Affinage

MAP3K1

Mitogen-activated protein kinase kinase kinase 1 · UniProt Q13233

Length
1512 aa
Mass
164.5 kDa
Annotated
2026-06-10
100 papers in source corpus 38 papers cited in narrative 38 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

MAP3K1 (MEKK1) is a central stress- and survival-signaling hub that couples diverse extracellular and intracellular cues to the JNK, ERK, and NF-κB cascades through dual kinase and E3 ubiquitin ligase activities (PMID:7992057, PMID:24386504). Its kinase domain directly phosphorylates and activates the JNK activator SEK1/MKK4 (PMID:7997270), can phosphorylate MEK1 at S218/S222 (PMID:7624324), and directly activates the IκBα/IKK complex to drive NF-κB (PMID:9008162, PMID:9689078), establishing parallel control of the c-Jun/JNK and NF-κB stress pathways. Activation requires autophosphorylation in the kinase activation loop and is triggered by oligomerization (GCK/TRAF2), upstream phosphorylation (RIP at S957/S994, PKG, GSK3β), and small-GTPase binding (Rho-GTP), with a long N-terminal regulatory domain serving as a scaffold that integrates these inputs (PMID:11784851, PMID:11369754, PMID:12584189, PMID:14581471). A distinct PHD/RING domain confers E3 ligase activity that mediates K63-linked ubiquitination of TAB1 via UBE2N to control TAK1/MAPK activation, and ubiquitin-dependent degradation of c-Jun, functions genetically separable from its kinase activity (PMID:25260751, PMID:17101801). The N-terminal domain anchors MEKK1 to α-actinin along stress fibers and focal adhesions and to tight junctions, linking it to cytoskeletal context and cell migration (PMID:10401575, PMID:24567356). Functionally, full-length MAP3K1 supports cell survival, migration, and uPA-dependent invasion and metastasis (PMID:12493778, PMID:16568086), whereas caspase-3 cleavage at D68/a DEVD motif liberates a C-terminal fragment that amplifies apoptosis through a caspase–MEKK1 feedback loop (PMID:9244305, PMID:9576928). Genetically, MAP3K1 missense mutations cause 46,XY disorder of sex development by altering cofactor binding (RHOA, MAP3K4, FRAT1) and shifting the SOX9-versus-WNT/β-catenin balance in the gonad (PMID:24135036, PMID:30608580).

Mechanistic history

Synthesis pass · year-by-year structured walk · 19 steps
  1. 1994 High

    Established MEKK1 as a JNK-pathway-selective MAP3K acting downstream of Ras and biochemically distinct from the Raf→ERK route, defining two parallel Ras-dependent MAPK cascades.

    Evidence Dominant-negative and overexpression constructs plus in vitro kinase assays showing direct phosphorylation of SEK1, in mammalian cells

    PMID:7992057 PMID:7997270

    Open questions at the time
    • Endogenous physiological stimuli not yet defined
    • ERK activation only under overexpression, leaving native ERK role ambiguous
  2. 1995 High

    Showed MEKK1 can directly phosphorylate MEK1 at its activating sites, raising the question of pathway selectivity between JNK and ERK modules.

    Evidence In vitro kinase assay with bacterial MEKK-C, yeast two-hybrid, and transfection

    PMID:7624324

    Open questions at the time
    • Inefficient ERK2 activation vs EGF leaves physiological relevance of MEK1 phosphorylation unclear
  3. 1997 High

    Extended MEKK1 beyond JNK to the NF-κB axis by demonstrating direct activation of the IκBα kinase complex, positioning it at the junction of two stress pathways.

    Evidence In vitro IKK activation assay and in vivo IκBα phosphorylation

    PMID:9008162

    Open questions at the time
    • How a single kinase selects JNK vs NF-κB output not resolved
  4. 1997 High

    Revealed a caspase–MEKK1 positive feedback loop in which caspase cleavage activates MEKK1 to amplify apoptosis, distinguishing pro-apoptotic from survival functions.

    Evidence Cleavage-resistant and kinase-inactive mutants with caspase inhibitors and anoikis assays

    PMID:9244305

    Open questions at the time
    • Precise cleavage site refined later
    • Balance between survival and apoptotic outputs context-dependent and not quantified
  5. 1998 High

    Mapped the apoptotic cleavage to caspase-3 at D68 and linked it to subcellular redistribution, clarifying how cleavage repartitions MEKK1 activity.

    Evidence Cleavage-product sequencing, immunofluorescence, and subcellular fractionation with caspase inhibitors during Fas-induced apoptosis

    PMID:9576928

    Open questions at the time
    • Functional consequence of particulate-to-soluble redistribution not mechanistically dissected
  6. 1998 High

    Defined IKK-α and IKK-β as MEKK1 targets and identified viral Tax as an N-terminus-binding activator, showing the regulatory domain controls NF-κB output.

    Evidence In vitro phosphorylation, co-IP of the IKK complex, and Tax dominant-negative studies

    PMID:9630230 PMID:9689078

    Open questions at the time
    • Stoichiometry and assembly of the high-MW IKK complex incompletely defined
  7. 1999 High

    Identified the N-terminal domain as a cytoskeletal scaffold by mapping direct α-actinin binding and localization to stress fibers/focal adhesions independent of kinase activity.

    Evidence Yeast two-hybrid, reciprocal co-IP, in vitro binding with purified α-actinin, and immunofluorescence colocalization

    PMID:10401575

    Open questions at the time
    • Signaling consequence of cytoskeletal anchoring not yet linked to pathway output
  8. 1999 High

    Genetic knockouts established a non-redundant requirement for MEKK1 in JNK activation by specific stresses (microtubule disruption, oxidative stress) and in cytoprotection.

    Evidence Targeted disruption in ES cells and cardiac myocytes with JNK/p38 kinase assays, TNF-α measurement, and apoptosis readouts

    PMID:10212239 PMID:10611349

    Open questions at the time
    • Stimulus-selectivity mechanism (why some stresses require MEKK1 and others do not) unexplained
  9. 2000 Medium

    Suggested MEKK1 can scaffold the entire ERK module and relay Raf-induced NF-κB, expanding its role from kinase to multi-pathway organizer.

    Evidence Endogenous co-IP of ERK2/MEK1/Raf-1 and dominant-negative epistasis in NF-κB reporter assays

    PMID:10758165 PMID:10969079

    Open questions at the time
    • Co-IP and epistasis only; no direct biochemical demonstration of scaffolding stoichiometry
  10. 2002 High

    Provided the first in vitro reconstitution of MEKK1 activation, defining oligomerization-induced activation-loop autophosphorylation by GCK/TRAF2 as the core activation mechanism.

    Evidence In vitro activation with purified GCK and TRAF2, forced-oligomerization assay, and kinase-domain mutagenesis

    PMID:11784851

    Open questions at the time
    • Endogenous triggers of oligomerization in specific pathways not enumerated
  11. 2002 High

    Connected MEKK1 to physiology and disease by showing it is essential for Gαq-induced cardiac hypertrophy and for inducible uPA expression driving invasion.

    Evidence MEKK1 knockout mice/ES-derived cardiomyocytes and MEKK1-/- fibroblasts with rescue, plus uPA activity assays and MKK/JNK dominant-negatives

    PMID:11891332 PMID:12493778

    Open questions at the time
    • Direct substrates linking JNK to uPA transcription not identified
  12. 2003 High

    Mapped multiple direct upstream activators (RIP phosphorylation, RhoA-GTP binding, GSK3β) onto the regulatory domain, explaining context-dependent activation.

    Evidence Co-IP, in vitro kinase assays with purified proteins, site-directed mutagenesis, GST pulldown, and knockout-cell rescue

    PMID:11369754 PMID:12584189 PMID:14581471

    Open questions at the time
    • How competing activator inputs are integrated into distinct outputs unresolved
  13. 2006 High

    Defined the PHD/RING domain as a functional E3 ligase, with c-Jun ubiquitination/degradation as a kinase-independent output controlling apoptosis.

    Evidence In vitro ubiquitination reconstitution, MEKK1-/- cells, and rescue under osmotic stress

    PMID:17101801

    Open questions at the time
    • Full substrate repertoire of the E3 activity not yet defined at this stage
  14. 2006 High

    Demonstrated an in vivo immune role via CD40/TRAF2 recruitment driving JNK/p38/c-Jun and germinal center formation.

    Evidence Map3k1 kinase-domain knockin mice, co-IP of CD40-TRAF2-MEKK1, and in vivo immunization

    PMID:17143273

    Open questions at the time
    • Whether kinase or E3 activity dominates in B-cell signaling not separated
  15. 2010 Medium

    Identified the E3 ligase activity as required for Wnt/β-catenin transcription via Axin1, broadening the ubiquitin-dependent functions of MEKK1.

    Evidence Axin1 IP-MS, co-IP, ligase-dead/kinase-dead mutants, and TCF/LEF reporter assays

    PMID:20128690

    Open questions at the time
    • Single lab; relevant ubiquitination substrate in the Wnt pathway not identified
  16. 2011 High

    Established a developmental intracrine feedback loop in eyelid closure where c-Jun drives Map3k1 transcription and MAP3K1 reactivates JNK-c-Jun/AP-1.

    Evidence ChIP of c-Jun on the Map3k1 promoter, RhoA knockout and Map3k1 hemizygote mice, and pathway phosphorylation readouts

    PMID:21969564

    Open questions at the time
    • Generality of the autoregulatory loop beyond eyelid morphogenesis untested
  17. 2014 High

    Resolved the E3 mechanism: the PHD motif uses UBE2N to build K63-linked chains on TAB1, controlling TAK1/MAPK responses to specific stimuli.

    Evidence Map3k1(mPHD) knockin ES cells/mice, protein-microarray substrate profiling, K63-linkage ubiquitination assays, and in vitro reconstitution

    PMID:25260751

    Open questions at the time
    • Why hyperosmotic-stress MAPK responses are PHD-independent not explained
  18. 2013 Medium

    Linked MAP3K1 mutations to 46,XY disorder of sex development through altered cofactor binding that tips the gonadal SOX9-versus-WNT balance.

    Evidence Transfection of mutant MAP3K1 with cofactor co-IP, downstream phosphorylation, structural domain mapping, and MAP3K4 rescue

    PMID:24135036 PMID:30608580

    Open questions at the time
    • Mechanistic basis of gain-of-function binding changes only partially defined
    • In vivo gonadal validation lacking
  19. 2018 High

    Showed MAP3K1 loss-of-function rewires drug sensitivity by disabling JNK-JUN feedback (sensitizing to MEK inhibitors) and stabilizing IRS-1 (conferring AKT-inhibitor resistance).

    Evidence CRISPR/genetic knockout in cancer cell lines and 168 PDX tumors, DUSP4 siRNA epistasis, and IRS-1/p85 co-IP

    PMID:29765551 PMID:29795445

    Open questions at the time
    • Predictive value across tumor types not generalized
    • Relative contribution of kinase vs E3 loss to these phenotypes not dissected

Open questions

Synthesis pass · forward-looking unresolved questions
  • How MEKK1 integrates competing upstream activators and partitions output between its kinase and E3 ligase activities to select among JNK, ERK, NF-κB, and ubiquitination programs remains unresolved.
  • No structural model of the full-length kinase/E3 protein
  • Quantitative rules for kinase-vs-ligase output selection unknown
  • Complete in vivo substrate map of the E3 activity incomplete

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 3 GO:0016874 ligase activity 3 GO:0060089 molecular transducer activity 3 GO:0140097 catalytic activity, acting on DNA 2
Localization
GO:0005829 cytosol 1 GO:0005856 cytoskeleton 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-1266738 Developmental Biology 2
Partners
ACTN1AXIN1GSK3BMAP2K1MAP2K4RHOARIPK1TRAF2
Complex memberships
Han11-DYRK1-HIPK2 complexIκBα/IKK kinase complex

Evidence

Reading pass · 38 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 MEKK1 (MAP3K1) activates the JNK pathway downstream of Ras but does not activate ERK unless overexpressed, demonstrating two distinct Ras-dependent MAPK cascades: Raf-1→ERK and MEKK→JNK. Dominant negative and overexpression constructs in mammalian cells, kinase assays Science High 7992057
1994 MEKK1 activates the stress-activated protein kinase (SAPK/JNK) pathway by phosphorylating its activator SEK1, which in turn phosphorylates and activates SAPK. Inducible MEKK1 expression in NIH3T3 cells, in vitro kinase assay with SEK1 as substrate Nature High 7997270
1995 A constitutively active catalytic domain fragment of MEKK1 (MEKK-C) directly phosphorylates MEK1 at S218 and S222 in vitro; MEKK1 also interacts with MEK1 in the yeast two-hybrid system and activates MEK1/2 in mammalian cells, but does not efficiently activate ERK2 compared to EGF stimulation. In vitro kinase assay with bacterially expressed MEKK-C, yeast two-hybrid, transfection in mammalian cells Proceedings of the National Academy of Sciences of the United States of America High 7624324
1997 MEKK1 induces site-specific phosphorylation of IκBα in vivo and directly activates the IκBα kinase complex in vitro, placing MEKK1 as a critical component of both the c-Jun and NF-κB stress response pathways. In vitro IκBα kinase activation assay, in vivo phosphorylation assay Cell High 9008162
1997 Caspase cleavage of MEKK1 at a DEVD motif is required for its kinase activation during anoikis; the cleavage product stimulates apoptosis, and a cleavage-resistant MEKK1 mutant partially protects cells from anoikis, establishing a positive feedback loop between caspases and MEKK1. Cleavage-resistant and kinase-inactive MEKK1 mutants, caspase inhibitors, cell death assays Cell High 9244305
1998 MEKK1 activates both IKK-α and IKK-β in vivo; IKK-α is present in the MEKK1-inducible high molecular weight IκBα kinase complex and MEKK1 treatment induces phosphorylation of IKK-α in vitro. In vitro phosphorylation assays, co-immunoprecipitation, transfection in mammalian cells Proceedings of the National Academy of Sciences of the United States of America High 9689078
1998 HTLV-I Tax protein binds to the amino terminus of MEKK1, stimulates MEKK1 kinase activity, and increases IKKβ-mediated phosphorylation of IκBα, leading to NF-κB activation. Co-immunoprecipitation, in vitro kinase assay, dominant-negative mutant studies, transfection Cell High 9630230
1998 Caspase-3 (CPP32) cleaves MEKK1 after residue D68 both in vivo and in vitro during Fas-induced apoptosis; this cleavage redistributes MEKK1 from a Triton-insoluble (particulate) compartment to a Triton-soluble (cytoplasmic) compartment and is required for MEKK1 and SAPK activation during apoptosis but not during rapid stress responses. Sequencing of cleavage products, immunofluorescence, subcellular fractionation, viral and chemical caspase inhibitors Proceedings of the National Academy of Sciences of the United States of America High 9576928
1999 MEKK1 interacts directly with α-actinin via residues 221–559 of its N-terminal regulatory domain, and both endogenous and overexpressed MEKK1 co-localize with α-actinin along actin stress fibers and at focal adhesions; kinase activity is not required for this localization. Yeast two-hybrid screen, co-immunoprecipitation, in vitro binding with purified α-actinin, immunofluorescence colocalization Cell motility and the cytoskeleton High 10401575
1999 MEKK1 is required for JNK activation in response to microtubule disruption (taxol) but not actin fiber disruption; targeted disruption of MEKK1 in ES cells abolishes JNK activation and increases apoptosis after taxol treatment; MEKK1 expression is elevated 3-fold in mitosis. Targeted gene disruption in embryonic stem cells, JNK kinase assays, cell cycle analysis The Journal of biological chemistry High 10212239
1999 MEKK-1 activates Smad2-mediated transcription in endothelial cells independently of the C-terminal SSXS motif of Smad2 (the TGF-β receptor phosphorylation site), increases Smad2 phosphorylation state, enhances Smad2-Smad4 interactions, induces nuclear localization of Smad2/Smad4, and stimulates Smad-coactivator interactions. Constitutively active MEKK-1 transfection, Gal4-Smad2 reporter assay, co-immunoprecipitation, nuclear fractionation, shear stress experiment The Journal of biological chemistry Medium 10085121
1999 MEKK1-deficient ES cell-derived cardiac myocytes fail to activate JNK in response to oxidative stress, leading to enhanced TNF-α production and increased apoptosis; the MEKK1-JNK pathway negatively regulates TNF-α production to protect cardiac myocytes. Targeted gene disruption (MEKK1-/- ES cells), JNK and p38 kinase assays, TNF-α ELISA, apoptosis assays Proceedings of the National Academy of Sciences of the United States of America High 10611349
2000 Endogenous MEKK1 physically binds to endogenous ERK2, MEK1, and Raf-1, indicating MEKK1 can scaffold all three kinases of the ERK MAP kinase module. Co-immunoprecipitation of endogenous proteins The Journal of biological chemistry Medium 10969079
2000 Raf-mediated NF-κB activation is blocked by a dominant-negative form of MEKK1, indicating Raf induces NF-κB via MEKK1 as a membrane shuttle kinase, but not through the classical MEK-ERK cascade. Dominant-negative MEKK1, pharmacological pathway inhibitors, NF-κB reporter assays, transformation assays Proceedings of the National Academy of Sciences of the United States of America Medium 10758165
2001 Protein kinase G (PKG) directly phosphorylates the N-terminal domain of MEKK1 in vitro, and constitutively active PKG activates JNK1 via a PKG→MEKK1→SEK1→JNK1 pathway; dominant-negative MEKK1 blocks PKG-induced JNK1 activation. In vitro kinase assay with purified PKG and MEKK1, dominant-negative MEKK1, JNK1 activation assays The Journal of biological chemistry Medium 11278263
2001 RIP (receptor-interacting protein) physically associates with MEKK1 in vitro and in vivo, phosphorylates MEKK1 at Ser-957 and Ser-994, and is required for TNF-α-induced MEKK1 activation; a non-phosphorylatable S957A/S994A MEKK1 mutant fails to be activated by RIP and blocks RIP-induced IKKβ and NF-κB activation. Co-immunoprecipitation, in vitro kinase assay, site-directed mutagenesis, RIP-deficient Jurkat cells The Journal of biological chemistry High 11369754
2002 Purified active GCK (germinal center kinase, a Ste20 homologue) and TRAF2 activate recombinant MEKK1 in vitro; autophosphorylation within the MEKK1 kinase domain activation loop is required for activation; GCK promotes MEKK1 oligomerization in vivo, suggesting activation via induced oligomerization and autophosphorylation. In vitro activation assay with purified proteins, forced oligomerization assay, kinase domain mutagenesis, co-immunoprecipitation Molecular and cellular biology High 11784851
2002 MEKK1 is required for inducible urokinase-type plasminogen activator (uPA) expression in response to PMA or FGF-2; MEKK1-deficient fibroblasts show greatly reduced uPA expression and activity, which is restored by MEKK1 transfection; this requires MEKK1-dependent MKK1 and JNK activity. MEKK1-/- fibroblasts, re-expression rescue, uPA activity assay, dominant-negative MKK constructs The Journal of biological chemistry High 12493778
2002 MEKK1 is essential for Gαq-induced cardiac hypertrophy in vivo; MEKK1 knockout abolishes JNK activation, cardiac mass increase, myocyte enlargement, ANF induction, and ventricular dysfunction caused by Gαq overexpression, while other terminal MAPKs are unaffected. MEKK1 gene knockout in mice, ES cell-derived cardiomyocytes, JNK/ERK/p38 kinase assays, echocardiography, histology Proceedings of the National Academy of Sciences of the United States of America High 11891332
2003 RhoA, but not Rac or Cdc42, binds to the N-terminal regulatory domain (including the PHD domain) of MEKK1; Rho-GTP stimulates MEKK1 kinase activity up to 10-fold toward MEK4 but does not result in RhoA ubiquitination by MEKK1. GST pulldown, in vitro kinase assay, PHD domain cysteine mutagenesis The Journal of biological chemistry High 14581471
2003 Glycogen synthase kinase 3β (GSK3β) physically associates with endogenous MEKK1 and activates MEKK1 kinase activity; GSK3β-mediated MEKK1 activation is inhibited by insulin via PI3K; MEKK1 activity is reduced in GSK3β-/- fibroblasts and restored by ectopic GSK3β expression. Co-immunoprecipitation of endogenous proteins, in vitro kinase assay, GSK3β knockout fibroblasts, pharmacological inhibition (wortmannin) The Journal of biological chemistry High 12584189
2004 GST Mu 1-1 (GST M1-1) directly binds MEKK1 and inhibits its kinase activity in vitro; GST M1-1 co-immunoprecipitates with endogenous MEKK1 in L929 cells, interferes with MEKK1-SEK1 binding, and suppresses MEKK1-mediated apoptosis. In vitro binding and kinase assays, endogenous co-immunoprecipitation, co-immunoprecipitation competition assay The Journal of biological chemistry Medium 15299005
2004 Ceramide directly binds to MEKK1 in glomerular endothelial cells as shown by radioiodinated photoaffinity labeling and ceramide-coupled Sepharose affinity chromatography; this binding activates the SAPK/JNK cascade, which mediates ceramide-induced apoptosis. Photoaffinity labeling with [125I]TID-ceramide, affinity chromatography with ceramide-Sepharose, JNK inhibitor functional assay Biochimica et biophysica acta Medium 15164763
2006 MEKK1 PHD/RING finger domain exhibits E3 ubiquitin ligase activity toward c-Jun in vitro and in vivo; MEKK1 mediates ubiquitination-dependent degradation of c-Jun in response to osmotic stress, and MEKK1-/- cells show higher c-Jun protein levels; c-Jun downregulation by MEKK1 promotes apoptosis. In vitro ubiquitination assay, MEKK1-/- cell lines, osmotic stress treatment, rescue by c-Jun overexpression Molecular and cellular biology High 17101801
2006 MEKK1 is required for CD40-mediated activation of JNK, p38, and c-Jun in B cells; MEKK1 is recruited to CD40 and TRAF2 after CD40 ligation; Map3k1(deltaKD) mice have defective germinal center formation and reduced thymus-dependent antibody production. Map3k1 kinase domain knockin mice, kinase assays, co-immunoprecipitation (CD40-TRAF2-MEKK1), B cell proliferation assays, in vivo immunization Nature immunology High 17143273
2006 MEKK1 controls mammary tumor cell dissemination and lung metastasis by regulating urokinase-type plasminogen activator (uPA) expression, gelatinase activity, and cell migration/invasion; MEKK1-/- mice with PyMT mammary tumors show delayed tumor cell dissemination associated with reduced uPA and gelatinase activity and prolonged basement membrane integrity. MEKK1-/- mouse model with PyMT transgene, siRNA knockdown in MDA-MB-231 cells, gelatin zymography, invasion assay, lung metastasis counts Oncogene High 16568086
2008 MEKK1 is an essential component of antiviral signaling downstream of IPS-1 in the RIG-I-like helicase pathway; forced expression of MEKK1 with IRF3 induces IFN-β, whereas MEKK1 siRNA knockdown inhibits IFN-β induction by poly(I:C); MEKK1 mediates NF-κB and MAPK activation but not IRF3 activation in this pathway. siRNA knockdown, forced expression, IFN-β promoter reporter assay, TRAF6-/- and TAK1-/- MEF comparison The Journal of biological chemistry Medium 18984593
2010 MEKK-1 mediates IL-1β-induced increase in intestinal epithelial tight junction permeability through activation of the canonical NF-κB pathway and MLCK gene activation; MEKK-1 knockdown inhibits these effects, while NIK (non-canonical pathway) knockdown does not affect TJ permeability. siRNA knockdown in Caco-2 monolayers, transepithelial resistance measurement, NF-κB pathway inhibitors The American journal of pathology Medium 21048223
2010 MAP3K1 interacts with Axin1; the Axin1-MAP3K1 interaction is induced and modulated by Wnt stimulation; MAP3K1 E3 ubiquitin ligase activity (not kinase activity) is required for Wnt/β-catenin-TCF/LEF transcriptional activity; MAP3K1 siRNA abolishes TCF/LEF-driven transcription and Wnt3A-driven endogenous gene expression. Immunoprecipitation-coupled proteomics (Axin1 IP-MS), co-IP in HEK293T cells, siRNA knockdown, ubiquitin ligase-dead and kinase-dead mutant transfection, TCF reporter assay Biological chemistry Medium 20128690
2010 The WD40-repeat scaffold protein Han11 directly binds MEKK1 in vitro and regulates the threshold and amplitude of MEKK1-triggered stress signaling; Han11 couples MEKK1 to DYRK1 and HIPK2 in a signaling complex; knockdown of Han11 alters the kinetics and amplitude of MEKK1-triggered gene expression. In vitro binding assays, knockdown experiments, reporter assays for MEKK1-triggered gene expression The EMBO journal Medium 20940704
2011 MAP3K1 integrates TGF-α/EGFR-RhoA signals and JNK-c-Jun signals during eyelid closure; c-Jun (induced by EGFR-RhoA) binds the Map3k1 promoter in a phosphorylation-independent manner to drive MAP3K1 expression; MAP3K1 then phosphorylates JNK-c-Jun to activate AP-1 and downstream targets (PAI-1), forming an intracrine regulatory loop. ChIP (c-Jun binding to Map3k1 promoter), RhoA knockout mice, Map3k1 hemizygote mice, JNK-c-Jun phosphorylation assays, PAI-1 expression Proceedings of the National Academy of Sciences of the United States of America High 21969564
2013 MAP3K1 missense mutations causing 46,XY disorder of sex development increase binding of RHOA, MAP3K4, and FRAT1 while reducing SOX9/FGF9/SRY expression and increasing WNT/β-catenin/FOXL2 activity; these effects are partially rescued by co-transfection with wild-type MAP3K4. Cell transfection with wild-type or mutant MAP3K1 in B-lymphoblastoid and NT2/D1 cells, Western blot for phosphorylation of downstream targets, siRNA phenocopying Human molecular genetics Medium 24135036
2013 MAP3K1 encodes both a kinase domain and a PHD/RING finger E3 ubiquitin ligase domain; full-length MAP3K1 regulates cell migration and pro-survival signaling, while its caspase-3 cleavage product promotes apoptosis; the E3 ligase domain ubiquitylates c-Jun and ERK1/2. Review synthesizing genetic knockouts, biochemical assays, and ubiquitination assays from multiple studies (not a primary experimental paper, but summarizes established experimental findings) Genes & cancer Medium 24386504
2014 The MEKK1 PHD motif functions as an E3 ubiquitin ligase that mediates Lys63-linked poly-ubiquitination of TAB1, using the conjugating enzyme UBE2N; this ubiquitination of TAB1 regulates TAK1 and MAPK (p38 and JNK) activation by TGF-β and EGF; PHD-inactive knockin (Map3k1(mPHD)) cells show defective MAPK responses to TGF-β, EGF, and microtubule disruption but not to hyperosmotic stress. Map3k1(mPHD) knockin ES cells and mice, protein microarray substrate profiling, ubiquitination assays (Lys63 linkage), in vitro E3 ligase reconstitution The EMBO journal High 25260751
2014 MarvelD3, a tight junction transmembrane component, recruits MEKK1 to junctions; MarvelD3 expression inversely correlates with JNK activity; loss of MarvelD3 increases MEKK1-JNK signaling, cell migration, and proliferation, while re-expression in metastatic cells inhibits these processes. MarvelD3 depletion and re-expression, JNK phosphorylation assays, cell migration and proliferation assays, in vivo tumor formation, MEKK1 co-immunoprecipitation The Journal of cell biology Medium 24567356
2018 Loss-of-function mutations in MAP3K1 disable the JNK-JUN-mediated feedback loop activated by MEK inhibition (via DUSP4 suppression and HER RTK activation), causing sensitivity to MEK inhibitors; this was confirmed in PDX tumor models. Genetic analysis with MEK inhibitor treatment in cancer cell lines and 168 PDX tumors, JNK-JUN pathway readouts, DUSP4 siRNA epistasis Cell research High 29795445
2018 MAP3K1 disruption enhances AKT phosphorylation and IRS-1 stability, promotes IRS-1 binding to p85 and PI3Kα activity; this results from deficient MAP3K1-JNK signaling increasing IRS-1 stability, thereby conferring resistance to AKT inhibitors. CRISPR knockout of MAP3K1 in PIK3CA-mutant cell lines, Western blot for p-AKT/IRS-1, co-immunoprecipitation (IRS-1/p85), 3D MCF10A models, in vivo xenograft Oncotarget Medium 29765551
2019 MAP3K1 mutations causing 46,XY gonadal dysgenesis cluster in three semi-contiguous domains: an N-terminal Guanine Exchange Factor-homology domain (residues 164–231), a PHD domain (residues 442–495), and an ARMadillo repeat domain (residues 566–862); these mutations increase binding of RHOA, MAP3K4, and FRAT1 and decrease binding of RAC1, with differential effects depending on domain location. Structural modeling, transfection of mutant MAP3K1 constructs, co-immunoprecipitation for co-factor binding, downstream phosphorylation assays Human molecular genetics Medium 30608580

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 and MEKK. Science (New York, N.Y.) 1056 7992057
1994 Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1. Nature 719 7997270
1997 Activation of the IkappaB alpha kinase complex by MEKK1, a kinase of the JNK pathway. Cell 652 9008162
1997 The regulation of anoikis: MEKK-1 activation requires cleavage by caspases. Cell 467 9244305
1998 MEKK1 activates both IkappaB kinase alpha and IkappaB kinase beta. Proceedings of the National Academy of Sciences of the United States of America 341 9689078
2008 MEKK1, MKK1/MKK2 and MPK4 function together in a mitogen-activated protein kinase cascade to regulate innate immunity in plants. Cell research 314 18982020
1998 HTLV-I Tax protein binds to MEKK1 to stimulate IkappaB kinase activity and NF-kappaB activation. Cell 225 9630230
1996 Molecular cloning of mitogen-activated protein/ERK kinase kinases (MEKK) 2 and 3. Regulation of sequential phosphorylation pathways involving mitogen-activated protein kinase and c-Jun kinase. The Journal of biological chemistry 215 8621389
1997 The MEKK-JNK pathway is stimulated by alpha1-adrenergic receptor and ras activation and is associated with in vitro and in vivo cardiac hypertrophy. The Journal of biological chemistry 212 9162028
2009 A major role of the MEKK1-MKK1/2-MPK4 pathway in ROS signalling. Molecular plant 191 19529823
2003 Mitogenic effect of orphan receptor TR3 and its regulation by MEKK1 in lung cancer cells. Molecular and cellular biology 173 14612408
2010 IL-1beta-induced increase in intestinal epithelial tight junction permeability is mediated by MEKK-1 activation of canonical NF-kappaB pathway. The American journal of pathology 170 21048223
2015 MAP2K1 and MAP3K1 mutations in Langerhans cell histiocytosis. Genes, chromosomes & cancer 162 25899310
1995 MEKK1 phosphorylates MEK1 and MEK2 but does not cause activation of mitogen-activated protein kinase. Proceedings of the National Academy of Sciences of the United States of America 158 7624324
2002 NPK1, an MEKK1-like mitogen-activated protein kinase kinase kinase, regulates innate immunity and development in plants. Developmental cell 156 12194859
2000 Raf induces NF-kappaB by membrane shuttle kinase MEKK1, a signaling pathway critical for transformation. Proceedings of the National Academy of Sciences of the United States of America 151 10758165
1999 MEKK-1, a component of the stress (stress-activated protein kinase/c-Jun N-terminal kinase) pathway, can selectively activate Smad2-mediated transcriptional activation in endothelial cells. The Journal of biological chemistry 144 10085121
2002 Androgen receptor acetylation governs trans activation and MEKK1-induced apoptosis without affecting in vitro sumoylation and trans-repression function. Molecular and cellular biology 140 11971970
2000 Phosphorylation of the MEKK Ste11p by the PAK-like kinase Ste20p is required for MAP kinase signaling in vivo. Current biology : CB 133 10837245
1996 Activation of the JNK pathway by distantly related protein kinases, MEKK and MUK. Oncogene 127 8637721
1999 MEKK1 suppresses oxidative stress-induced apoptosis of embryonic stem cell-derived cardiac myocytes. Proceedings of the National Academy of Sciences of the United States of America 119 10611349
1998 Fas-induced proteolytic activation and intracellular redistribution of the stress-signaling kinase MEKK1. Proceedings of the National Academy of Sciences of the United States of America 118 9576928
2001 Vitamin D(3)-induced apoptosis of murine squamous cell carcinoma cells. Selective induction of caspase-dependent MEK cleavage and up-regulation of MEKK-1. The Journal of biological chemistry 116 11331275
2005 Anti-inflammatory effects of magnolol and honokiol are mediated through inhibition of the downstream pathway of MEKK-1 in NF-kappaB activation signaling. Planta medica 112 15856410
1999 MEK kinase 1 (MEKK1) transduces c-Jun NH2-terminal kinase activation in response to changes in the microtubule cytoskeleton. The Journal of biological chemistry 112 10212239
2013 MAP3K1: Genomic Alterations in Cancer and Function in Promoting Cell Survival or Apoptosis. Genes & cancer 107 24386504
1998 The TAO of MEKK. Frontiers in bioscience : a journal and virtual library 106 9820741
2010 Calcium/calmodulin-regulated receptor-like kinase CRLK1 interacts with MEKK1 in plants. Plant signaling & behavior 102 20724845
1998 Heat stress activates fission yeast Spc1/StyI MAPK by a MEKK-independent mechanism. Molecular biology of the cell 102 9614178
2000 MEKK1 binds raf-1 and the ERK2 cascade components. The Journal of biological chemistry 101 10969079
2018 MAP3K1 and MAP2K4 mutations are associated with sensitivity to MEK inhibitors in multiple cancer models. Cell research 98 29795445
1998 Functional binding between Gbeta and the LIM domain of Ste5 is required to activate the MEKK Ste11. Current biology : CB 98 9501067
2002 Cell stress and MEKK1-mediated c-Jun activation modulate NFkappaB activity and cell viability. Molecular biology of the cell 91 12181357
1997 Direct activation of the stress-activated protein kinase (SAPK) and extracellular signal-regulated protein kinase (ERK) pathways by an inducible mitogen-activated protein Kinase/ERK kinase kinase 3 (MEKK) derivative. The Journal of biological chemistry 91 9006902
2006 Kinase MEKK1 is required for CD40-dependent activation of the kinases Jnk and p38, germinal center formation, B cell proliferation and antibody production. Nature immunology 89 17143273
2008 TRAF6 and MEKK1 play a pivotal role in the RIG-I-like helicase antiviral pathway. The Journal of biological chemistry 88 18984593
1999 MEKK1 interacts with alpha-actinin and localizes to stress fibers and focal adhesions. Cell motility and the cytoskeleton 88 10401575
2002 MEKK1 is essential for cardiac hypertrophy and dysfunction induced by Gq. Proceedings of the National Academy of Sciences of the United States of America 86 11891332
2016 MiR-302a/b/c/d cooperatively sensitizes breast cancer cells to adriamycin via suppressing P-glycoprotein(P-gp) by targeting MAP/ERK kinase kinase 1 (MEKK1). Journal of experimental & clinical cancer research : CR 82 26842910
2008 Hormone-dependent effects of FGFR2 and MAP3K1 in breast cancer susceptibility in a population-based sample of post-menopausal African-American and European-American women. Carcinogenesis 80 19028704
2002 Direct activation of mitogen-activated protein kinase kinase kinase MEKK1 by the Ste20p homologue GCK and the adapter protein TRAF2. Molecular and cellular biology 78 11784851
2006 Adaptor protein Ste50p links the Ste11p MEKK to the HOG pathway through plasma membrane association. Genes & development 77 16543225
2004 Wiring diagrams of MAPK regulation by MEKK1, 2, and 3. Biochemistry and cell biology = Biochimie et biologie cellulaire 77 15674433
2003 Glycogen synthase kinase 3 beta is a natural activator of mitogen-activated protein kinase/extracellular signal-regulated kinase kinase kinase 1 (MEKK1). The Journal of biological chemistry 75 12584189
1996 Activation of MEKK by formyl-methionyl-leucyl-phenylalanine in human neutrophils. Mapping pathways for mitogen-activated protein kinase activation. The Journal of biological chemistry 75 8969228
2004 Regulation of c-Jun N-terminal kinase by MEKK-2 and mitogen-activated protein kinase kinase kinases in rheumatoid arthritis. Journal of immunology (Baltimore, Md. : 1950) 73 14734742
2001 Protein kinase G activates the JNK1 pathway via phosphorylation of MEKK1. The Journal of biological chemistry 72 11278263
2002 Cisplatin potentiates 1,25-dihydroxyvitamin D3-induced apoptosis in association with increased mitogen-activated protein kinase kinase kinase 1 (MEKK-1) expression. Molecular cancer therapeutics 71 12492115
2013 Mutations in MAP3K1 tilt the balance from SOX9/FGF9 to WNT/β-catenin signaling. Human molecular genetics 70 24135036
2008 G alpha o mediates WNT-JNK signaling through dishevelled 1 and 3, RhoA family members, and MEKK 1 and 4 in mammalian cells. Journal of cell science 70 18187455
2003 RhoA binds to the amino terminus of MEKK1 and regulates its kinase activity. The Journal of biological chemistry 68 14581471
2006 MEKK1 mediates the ubiquitination and degradation of c-Jun in response to osmotic stress. Molecular and cellular biology 65 17101801
2014 MarvelD3 couples tight junctions to the MEKK1-JNK pathway to regulate cell behavior and survival. The Journal of cell biology 64 24567356
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
2006 MEKK1 controls matrix degradation and tumor cell dissemination during metastasis of polyoma middle-T driven mammary cancer. Oncogene 58 16568086
2003 Axin utilizes distinct regions for competitive MEKK1 and MEKK4 binding and JNK activation. The Journal of biological chemistry 57 12878610
2002 Evidence of functional modulation of the MEKK/JNK/cJun signaling cascade by the low density lipoprotein receptor-related protein (LRP). The Journal of biological chemistry 56 12193592
1994 Mammalian mitogen-activated protein kinase kinase kinase (MEKK) can function in a yeast mitogen-activated protein kinase pathway downstream of protein kinase C. Proceedings of the National Academy of Sciences of the United States of America 56 8197159
2010 The WD40-repeat protein Han11 functions as a scaffold protein to control HIPK2 and MEKK1 kinase functions. The EMBO journal 51 20940704
2017 miR-145-5p inhibits epithelial-mesenchymal transition via the JNK signaling pathway by targeting MAP3K1 in non-small cell lung cancer cells. Oncology letters 50 29344125
2021 Tumor Cell-Derived Exosomal miR-770 Inhibits M2 Macrophage Polarization via Targeting MAP3K1 to Inhibit the Invasion of Non-small Cell Lung Cancer Cells. Frontiers in cell and developmental biology 48 34195198
2004 Negative regulation of MEKK1-induced signaling by glutathione S-transferase Mu. The Journal of biological chemistry 47 15299005
2019 Disruption of the MAMP-Induced MEKK1-MKK1/MKK2-MPK4 Pathway Activates the TNL Immune Receptor SMN1/RPS6. Plant & cell physiology 45 30590768
2015 Let-7g induces granulosa cell apoptosis by targeting MAP3K1 in the porcine ovary. The international journal of biochemistry & cell biology 43 26299328
2007 Differential transmission of MEKK1 morphogenetic signals by JNK1 and JNK2. Development (Cambridge, England) 43 18032450
2018 Functional significance of co-occurring mutations in PIK3CA and MAP3K1 in breast cancer. Oncotarget 41 29765551
2015 A RING to rule them all? Insights into the Map3k1 PHD motif provide a new mechanistic understanding into the diverse roles of Map3k1. Cell death and differentiation 41 25613373
2014 The MEKK1 PHD ubiquitinates TAB1 to activate MAPKs in response to cytokines. The EMBO journal 41 25260751
2005 JNK1 differentially regulates osteopontin-induced nuclear factor-inducing kinase/MEKK1-dependent activating protein-1-mediated promatrix metalloproteinase-9 activation. The Journal of biological chemistry 41 15757900
2000 Phorbol ester-induced expression of airway squamous cell differentiation marker, SPRR1B, is regulated by protein kinase Cdelta /Ras/MEKK1/MKK1-dependent/AP-1 signal transduction pathway. The Journal of biological chemistry 41 10918063
2020 LncRNA NEAT1 promotes malignant phenotypes and TMZ resistance in glioblastoma stem cells by regulating let-7g-5p/MAP3K1 axis. Bioscience reports 38 33057597
2017 MAP3K1-related gonadal dysgenesis: Six new cases and review of the literature. American journal of medical genetics. Part C, Seminars in medical genetics 38 28504475
2011 Mitogen-activated protein kinase kinase kinase 1 (MAP3K1) integrates developmental signals for eyelid closure. Proceedings of the National Academy of Sciences of the United States of America 38 21969564
2019 PIK3CA and MAP3K1 alterations imply luminal A status and are associated with clinical benefit from pan-PI3K inhibitor buparlisib and letrozole in ER+ metastatic breast cancer. NPJ breast cancer 37 31552290
2015 MiR-451 inhibits proliferation of esophageal carcinoma cell line EC9706 by targeting CDKN2D and MAP3K1. World journal of gastroenterology 37 26019450
2023 Resveratrol inhibits autophagy against myocardial ischemia-reperfusion injury through the DJ-1/MEKK1/JNK pathway. European journal of pharmacology 35 37149277
2019 A role for peroxiredoxins in H2O2- and MEKK-dependent activation of the p38 signaling pathway. Redox biology 35 31629169
2012 Genetic variants in FGFR2 and MAP3K1 are associated with the risk of familial and early-onset breast cancer in a South-American population. Breast cancer research and treatment 31 23225170
2016 MAP3K1-targeting therapeutic artificial miRNA suppresses the growth and invasion of breast cancer in vivo and in vitro. SpringerPlus 30 26759750
2010 MAP3K1 functionally interacts with Axin1 in the canonical Wnt signalling pathway. Biological chemistry 30 20128690
2001 Role of receptor-interacting protein in tumor necrosis factor-alpha -dependent MEKK1 activation. The Journal of biological chemistry 29 11369754
2015 BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4. Leukemia 28 26050649
2007 Negative regulation of MEKK1/2 signaling by serine-threonine kinase 38 (STK38). Oncogene 28 17906693
2002 p115 Rho GTPase activating protein interacts with MEKK1. Journal of cellular physiology 28 12115726
2001 Extracellular ATP stimulates an inhibitory pathway towards growth factor-induced cRaf-1 and MEKK activation in astrocyte cultures. Journal of neurochemistry 28 11359865
2019 Mutations in MAP3K1 that cause 46,XY disorders of sex development disrupt distinct structural domains in the protein. Human molecular genetics 27 30608580
2010 MEKK1/MEKK4 are responsible for TRAIL-induced JNK/p38 phosphorylation. Oncology reports 27 21152872
2018 MEKK1, JNK, and SMAD3 mediate CXCL12-stimulated connective tissue growth factor expression in human lung fibroblasts. Journal of biomedical science 26 29499695
2011 Loss of MAP3K1 enhances proliferation and apoptosis during retinal development. Development (Cambridge, England) 26 21862560
2009 Depleting MEKK1 expression inhibits the ability of invasion and migration of human pancreatic cancer cells. Journal of cancer research and clinical oncology 25 19513748
2004 Differential binding of ceramide to MEKK1 in glomerular endothelial and mesangial cells. Biochimica et biophysica acta 25 15164763
2002 MEKK1 is required for inducible urokinase-type plasminogen activator expression. The Journal of biological chemistry 25 12493778
2010 Involvement of the MEKK1 signaling pathway in the regulation of epicardial cell behavior by hyaluronan. Cellular signalling 24 20159036
1997 Overexpression of the G1-cyclin gene CLN2 represses the mating pathway in Saccharomyces cerevisiae at the level of the MEKK Ste11. The Journal of biological chemistry 23 9148934
2022 Berberine Improves TNF-α-Induced Hepatic Insulin Resistance by Targeting MEKK1/MEK Pathway. Inflammation 22 35460012
2021 Integrated Transcriptomic and Epigenetic Study of PCOS: Impact of Map3k1 and Map1lc3a Promoter Methylation on Autophagy. Frontiers in genetics 22 33763111
2020 Long noncoding RNA FOXD2-AS1 aggravates hepatocellular carcinoma tumorigenesis by regulating the miR-206/MAP3K1 axis. Cancer medicine 21 32558350
2020 miR-31-5p promotes proliferation and inhibits apoptosis of goat hair follicle stem cells by targeting RASA1/MAP3K1 pathway. Experimental cell research 21 33338478
2004 Induced eosinophilia and proliferation in Angiostrongylus cantonensis-infected mouse brain are associated with the induction of JAK/STAT1, IAP/NF-kappaB and MEKK1/JNK signals. Journal of helminthology 21 15575987
1999 Characterisation of novel plant genes encoding MEKK/STE11 and RAF-related protein kinases. Gene 20 10095117

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