phosphorylated TAK1 inhibits MEKK3 phosphorylation and NF-κB signaling; TAB1-mediated TAK1 autophosphorylation reverses this inhibition, providing homeostatic regulation of basal NF-κB levels. Tandem affinity purification, FRET, co-immunoprecipitation, NF-κB reporter, TAK1-deficient MEFs Cellular signalling Medium 18206350
2004 RIP functions to specifically recruit MEKK3 to the TNF-α receptor complex; a MEKK3-RIP death domain fusion (MEKK3-DD) fully restores TNF-α-induced NF-κB activation in RIP-deficient cells, while MEKK2-DD or NEMO-DD cannot, demonstrating MEKK3-specific requirement. Reconstitution of RIP-deficient Jurkat cells with fusion proteins, co-immunoprecipitation, NF-κB activation assays Molecular and cellular biology High 15572679
2003 MEKK3 interacts with PA28γ (a proteasome activator subunit) but not PA28α; the PA28γ-binding domain of MEKK3 is in its N-terminal regulatory domain (aa 1-178); in vitro assays showed PA28γ is a MEKK3 substrate; MEKK3 expression increases PA28γ protein levels in a kinase-activity-dependent manner. Co-immunoprecipitation, in vitro kinase assay, domain deletion mapping The Biochemical journal Medium 12650640
2002 Activation of MEKK3 induces G2 cell cycle arrest dependent on p38α/β2 signaling, associated with down-regulation of cyclin A and B1 expression and inhibition of CDK1/CDK2 activity; p38 inhibitor SB203580 partially rescues the G2 arrest. Conditional MEKK3:ER* activation, cell cycle synchronization, CDK activity assays, p38 inhibitor Oncogene Medium 12444545
2007 NMR solution structure of MEKK3 PB1 domain reveals prolyl isomerization at Gln38-Pro39 producing two structural isomers; the MEKK3 PB1 domain binds MEK5 PB1 with Kd ~10^-8 M; Lys7 and Arg5 in the basic cluster are key residues for this interaction. NMR structure determination, mutagenesis, binding affinity measurement Biochemistry High 17985933
2005 MEKK3 is essential for angiotensin II-induced calcineurin/NFAT activation in cardiac myocytes; MEKK3-deficient MEFs fail to activate NFAT in response to angiotensin II; restoring MEKK3 rescues NFAT activation; MEKK3 is phosphorylated in response to angiotensin II and functions downstream of the AT1 receptor. MEKK3-/- MEFs, siRNA knockdown, dominant-negative MEKK3, NFAT reporter, reconstitution The Journal of biological chemistry High 16126726
2006 MEKK3 is required for hypertonic stress-induced p38 activation and downstream TonE-driven gene (BGT1) induction in kidney cells; siRNA-mediated MEKK3 depletion downregulates p38 activity and reduces BGT1 expression. Stable transfection of activated MEKK3, siRNA knockdown, TonE-luciferase reporter American journal of physiology. Renal physiology Medium 16684924
2008 Phosphorylation of MEKK3 at Thr294 promotes 14-3-3 binding to negatively regulate MEKK3; TNFα or LPS stimulation causes rapid dephosphorylation of Thr294 and loss of 14-3-3 association, correlating with MEKK3 pathway activation; Thr294 phosphorylation does not affect Ser526 phosphorylation. Phospho-specific antibody, mutagenesis (T294A), co-immunoprecipitation with 14-3-3, NF-κB reporter The Journal of biological chemistry Medium 18308725
2002 MEKK3 is phosphorylated at Ser166 and Ser337 in response to TNF, arsenite, forskolin, and serum; 14-3-3 proteins interact with MEKK3; however, Ser166 and Ser337 phosphorylation are not required for 14-3-3 association or MEKK3-dependent ERK and JNK activity. LC-MS phosphopeptide mapping, phospho-specific antibodies, co-precipitation with 14-3-3 Archives of biochemistry and biophysics Medium 12392720
2010 Protein phosphatase 2A (PP2A) acts as a MEKK3 phosphatase; PP2Acβ associates with phosphorylated MEKK3 in a transient LPA-induced manner, dephosphorylates MEKK3 at Thr516 and Ser520, and terminates MEKK3-mediated IKKβ/NF-κB activation. Functional genomic screen, co-immunoprecipitation, overexpression/knockdown of PP2Ac, IKKβ phosphorylation assay The Journal of biological chemistry Medium 20448038
2010 Phosphorylation of MEKK3 at Thr516 and Ser520 within the kinase activation loop is required for MEKK3-mediated IKKβ/NF-κB activation; alanine substitution abolishes activity, while acidic substitution renders constitutive activity. Alanine/aspartate mutagenesis, IKKβ phosphorylation assay, NF-κB reporter The Journal of biological chemistry High 20068038
2009 MEKK3 is required for LPA-induced IKK-NF-κB activation and cytokine (IL-6, MIP-2) production via GPCR signaling; this is MEKK3-specific and TAK1-independent, as shown by selective loss in MEKK3-/- but not TAK1-/- MEFs. MEKK3-/- and TAK1-/- MEFs, IKK activation assay, cytokine ELISA Cellular signalling High 19465115
2011 MEKK2 and MEKK3 negatively regulate TGF-β-mediated Th cell differentiation by phosphorylating SMAD2 and SMAD3 at their linker regions; T cell-specific Map3k2/Map3k3 double knockout mice show accumulation of Treg and Th17 cells consistent with enhanced TGF-β responses. T cell conditional knockout mice, in vitro differentiation assays, SMAD phosphorylation analysis Immunity Medium 21333552
2011 MEKK3 is required for TCR-induced ERK1/2, JNK, and p38 activation and IFN-γ production in CD4+ T cells; TCR-mediated MEKK3 activation requires Rac1/2, as shown in Mekk3 T cell conditional knockout mice. T cell-specific conditional Mekk3 knockout mice, cytokine measurement, MAPK activation assays, bacterial infection model Journal of immunology High 21471448
2014 NBR1 interacts with MEKK3 via PB1 domain interaction; the NBR1-MEKK3 complex is required for JNK activation in macrophages and drives adipose tissue inflammation in obesity; myeloid-specific NBR1 inactivation impairs JNK signaling and macrophage inflammatory function. PB1 domain interaction assay, myeloid-specific conditional KO mice, JNK activation assay, metabolic phenotyping Cell metabolism High 25043814
2008 MEKK3 kinase activity is required for and sufficient to initiate TGFβ2-dependent epithelial-to-mesenchymal transition (EMT) during endocardial cushion morphogenesis; kinase-inactive MEKK3 blocks EMT while constitutively active MEKK3 triggers EMT in normally non-EMT ventricular endocardium. In vitro cushion EMT assay, kinase-inactive and constitutively active MEKK3 constructs, gene expression analysis Circulation research Medium 19008476
2009 MEKK3 is required for lymphopenia-induced T cell proliferation and homeostatic survival; MEKK3-deficient T cells show attenuated ERK1/2 (but not p38) activation during homeostatic proliferation, while antigen-induced proliferation is unaffected. T cell-specific MEKK3 conditional KO mice, adoptive transfer, MAPK activation assays Journal of immunology Medium 19265138
2021 MEKK3-MEK5-ERK5 signaling pathway is required for basal lysosome-mediated mitochondrial degradation; genetic or pharmacological inhibition of MEKK3-MEK5-ERK5 increases mitochondrial content by reducing basal mitophagic degradation without affecting bulk autophagy or damage-induced mitophagy. Genetic inhibition (CRISPR), pharmacological inhibition, mitochondrial content assays, lysosomal inhibition studies Cell death discovery Medium 33101709
2019 CDC42 deletion in endothelial cells causes increased MEKK3-MEK5-ERK5-KLF2/4 signaling and CCM-like vascular malformations; CDC42 interacts with CCM proteins and CCM3 promotes CDC42 activity; Klf4 co-inactivation reduces severity of Cdc42-mutant vascular malformations. Endothelial-specific inducible Cdc42 knockout mice, genetic epistasis (Klf4 co-deletion), MEKK3 pathway signaling assays Circulation research High 30732528
2015 Both CCM2 and CCM2L bind MEKK3 in a complex with CCM1 and prevent MEKK3 activation and its ability to phosphorylate MEK5; ccm2l/ccm2 double knockdown in zebrafish is rescued by mekk3 knockdown, confirming CCM2L-CCM2 co-regulation of MEKK3 in vivo. In vitro binding assays, MEK5 phosphorylation assay, zebrafish morpholino knockdown with genetic rescue Proceedings of the National Academy of Sciences High 26540726
2018 MEKK3 inhibits GLI1 transcriptional activity and oncogenic function by phosphorylating multiple Ser/Thr sites on GLI1, reducing GLI1 protein stability, DNA-binding ability, and increasing GLI1-SUFU association; MEKK3 mediates FGF2-dependent inhibition of Hedgehog signaling. In vitro kinase assay, GLI1 mutagenesis, protein stability assays, SUFU co-immunoprecipitation, medulloblastoma cell proliferation Oncogene Medium 29662197
2018 MEKK3 forms a complex with WDR62 to promote JNK signaling synergistically in neural progenitor cells; MEKK3 positively regulates WDR62 protein stability in the developing brain; WDR62 is negatively regulated by T1053 phosphorylation leading to FBW7-mediated proteasomal degradation. Conditional Mekk3 knockout mice, WDR62 stability assays, JNK signaling analysis, FBW7 co-immunoprecipitation PLoS biology Medium 30566428
2021 MEKK3 and MEKK2 phosphorylate LATS1/2 and YAP/TAZ to activate Hippo signaling in response to TNF and other stimuli; STRIPAK complex associates with MEKK3 via CCM2 and CCM3 to inactivate MEKK3, and upstream Hippo signals trigger MEKK3 dissociation from STRIPAK to release MEKK3 activity. Co-immunoprecipitation, kinase assay (LATS1/2 and YAP/TAZ phosphorylation), STRIPAK complex analysis The Journal of biological chemistry Medium 33571521
2009 Hsp90 interacts with MEKK3 and acts as its molecular chaperone to maintain MEKK3 stability; Hsp90 inhibitors (geldanamycin) shorten MEKK3 half-life and induce MEKK3 ubiquitination and proteasomal degradation. Co-immunoprecipitation, Hsp90 RNAi, geldanamycin treatment, protein stability/half-life assay, ubiquitination assay Cellular immunology Medium 19560753
2022 PIEZO1 mechanosensitive channel activation by shear stress leads to calcium influx that activates CaMKII; CaMKII interacts with and activates MEKK3, promoting MEKK3/MEK5/ERK5 signaling and KLF2/4 transcription in endothelial cells. Endothelial-specific Piezo1 knockout mice, CaMKII-MEKK3 co-immunoprecipitation, ERK5/KLF2/4 pathway readouts Cells Medium 35883633
2021 MEKK3 activates IRF7 through direct interaction and phosphorylation of IRF7 at multiple sites in response to TLR7/9 activation; endogenous MEKK3 binds and phosphorylates IRF7 after TLR9 activation by CpG DNA, triggering type I IFN induction. Co-immunoprecipitation, in vitro phosphorylation assay, MEKK3 knockdown in vivo, TLR7/9 ligand stimulation Molecular immunology Medium 33812250
2021 MEKK3-TGFβ crosstalk controls inward arterial remodeling; endothelial-specific MEKK3 deletion causes inward remodeling of pulmonary and systemic arteries, spontaneous hypertension, and accelerated atherosclerosis; molecular analysis reveals MEKK3 deletion activates TGFβR1-Smad2/3 signaling, and endothelial TGFβR1 knockout prevents this remodeling. Adult endothelial-specific Mekk3 knockout, endothelial TGFβR1 knockout epistasis, vascular phenotyping, Smad2/3 phosphorylation Proceedings of the National Academy of Sciences High 34911761
2022 RAGE binds MKK3 via C-terminal amino acids 2-5, and this interaction is required for assembly of the MEKK3-MKK3-p38 signaling module and activation of p38 MAPK/NF-κB signaling; specific RAGE ctRAGE R2A-K3A-R4A-Q5A mutation suppresses neuronal damage and improves synaptic plasticity in diabetic mice. Co-immunoprecipitation, GST pull-down, point mutagenesis, electrophysiology, behavioral assays in db/db mice Aging cell Medium 35080104
2022 MEKK3 and KLF2/4 signaling in endothelial cells integrates hemodynamic (shear/fluid forces) and inflammatory signals (LPS, IFN-γ) to specify RUNX1+ hemogenic endothelial cells and drive endothelial-to-hematopoietic transition (EHT) in the embryo. Endothelial-specific Mekk3 conditional KO mice, LPS and IFN-γ stimulation, catecholamine stimulation, RUNX1+ cell quantification Blood High 35245372
2023 STK24/25 (CCM3-interacting kinases) limit constitutive MEKK3 activity by being recruited to MEKK3 via CCM2 as adaptor; loss of STK24/25 in endothelial cells causes MEKK3 activation and CCM lesion formation; a hybrid STK kinase domain–CCM2 MEKK3-interacting domain fusion rescues CCM loss-of-function in zebrafish. Endothelial-specific STK24/25 conditional KO mice, zebrafish genetic rescue with hybrid protein, CCM lesion quantification JCI insight High 36692953
2024 MAP3K3 phosphorylates YAP at Ser405, preventing FBXW7 binding and thereby inhibiting p62-mediated lysosomal degradation of YAP; this stabilization mechanism is independent of canonical Hippo kinases and supports YAP-dependent drug resistance in melanoma and breast cancer. Mass spectrometry phosphoproteomics, MAP3K3 depletion (siRNA/CRISPR), in vitro phosphorylation, FBXW7 co-immunoprecipitation, lysosomal degradation assay Experimental & molecular medicine Medium 38622197
2021 MAP3K2 and MAP3K3 mediate phosphorylation of NADPH oxidase 2 subunit p47phox at Ser208, promoting ROS formation in myeloid cells; pazopanib inhibits MAP3K2/MAP3K3 to reduce this phosphorylation; myeloid-specific MAP3K2/MAP3K3 double inactivation or p47phox S208A mutation attenuates acute lung injury. In vitro kinase assay (p47phox phosphorylation), myeloid-specific conditional KO, p47phox S208A knock-in mice, ALI models Science translational medicine High 33910977
2007 MEKK3 is required for angiopoietin-1/Tie2-induced p38 and ERK5 activation in endothelial cells; MEKK3-deficient endothelial cells show defects in proliferation, apoptosis, and interaction with myocardium. Mekk3-deficient endothelial cells from embryos, Ang1 stimulation, p38 and ERK5 activation assays American journal of physiology. Cell physiology Medium 17687003
2014 H. pylori induces transient IKK complex activation via mutual control by MEKK3 and TAK1; TAK1 transiently interacts with TRAF6 and undergoes autophosphorylation and K63-linked ubiquitination; MEKK3 and TAK1 synergize to activate the IKK complex in a T4SS-dependent, CagA-independent manner. Co-immunoprecipitation, H. pylori infection of gastric epithelial cells, TAK1/MEKK3 pathway analysis Biochimica et biophysica acta Medium 24418622
2018 In platelets, MEKK3 is required for agonist-induced activation of ERK1/2 and JNK2 (but not p38 or ERK5) and integrin αIIbβ3-mediated inside-out signaling; megakaryocyte/platelet-specific MEKK3 deletion impairs aggregation, degranulation, and in vivo thrombus formation. Megakaryocyte/platelet-specific MEKK3 knockout mice, MAPK activation assays, platelet aggregation, FeCl3 carotid injury model Blood advances High 29941457
2019 MEKK3 knockout reduces YAP/TAZ promoter recruitment and target gene expression, and inhibits EMT, cell migration, 3D colony formation, and cancer stem cell populations in pancreatic cancer cells; MEKK3 loss reduces tumor growth in vivo. CRISPR/Cas9 MEKK3 knockout in pancreatic cancer cell lines, YAP/TAZ promoter chromatin immunoprecipitation, in vivo xenograft Anticancer research Low 29599309
2016 Mekk3 heterozygosity (loss of one allele) prevents CCM lesion formation in Ccm2-deficient neonatal mice, as quantified by micro-CT imaging, providing genetic evidence that MEKK3 is the downstream effector of CCM2 loss. Micro-CT quantification of CCM lesions in Ccm2-/Mekk3+/- compound mutant mice PloS one Medium 27513872
2034 HDAC4 prevents p62-dependent autophagic degradation of MEKK3 by inhibiting MEF2A-driven transcription of ATG4B, thereby activating p38 MAPK signaling; downstream transcription factor USF1 forms a positive feedback loop by enhancing HDAC4 expression. ChIP, dual-luciferase reporter, immunofluorescence, western blot in gastric cancer cells British journal of cancer Medium 35637410

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 The essential role of MEKK3 in TNF-induced NF-kappaB activation. Nature immunology 346 11429546
2003 Rac-MEKK3-MKK3 scaffolding for p38 MAPK activation during hyperosmotic shock. Nature cell biology 320 14634666
2016 Cerebral cavernous malformations arise from endothelial gain of MEKK3-KLF2/4 signalling. Nature 256 27027284
2003 Differential regulation of interleukin 1 receptor and Toll-like receptor signaling by MEKK3. Nature immunology 219 14661019
2000 Mekk3 is essential for early embryonic cardiovascular development. Nature genetics 198 10700190
1999 MEKK3 directly regulates MEK5 activity as part of the big mitogen-activated protein kinase 1 (BMK1) signaling pathway. The Journal of biological chemistry 160 10593883
2002 Insulin-like growth factor-1 enhances inflammatory responses in endothelial cells: role of Gab1 and MEKK3 in TNF-alpha-induced c-Jun and NF-kappaB activation and adhesion molecule expression. Circulation research 159 12065326
2004 TRAF7 potentiates MEKK3-induced AP1 and CHOP activation and induces apoptosis. The Journal of biological chemistry 147 15001576
2015 The cerebral cavernous malformation pathway controls cardiac development via regulation of endocardial MEKK3 signaling and KLF expression. Developmental cell 143 25625206
2018 MicroRNA-124 regulates the expression of MEKK3 in the inflammatory pathogenesis of Parkinson's disease. Journal of neuroinflammation 123 29329581
2005 TAK1 is recruited to the tumor necrosis factor-alpha (TNF-alpha) receptor 1 complex in a receptor-interacting protein (RIP)-dependent manner and cooperates with MEKK3 leading to NF-kappaB activation. The Journal of biological chemistry 115 16260783
2009 PB1 domain interaction of p62/sequestosome 1 and MEKK3 regulates NF-kappaB activation. The Journal of biological chemistry 111 19903815
2015 A somatic MAP3K3 mutation is associated with verrucous venous malformation. American journal of human genetics 99 25728774
2006 Interleukin-1 (IL-1)-induced TAK1-dependent Versus MEKK3-dependent NFkappaB activation pathways bifurcate at IL-1 receptor-associated kinase modification. The Journal of biological chemistry 99 17197697
2015 Structure and vascular function of MEKK3-cerebral cavernous malformations 2 complex. Nature communications 85 26235885
2021 Somatic MAP3K3 and PIK3CA mutations in sporadic cerebral and spinal cord cavernous malformations. Brain : a journal of neurology 84 33729480
2006 TLR8-mediated NF-kappaB and JNK activation are TAK1-independent and MEKK3-dependent. The Journal of biological chemistry 84 16737960
2003 PB1 domains of MEKK2 and MEKK3 interact with the MEK5 PB1 domain for activation of the ERK5 pathway. The Journal of biological chemistry 78 12912994
2021 Somatic MAP3K3 mutation defines a subclass of cerebral cavernous malformation. American journal of human genetics 76 33891857
2003 Overexpression of MEKK3 confers resistance to apoptosis through activation of NFkappaB. The Journal of biological chemistry 67 14662759
2015 The cerebral cavernous malformation proteins CCM2L and CCM2 prevent the activation of the MAP kinase MEKK3. Proceedings of the National Academy of Sciences of the United States of America 62 26540726
2011 The kinases MEKK2 and MEKK3 regulate transforming growth factor-β-mediated helper T cell differentiation. Immunity 52 21333552
2022 Mechanosensitive Channel PIEZO1 Senses Shear Force to Induce KLF2/4 Expression via CaMKII/MEKK3/ERK5 Axis in Endothelial Cells. Cells 48 35883633
2005 The essential role of MEKK3 signaling in angiotensin II-induced calcineurin/nuclear factor of activated T-cells activation. The Journal of biological chemistry 48 16126726
2018 Ponatinib (AP24534) inhibits MEKK3-KLF signaling and prevents formation and progression of cerebral cavernous malformations. Science advances 45 30417093
2006 Phosphorylation of serine 526 is required for MEKK3 activity, and association with 14-3-3 blocks dephosphorylation. The Journal of biological chemistry 45 16407301
2002 Delta MEKK3:ER* activation induces a p38 alpha/beta 2-dependent cell cycle arrest at the G2 checkpoint. Oncogene 45 12444545
2019 CDC42 Deletion Elicits Cerebral Vascular Malformations via Increased MEKK3-Dependent KLF4 Expression. Circulation research 44 30732528
2014 A macrophage NBR1-MEKK3 complex triggers JNK-mediated adipose tissue inflammation in obesity. Cell metabolism 44 25043814
2021 MiR-150-5p protects against septic acute kidney injury via repressing the MEKK3/JNK pathway. Cellular signalling 42 34333083
2018 MEKK3 Sustains EMT and Stemness in Pancreatic Cancer by Regulating YAP and TAZ Transcriptional Activity. Anticancer research 42 29599309
2004 Restoration of NF-kappaB activation by tumor necrosis factor alpha receptor complex-targeted MEKK3 in receptor-interacting protein-deficient cells. Molecular and cellular biology 39 15572679
2022 HDAC4 promotes the growth and metastasis of gastric cancer via autophagic degradation of MEKK3. British journal of cancer 38 35637410
2018 MiroRNA-188 Acts as Tumor Suppressor in Non-Small-Cell Lung Cancer by Targeting MAP3K3. Molecular pharmaceutics 38 29528232
2014 MEKK3 and TAK1 synergize to activate IKK complex in Helicobacter pylori infection. Biochimica et biophysica acta 36 24418622
2022 Overlapping functions of YDA and MAPKKK3/MAPKKK5 upstream of MPK3/MPK6 in plant immunity and growth/development. Journal of integrative plant biology 34 35652263
2011 Rac1/osmosensing scaffold for MEKK3 contributes via phospholipase C-gamma1 to activation of the osmoprotective transcription factor NFAT5. Proceedings of the National Academy of Sciences of the United States of America 33 21712438
2018 Platelet MEKK3 regulates arterial thrombosis and myocardial infarct expansion in mice. Blood advances 32 29941457
2018 MEKK2 and MEKK3 suppress Hedgehog pathway-dependent medulloblastoma by inhibiting GLI1 function. Oncogene 31 29662197
2019 The miR-193a-3p-MAP3k3 Signaling Axis Regulates Substrate Topography-Induced Osteogenesis of Bone Marrow Stem Cells. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 30 31921551
2014 Amplification and over-expression of MAP3K3 gene in human breast cancer promotes formation and survival of breast cancer cells. The Journal of pathology 30 24122835
2011 MEKK3 regulates IFN-gamma production in T cells through the Rac1/2-dependent MAPK cascades. Journal of immunology (Baltimore, Md. : 1950) 30 21471448
2007 MEKK3 is required for endothelium function but is not essential for tumor growth and angiogenesis. American journal of physiology. Cell physiology 30 17687003
2006 MEKK3 is essential for lipopolysaccharide-induced interleukin-6 and granulocyte-macrophage colony-stimulating factor production in macrophages. Immunology 30 17116170
2008 Homeostatic interactions between MEKK3 and TAK1 involved in NF-kappaB signaling. Cellular signalling 29 18206350
2021 MEKK3-TGFβ crosstalk regulates inward arterial remodeling. Proceedings of the National Academy of Sciences of the United States of America 28 34911761
2006 MEKK3-mediated signaling to p38 kinase and TonE in hypertonically stressed kidney cells. American journal of physiology. Renal physiology 28 16684924
2003 MEKK3 interacts with the PA28 gamma regulatory subunit of the proteasome. The Biochemical journal 28 12650640
2023 Somatic variants of MAP3K3 are sufficient to cause cerebral and spinal cord cavernous malformations. Brain : a journal of neurology 27 36995941
2019 LncRNA-MALAT1 promotes tumorogenesis of infantile hemangioma by competitively binding miR-424 to stimulate MEKK3/NF-κB pathway. Life sciences 27 31610202
2018 miR‑505 inhibits cell growth and EMT by targeting MAP3K3 through the AKT‑NFκB pathway in NSCLC cells. International journal of molecular medicine 27 30628663
2009 MEKK3 expression correlates with nuclear factor kappa B activity and with expression of antiapoptotic genes in serous ovarian carcinoma. Cancer 27 19517469
2004 NF-kappaB activation by the chemopreventive dithiolethione oltipraz is exerted through stimulation of MEKK3 signaling. The Journal of biological chemistry 27 15047705
2009 MEKK3 is required for lysophosphatidic acid-induced NF-kappaB activation. Cellular signalling 24 19465115
2021 MiR-132-3p Modulates MEKK3-Dependent NF-κB and p38/JNK Signaling Pathways to Alleviate Spinal Cord Ischemia-Reperfusion Injury by Hindering M1 Polarization of Macrophages. Frontiers in cell and developmental biology 23 33644040
2021 Circ_0006988 promotes the proliferation, metastasis and angiogenesis of non-small cell lung cancer cells by modulating miR-491-5p/MAP3K3 axis. Cell cycle (Georgetown, Tex.) 23 34189997
2023 Endothelial hyperactivation of mutant MAP3K3 induces cerebral cavernous malformation enhanced by PIK3CA GOF mutation. Angiogenesis 21 36719480
2023 Young Sca-1+ bone marrow stem cell-derived exosomes preserve visual function via the miR-150-5p/MEKK3/JNK/c-Jun pathway to reduce M1 microglial polarization. Journal of nanobiotechnology 21 37322478
2020 MiR-212-3p suppresses high-grade serous ovarian cancer progression by directly targeting MAP3K3. American journal of translational research 21 32269720
2018 MiR-194 regulates nasopharyngeal carcinoma progression by modulating MAP3K3 expression. FEBS open bio 21 30652073
2008 MEKK3 initiates transforming growth factor beta 2-dependent epithelial-to-mesenchymal transition during endocardial cushion morphogenesis. Circulation research 21 19008476
2020 Effects of miR-124-3p regulation of the p38MAPK signaling pathway via MEKK3 on apoptosis and proliferation of macrophages in mice with coronary atherosclerosis. Advances in clinical and experimental medicine : official organ Wroclaw Medical University 20 32750754
2010 Protein phosphatase 2A acts as a mitogen-activated protein kinase kinase kinase 3 (MEKK3) phosphatase to inhibit lysophosphatidic acid-induced IkappaB kinase beta/nuclear factor-kappaB activation. The Journal of biological chemistry 20 20448038
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
2015 MAP3K3 expression in tumor cells and tumor-infiltrating lymphocytes is correlated with favorable patient survival in lung cancer. Scientific reports 19 26088427
2009 MEKK3 is essential for lymphopenia-induced T cell proliferation and survival. Journal of immunology (Baltimore, Md. : 1950) 19 19265138
2007 Insight into the binding properties of MEKK3 PB1 to MEK5 PB1 from its solution structure. Biochemistry 19 17985933
2022 Endothelial MEKK3-KLF2/4 signaling integrates inflammatory and hemodynamic signals during definitive hematopoiesis. Blood 18 35245372
2021 ETV5-mediated upregulation of lncRNA CTBP1-DT as a ceRNA facilitates HGSOC progression by regulating miR-188-5p/MAP3K3 axis. Cell death & disease 18 34887384
2005 hKSR-2 inhibits MEKK3-activated MAP kinase and NF-kappaB pathways in inflammation. Biochemical and biophysical research communications 18 16039990
2021 Pazopanib ameliorates acute lung injuries via inhibition of MAP3K2 and MAP3K3. Science translational medicine 17 33910977
2014 Novel TNS3-MAP3K3 and ZFPM2-ELF5 fusion genes identified by RNA sequencing in multicystic mesothelioma with t(7;17)(p12;q23) and t(8;11)(q23;p13). Cancer letters 17 25484136
2008 Phosphorylation of MEKK3 at threonine 294 promotes 14-3-3 association to inhibit nuclear factor kappaB activation. The Journal of biological chemistry 17 18308725
2002 Phosphorylation of the stress-activated protein kinase, MEKK3, at serine 166. Archives of biochemistry and biophysics 17 12392720
2021 MEKK2 and MEKK3 orchestrate multiple signals to regulate Hippo pathway. The Journal of biological chemistry 16 33571521
2020 Long non-coding RNA CDKN2B-AS1 promotes osteosarcoma by increasing the expression of MAP3K3 via sponging miR-4458. In vitro cellular & developmental biology. Animal 16 31950433
2019 Overexpression of MAP3K3 promotes tumour growth through activation of the NF-κB signalling pathway in ovarian carcinoma. Scientific reports 16 31182739
2018 MEKK3 coordinates with FBW7 to regulate WDR62 stability and neurogenesis. PLoS biology 16 30566428
2009 Regulation of NF-kappaB-dependent T cell activation and development by MEKK3. International immunology 16 19223432
2019 Silencing of the MEKK2/MEKK3 Pathway Protects against Spinal Cord Injury via the Hedgehog Pathway and the JNK Pathway. Molecular therapy. Nucleic acids 14 31382189
2016 Micro-CT Imaging Reveals Mekk3 Heterozygosity Prevents Cerebral Cavernous Malformations in Ccm2-Deficient Mice. PloS one 14 27513872
2022 LncRNA OGFRP1 promotes cell proliferation and suppresses cell radiosensitivity in gastric cancer by targeting the miR-149-5p/MAP3K3 axis. Journal of molecular histology 13 35050465
2022 miR-181b regulates vascular endothelial aging by modulating an MAP3K3 signaling pathway. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 13 35593587
2021 CircSETDB1 knockdown inhibits the malignant progression of serous ovarian cancer through miR-129-3p-dependent regulation of MAP3K3. Journal of ovarian research 13 34789310
2017 miR-188 promotes senescence of lineage-negative bone marrow cells by targeting MAP3K3 expression. FEBS letters 13 28640956
2010 MEKK3 overexpression contributes to the hyperresponsiveness of IL-12-overproducing cells and CD4+ T conventional cells in nonobese diabetic mice. Journal of immunology (Baltimore, Md. : 1950) 13 20720201
2024 Overcoming BRAF and CDK4/6 inhibitor resistance by inhibiting MAP3K3-dependent protection against YAP lysosomal degradation. Experimental & molecular medicine 10 38622197
2023 Release of STK24/25 suppression on MEKK3 signaling in endothelial cells confers cerebral cavernous malformation. JCI insight 10 36692953
2010 Phosphorylation of Thr-516 and Ser-520 in the kinase activation loop of MEKK3 is required for lysophosphatidic acid-mediated optimal IkappaB kinase beta (IKKbeta)/nuclear factor-kappaB (NF-kappaB) activation. The Journal of biological chemistry 10 20068038
2021 MEKK3 activates IRF7 to trigger a potent type I interferon induction in response to TLR7/9 signaling. Molecular immunology 9 33812250
2021 XJ-8, a natural compound isolated from Sanguis draxonis, inhibits platelet function and thrombosis by targeting MAP3K3. Journal of thrombosis and haemostasis : JTH 9 34780114
2011 RNAi silencing of the MEKK3 gene promotes TRAIL-induced apoptosis in MCF-7 cells and suppresses the transcriptional activity of NF-κB. Oncology reports 9 22020406
2021 DNM3OS Facilitates Ovarian Cancer Progression by Regulating miR-193a-3p/MAP3K3 Axis. Yonsei medical journal 8 34027641
2020 MEKK3-MEK5-ERK5 signaling promotes mitochondrial degradation. Cell death discovery 8 33101709
2022 Simplex cerebral cavernous malformations with MAP3K3 mutation have distinct clinical characteristics. Frontiers in neurology 7 36090889
2014 The expression and role of MEKK3 in renal clear cell carcinoma. Anatomical record (Hoboken, N.J. : 2007) 7 25388155
2009 Heat shock protein 90 regulates the stability of MEKK3 in HEK293 cells. Cellular immunology 7 19560753
2025 Map3k3  I441M Knock-In Mouse Model of Cerebral Cavernous Malformations. Stroke 6 40127145
2021 Brain-specific TRAF7 deletion ameliorates traumatic brain injury by suppressing MEKK3-regulated glial inflammation and neuronal death. International immunopharmacology 6 34953447
2016 TAK1 knockdown enhances lipopolysaccharide-induced secretion of proinflammatory cytokines in myeloid cells via unleashing MEKK3 activity. Cellular immunology 6 27671672

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