Affinage

MAP3K1

Mitogen-activated protein kinase kinase kinase 1 · UniProt Q13233

Length
1512 aa
Mass
164.5 kDa
Annotated
2026-04-28
100 papers in source corpus 41 papers cited in narrative 41 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAP3K1 (MEKK1) is a multifunctional serine/threonine kinase and E3 ubiquitin ligase that integrates stress, cytokine, and developmental signals by acting as both a catalytic activator and a scaffold for multiple MAPK cascades. Its kinase domain phosphorylates and activates SEK1/MKK4 and MKK7 to drive JNK/SAPK signaling, and MEK1 to activate ERK1/2, while its PHD/RING finger domain functions as an E3 ubiquitin ligase that ubiquitinates ERK1/2, c-Jun, and Fra-2 for proteasomal degradation, and promotes Wnt/β-catenin-dependent transcription through interaction with Axin (PMID:7997270, PMID:12049732, PMID:17101801, PMID:20128690). MAP3K1 is activated by caspase-3 cleavage at Asp-68, which releases a 91-kDa kinase fragment that relocalizes from a particulate compartment to the cytosol to drive apoptosis, by RIP-mediated phosphorylation at Ser-957/994 downstream of TNF-α, and by RhoA-GTP binding to its N-terminal/PHD region; it is negatively regulated by PAK1 phosphorylation at Ser-67, DJ-1-mediated cytoplasmic sequestration, and STK38 binding (PMID:9576928, PMID:11782455, PMID:11369754, PMID:14581471, PMID:12228228, PMID:18309325). Gain-of-function mutations in MAP3K1 cause 46,XY disorders of sex development by shifting MAPK signaling toward WNT/β-catenin/FOXL2 at the expense of SOX9/FGF9 through altered binding of RHOA, MAP3K4, RAC1, and FRAT1 (PMID:21129722, PMID:24135036).

Mechanistic history

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

    Establishing MAP3K1 as a MAP3K in the JNK cascade resolved the identity of the kinase upstream of SEK1/MKK4 in stress signaling, placing MEKK1 at the apex of a three-tiered kinase module.

    Evidence In vitro kinase assay and COS-7/NIH3T3 expression showing MEKK1 phosphorylates SEK1 which activates SAPK/JNK

    PMID:7997270

    Open questions at the time
    • Whether MEKK1 also phosphorylates other MKKs (e.g., MKK7, MEK1) was not addressed
    • Physiological stimuli activating MEKK1 were unknown
  2. 1997 High

    Identifying caspase-3 cleavage at Asp-68 and autophosphorylation at Thr-575 revealed two distinct activation mechanisms — proteolytic release of an active kinase fragment during apoptosis and autophosphorylation-dependent catalytic competence — establishing how MEKK1 integrates apoptotic and stress signals.

    Evidence Sequencing of cleavage products, in vitro/in vivo caspase assays, subcellular fractionation, site-directed mutagenesis of autophosphorylation sites

    PMID:9078260 PMID:9244305 PMID:9576928

    Open questions at the time
    • Whether other caspases (e.g., caspase-7) also cleave MEKK1 was not fully defined
    • The phosphatase reversing Thr-575 autophosphorylation was not identified
  3. 1997 High

    Demonstrating direct JNK binding to the MEKK1 N-terminal domain established that MEKK1 functions as a scaffold, not merely a kinase, physically recruiting its downstream target.

    Evidence In vitro peptide binding, co-immunoprecipitation in transfected cells

    PMID:9405400

    Open questions at the time
    • Whether the scaffold function is separable from kinase activation in vivo was unclear
    • Stoichiometry of the MEKK1-JNK complex was not determined
  4. 1998 High

    Linking MEKK1–JNK signaling to p53 stabilization (by blocking MDM2 binding) and to NF-AT4 nuclear import suppression (via CKIα) expanded MEKK1's functional reach beyond MAPK cascades into transcription factor regulation and cell-fate decisions.

    Evidence In vivo ubiquitination assays, p53-MDM2 co-IP, NF-AT4 nuclear import assays

    PMID:9630228 PMID:9724739

    Open questions at the time
    • Whether MEKK1 directly phosphorylates CKIα was not tested
    • The relative contribution of p53 stabilization vs. JNK-mediated phosphorylation to apoptosis was not dissected
  5. 1999 High

    MEKK1 knockout studies in ES cells and cardiomyocytes established stimulus-specific requirements: MEKK1 is essential for JNK activation by microtubule toxins and oxidative stress but dispensable for p38 activation, and protects cardiomyocytes from apoptosis by suppressing TNF-α.

    Evidence Targeted MEKK1 gene disruption in ES cells; JNK, p38 kinase assays; apoptosis and TNF-α measurement

    PMID:10212239 PMID:10611349

    Open questions at the time
    • MEKK1's role in response to other stress stimuli (e.g., UV, osmotic) in KO cells was not systematically tested
    • Compensatory mechanisms by other MAP3Ks were not fully explored
  6. 1999 High

    Identifying α-actinin as a direct MEKK1-binding partner that tethers it to actin stress fibers and focal adhesions linked MEKK1 to cytoskeletal mechanotransduction, independent of its kinase activity.

    Evidence Yeast two-hybrid, in vitro binding with purified α-actinin, immunofluorescence co-localization with kinase-dead mutant

    PMID:10401575

    Open questions at the time
    • Whether focal adhesion localization is required for anoikis signaling was not tested
    • The full set of cytoskeletal anchors for MEKK1 was not defined
  7. 2000 Medium

    Demonstrating that MEKK1's N-terminal domain binds ERK2, MEK1, and Raf-1 established it as a scaffold for the entire ERK module in addition to the JNK module, and linked MEKK1 to NF-κB activation via IKK-2 downstream of Raf.

    Evidence Co-immunoprecipitation of endogenous proteins; dominant-negative MEKK1 blocking NF-κB reporter

    PMID:10758165 PMID:10969079

    Open questions at the time
    • Scaffold function for ERK was based on co-IP without in vitro reconstitution
    • Whether MEKK1 scaffolding of ERK and JNK modules is mutually exclusive was not tested
  8. 2001 High

    Discovering that the PHD/RING domain of MEKK1 is an E3 ubiquitin ligase for ERK1/2 revealed an unprecedented dual kinase–ligase mechanism by which MEKK1 simultaneously activates JNK and degrades ERK during stress, explaining pathway selectivity during apoptosis.

    Evidence In vitro E3 ligase reconstitution with ubiquitin, E1, E2; in vivo ubiquitination; ERK2 docking-motif mutants

    PMID:12049732

    Open questions at the time
    • The identity of the E2 ubiquitin-conjugating enzyme was not determined
    • Structural basis for how kinase and ligase domains coordinate was unknown
  9. 2002 High

    Multiple studies in 2001–2002 defined the regulatory network controlling MEKK1: RIP phosphorylates Ser-957/994 to activate MEKK1 for TNF-α/NF-κB signaling; PAK1 phosphorylates Ser-67 to block JNK binding; and caspase-generated 91-kDa fragment relocalization (not downstream kinase activation) drives apoptosis.

    Evidence In vitro kinase assays with phospho-site mutants; co-IP in RIP-deficient Jurkat cells; membrane-targeting of 91-kDa fragment

    PMID:11369754 PMID:11782455 PMID:12228228

    Open questions at the time
    • The phosphatase that dephosphorylates Ser-67 upon stress was not identified
    • Whether RIP-mediated activation and caspase cleavage are sequential or alternative was unclear
  10. 2002 High

    In vivo cardiac studies showed MEKK1 is required for pressure overload-induced JNK activation and Gαq-mediated cardiac hypertrophy, establishing a non-redundant physiological role in the heart.

    Evidence MEKK1 KO mice with aortic banding and Gαq transgenic cross; JNK activity, echocardiography, ANF expression

    PMID:11891332 PMID:12122119

    Open questions at the time
    • Whether MEKK1 kinase or E3 ligase activity mediates the cardiac phenotype was not dissected
    • Downstream transcriptional targets in hypertrophy beyond ANF were not characterized
  11. 2003 High

    Identifying RhoA-GTP as a direct activator and Axin as a scaffold partner of MEKK1 connected it to cytoskeletal Rho signaling and the Wnt pathway, while demonstrating that MEKK1 drives uPA expression for cell migration/invasion revealed its role in tissue remodeling.

    Evidence In vitro binding/kinase assays with RhoA and PHD mutants; Axin co-IP in MEKK1−/− MEFs; uPA activity in KO fibroblasts with rescue

    PMID:12493778 PMID:12878610 PMID:14581471

    Open questions at the time
    • Whether RhoA activates MEKK1 in the context of focal adhesions was not shown
    • The Axin–MEKK1 binding site on MEKK1 was not mapped
  12. 2006 High

    Extending the E3 ligase substrates to c-Jun and Fra-2 showed that MEKK1 remodels the AP-1 transcription factor repertoire: it ubiquitinates and degrades c-Jun and Fra-2, while suppressing JunB mRNA, thereby sculpting AP-1 composition to control uPA expression and apoptotic sensitivity.

    Evidence In vitro/in vivo ubiquitination of c-Jun; MEKK1−/− cells with elevated c-Jun/JunB; Fra-2 ubiquitination assay; AP-1 and uPA reporter

    PMID:15558021 PMID:17101801

    Open questions at the time
    • Whether additional AP-1 family members are MEKK1 E3 substrates was not tested
    • The relative contribution of kinase vs. ligase activity to AP-1 remodeling was not fully separated
  13. 2006 High

    Identifying DJ-1 as a cytoplasmic sequestrator of MEKK1 that inhibits its kinase activity, with the Parkinson-associated L166P mutant losing this ability, linked MEKK1 regulation to neurodegeneration.

    Evidence Co-IP, in vitro kinase assay, subcellular fractionation, immunofluorescence with DJ-1 KD and L166P mutant

    PMID:18309325

    Open questions at the time
    • Whether DJ-1 loss contributes to dopaminergic neuron death via MEKK1 in vivo was not tested
    • The DJ-1 binding site on MEKK1 was not mapped
  14. 2006 High

    In vivo metastasis studies confirmed that MEKK1 controls tumor cell dissemination through uPA and gelatinase regulation, establishing a physiological role for the MEKK1–uPA axis in cancer progression.

    Evidence MEKK1−/− × PyMT transgenic mice; lung metastasis quantification; uPA/gelatinase assays; siRNA in MDA-MB-231 cells

    PMID:16568086

    Open questions at the time
    • Whether kinase or E3 ligase activity of MEKK1 drives the metastatic phenotype was not determined
    • Human tumor validation beyond siRNA in cell lines was limited
  15. 2007 High

    Compound mutant mouse studies showed MEKK1 preferentially phosphorylates JNK1 over JNK2 via MKK4 to control eyelid closure morphogenesis, demonstrating isoform selectivity in a developmental context.

    Evidence Mekk1/Jnk1/Jnk2 compound mutant mice; JNK isoform phosphorylation; c-Jun and PAI1 readouts

    PMID:18032450

    Open questions at the time
    • Structural basis for JNK1 preference was not resolved
    • Whether MKK7 also contributes to eyelid closure was not addressed
  16. 2008 High

    Placing MEKK1 downstream of TRAF6/IPS-1 in the RIG-I/MDA5 innate antiviral pathway showed that MEKK1 is required for IFN-β induction, extending its role to innate immunity.

    Evidence TRAF6−/− and TAK1−/− MEFs; MEKK1 siRNA; MEKK1+IRF3 co-expression; IFN-β reporter

    PMID:18984593

    Open questions at the time
    • Whether MEKK1 directly phosphorylates IRF3 or acts through an intermediate kinase was not determined
    • Redundancy with other MAP3Ks in antiviral signaling was incompletely explored
  17. 2010 High

    Patient mutation studies established that MAP3K1 gain-of-function mutations cause 46,XY disorders of sex development by enhancing RHOA/MAP3K4/FRAT1 binding and reducing RAC1 binding, shifting signaling toward WNT/β-catenin/FOXL2 and away from SOX9/FGF9, while Axin-MEKK1 interaction was shown to require E3 ligase (not kinase) activity for Wnt-driven transcription.

    Evidence Linkage analysis and sequencing in DSD families; phospho-p38/ERK assays; co-IP for RHOA/RAC1/MAP3K4/FRAT1; Axin co-IP with ligase/kinase mutants; TCF/LEF reporter

    PMID:20128690 PMID:21129722 PMID:24135036

    Open questions at the time
    • Whether mutations affect MEKK1 E3 ligase activity specifically was not tested
    • The mechanism by which altered RHOA binding shifts downstream pathway selection was not fully resolved
  18. 2011 High

    MAP3K1 deficiency causes JNK-independent retinal defects including Müller glia overproduction through cyclin D1/CDK4/6-RB-E2F dysregulation, revealing a kinase-cascade-independent developmental role.

    Evidence Map3k1 KO mice; BrdU, TUNEL, cell-type immunostaining; compound mutants with Jnk1−/− and Jnk1/2 hemizygotes

    PMID:21862560

    Open questions at the time
    • Whether the E3 ligase activity mediates the retinal phenotype was not tested
    • Direct substrates controlling cyclin D1 were not identified
  19. 2018 High

    CRISPR knockout of MAP3K1 in PIK3CA-mutant breast cancer cells revealed that MAP3K1 normally promotes IRS-1 degradation via JNK signaling; its loss stabilizes IRS-1 and enhances PI3Kα/AKT signaling, explaining the frequent co-occurrence of MAP3K1 and PIK3CA mutations in breast cancer.

    Evidence CRISPR KO; phospho-AKT/IRS-1 immunoblotting; IRS-1/p85 co-IP; 3D acinar growth; xenograft studies

    PMID:29765551

    Open questions at the time
    • Whether MEKK1 E3 ligase activity directly ubiquitinates IRS-1 was not tested
    • Clinical validation of combined PI3Kα inhibitor sensitivity in MAP3K1-mutant tumors was not provided

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis for how the kinase and E3 ligase domains of MEKK1 are coordinately regulated, the identity of the E2 enzyme(s) for its ubiquitin ligase activity, and the mechanism by which DSD-associated mutations alter the balance between RHOA and RAC1 binding at the structural level.
  • No crystal or cryo-EM structure of full-length MEKK1 or its PHD/RING domain in complex with substrates
  • E2 ubiquitin-conjugating enzyme identity unknown
  • Structural mechanism of DSD mutation-induced binding partner switching unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016874 ligase activity 4 GO:0016740 transferase activity 3 GO:0060090 molecular adaptor activity 3 GO:0098772 molecular function regulator activity 3
Localization
GO:0005829 cytosol 2 GO:0005856 cytoskeleton 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-5357801 Programmed Cell Death 5 R-HSA-1266738 Developmental Biology 4 R-HSA-392499 Metabolism of proteins 3 R-HSA-168256 Immune System 1
Partners
ACTN1AXIN1DJ-1ERK2JNK1MKK4RHOARIPK1

Evidence

Reading pass · 41 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 MEKK1 (MAP3K1) phosphorylates and activates SEK1 (MKK4), which in turn phosphorylates and activates SAPK/JNK stress-activated protein kinases, defining MEKK1 as a MAP3K in the JNK signaling cascade. In vitro kinase assay; expression in COS-7 cells and NIH3T3 inducible cell lines Nature High 7997270
1997 MEKK1 is cleaved by caspase 3 (CPP32) after residue D68 in response to Fas ligation; this cleavage is required for MEKK1 kinase activation and redistributes MEKK1 from a Triton-insoluble (particulate) compartment to a Triton-soluble (diffuse cytoplasmic) compartment. Sequencing of proteolytic cleavage products; in vitro and in vivo caspase cleavage assays; immunofluorescence; subcellular fractionation; viral and chemical caspase inhibitors Proceedings of the National Academy of Sciences of the United States of America High 9576928
1997 MEKK1 binds directly to the N-terminal non-catalytic domain of JNK/SAPK in vitro and in transfected cells; this interaction facilitates JNK activation by MEKK1. In vitro binding with immobilized MEKK1-derived peptides; co-immunoprecipitation in transfected cells; selective extraction from cell lysates The Journal of biological chemistry High 9405400
1997 MEKK1 autophosphorylates on Thr-575 within its activation loop (between kinase subdomains VII and VIII), and this autophosphorylation is required for full kinase activity; mutation of Thr-587 to alanine eliminates substrate (MEK/SEK) phosphorylation but not autophosphorylation. Site-directed mutagenesis; in vitro kinase assay; phosphatase treatment; metabolic labeling The Biochemical journal High 9078260
1997 Caspase cleavage of MEKK1 is required for its activation during anoikis; the MEKK1 cleavage product stimulates apoptosis, and a cleavage-resistant MEKK1 mutant partially protects cells from anoikis, establishing a caspase–MEKK1 positive feedback loop. Overexpression of MEKK1 cleavage product and cleavage-resistant mutant; caspase activity assays; anoikis functional assays Cell High 9244305
1998 MEKK1 activates the MEKK1-JNK signaling axis to stabilize p53 by reducing its ubiquitination; JNK phosphorylates p53, which abolishes MDM2 binding and prevents p53 ubiquitination, leading to increased p53 transcriptional activity and apoptosis. Expression of constitutively active ΔMEKK1; in vivo ubiquitination assay; in vitro phosphorylation of p53 by immunopurified JNK; co-immunoprecipitation of p53-MDM2; luciferase reporter assay Proceedings of the National Academy of Sciences of the United States of America High 9724739
1998 MEKK1 suppresses NF-AT4 nuclear import by stabilizing the interaction between NF-AT4 and casein kinase Iα (CKIα), which phosphorylates NF-AT4 and causes intramolecular masking of its nuclear localization signal. Identification of CKIα as NF-AT4 binding partner; co-immunoprecipitation; nuclear import assays; phosphorylation assays Cell High 9630228
1999 MEKK1 is required for JNK activation in response to microtubule toxins (taxol) but not actin fiber disruption; MEKK1-deficient embryonic stem cells fail to activate JNK and show increased apoptosis in response to taxol, while MEKK2 disruption has no effect. Targeted gene disruption (MEKK1-/- ES cells); JNK kinase assay; apoptosis assay; cell cycle analysis The Journal of biological chemistry High 10212239
1999 MEKK1 interacts with the actin-crosslinking protein α-actinin via residues 221–559 in its N-terminal 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 co-localization; kinase-inactive mutant Cell motility and the cytoskeleton High 10401575
1999 MEKK1 deficiency in embryonic stem cell-derived cardiac myocytes abolishes JNK activation but not p38 activation in response to oxidative stress (H2O2); the MEKK1-JNK pathway protects against apoptosis by suppressing TNF-α production. Targeted MEKK1 gene disruption in ES cells; JNK and p38 kinase assays; TNF-α measurement; apoptosis assay Proceedings of the National Academy of Sciences of the United States of America High 10611349
2000 MEKK1 binds directly to ERK2, MEK1, and Raf-1 via its N-terminal regulatory domain, demonstrating that MEKK1 can scaffold the entire ERK MAP kinase module. Co-immunoprecipitation of endogenous proteins The Journal of biological chemistry Medium 10969079
2000 Raf-mediated NF-κB activation requires MEKK1 as a membrane shuttle kinase; a dominant-negative MEKK1 blocks Raf- and PMA-induced NF-κB activation, which depends on IKK-2 but not the classical MEK-ERK cascade. Dominant-negative MEKK1 expression; NF-κB reporter assay; IKK activity assay; pharmacological inhibitors Proceedings of the National Academy of Sciences of the United States of America Medium 10758165
2001 The PHD/RING finger-like domain of MEKK1 functions as an E3 ubiquitin ligase that ubiquitinates ERK1/2, promoting their proteasome-dependent degradation during stress; both MEKK1 kinase activity and a docking motif on ERK1/2 are required for ERK ubiquitination. In vitro ubiquitin ligase assay; in vivo ubiquitination; docking motif mutations on ERK2; apoptosis assay in ERK2 docking mutant cells Molecular cell High 12049732
2002 Caspase-generated 91-kDa MEKK1 kinase fragment relocalizes from a particulate fraction to a soluble cytoplasmic fraction; this relocalization (not JNK, ERK, NF-κB, or p300 activation) is necessary for MEKK1's pro-apoptotic function. Subcellular fractionation; membrane-targeting signal added to 91-kDa fragment; caspase activation assays; kinase activity assays The Journal of biological chemistry High 11782455
2002 MEKK1 mediates pressure overload-induced JNK activation in the heart; MEKK1-deficient mice show loss of JNK activation after aortic banding while cardiac hypertrophy still occurs, indicating MEKK1 is required for JNK activation but not hypertrophy. MEKK1 protects against apoptosis and inflammation under pressure overload. MEKK1 knockout mice; aortic banding model; JNK activity assay; cardiac morphometry; apoptosis assay The Journal of clinical investigation High 12122119
2002 MEKK1 is essential for Gαq-induced cardiac hypertrophy; MEKK1 knockout abolishes JNK activation, cardiac mass increase, myocyte hypertrophy, and ANF induction by Gαq, while improving ventricular function. MEKK1 knockout ES cell-derived cardiac myocytes; Gαq-overexpressing transgenic mice crossed with MEKK1-/- mice; JNK kinase assay; echocardiography; ANF expression Proceedings of the National Academy of Sciences of the United States of America High 11891332
2002 Receptor-interacting protein (RIP) physically associates with and phosphorylates MEKK1 at Ser-957 and Ser-994, thereby activating MEKK1; this RIP-MEKK1 interaction mediates TNF-α-induced IKKβ/NF-κB activation. In vitro binding; co-immunoprecipitation; in vitro kinase assay (RIP phosphorylation of MEKK1); phosphorylation-site mutants; RIP-deficient Jurkat cells The Journal of biological chemistry High 11369754
2002 PAK1 phosphorylates MEKK1 on Ser-67 within a D domain that mediates JNK/SAPK binding; constitutive Ser-67 phosphorylation in resting cells inhibits JNK binding to MEKK1, and stress stimuli cause dephosphorylation of Ser-67 to allow JNK binding. In vitro kinase assay (PAK1 phosphorylation of MEKK1 N-terminus); phosphorylation-site mutants; co-immunoprecipitation; phospho-specific analysis in stressed cells The Journal of biological chemistry High 12228228
2003 RhoA (but not Rac or Cdc42) binds to the N-terminal one-third of MEKK1 including its PHD domain; RhoA-GTP stimulates MEKK1 kinase activity up to 10-fold toward MEK4, and mutation of the essential PHD cysteine prevents RhoA interaction. In vitro binding assay; co-immunoprecipitation; in vitro kinase assay; PHD domain mutagenesis The Journal of biological chemistry High 14581471
2003 MEKK1 is required for inducible urokinase-type plasminogen activator (uPA) expression; MEKK1-deficient fibroblasts show greatly reduced uPA expression/activity in response to PMA or FGF-2, dependent on MEKK1-driven MKK1 and JNK activity; MEKK2 disruption has no effect. MEKK1 knockout fibroblasts; rescue by MEKK1 transfection; uPA activity assay; genetic specificity via MEKK2 disruption The Journal of biological chemistry High 12493778
2003 MEKK1 activity drives formation of polyglutamine-containing inclusion bodies by recruiting polyQ-containing huntingtin fragments into a particulate/insoluble fraction; kinase-dead MEKK1 cannot stimulate inclusion body formation. Overexpression of active vs. kinase-dead MEKK1; cellular fractionation; fluorescence microscopy of huntingtin-GFP inclusion bodies The Journal of cell biology Medium 11352944
2004 Ceramide directly binds MEKK1 (but not c-Raf) in glomerular endothelial cells, as demonstrated by photoaffinity labeling and ceramide-sepharose affinity chromatography, leading to SAPK/JNK cascade activation. Radioiodinated photoaffinity ceramide analogue labeling; ceramide-sepharose affinity chromatography; JNK/SEK phosphorylation assays Biochimica et biophysica acta Medium 15164763
2004 Glutathione S-transferase Mu 1-1 (GST M1-1) directly binds MEKK1, inhibits its kinase activity in a catalysis-independent manner, and interferes with MEKK1-SEK1 interaction, thereby suppressing MEKK1-induced apoptosis. In vitro binding assay; in vitro kinase assay; co-immunoprecipitation of endogenous proteins; binding competition assay The Journal of biological chemistry Medium 15299005
2006 The PHD/RING finger domain of MEKK1 acts as an E3 ubiquitin ligase toward c-Jun in response to osmotic stress; MEKK1 ubiquitinates and degrades c-Jun in vitro and in vivo, and MEKK1-/- cells have elevated c-Jun levels. c-Jun downregulation by MEKK1 promotes apoptosis. In vitro ubiquitin ligase assay; in vivo ubiquitination; MEKK1-/- cells; apoptosis assay with c-Jun overexpression Molecular and cellular biology High 17101801
2006 MEKK1 controls tumor cell dissemination and lung metastasis in PyMT mammary cancer by regulating urokinase-type plasminogen activator (uPA) expression, gelatinase activity, and basement membrane integrity; MEKK1-/- tumors show markedly reduced uPA, reduced cell migration and invasion. MEKK1-/- mice crossed with PyMT transgenic; in vivo metastasis assay; uPA expression and activity; gelatinase zymography; siRNA knockdown in MDA-MB-231 cells; invasion assays Oncogene High 16568086
2006 DJ-1 directly binds and inhibits MEKK1 kinase activity through its C-terminus, sequesters MEKK1 in the cytoplasm; the pathogenic DJ-1 L166P mutant cannot associate with MEKK1 and allows MEKK1 nuclear translocation, sensitizing cells to UV-induced MEKK1-SEK1-JNK1-mediated cell death. Co-immunoprecipitation; in vitro kinase assay; subcellular fractionation; immunofluorescence; DJ-1 knockdown; L166P mutant analysis Cell death and differentiation High 18309325
2006 MEKK1 regulates the AP-1 transcription factor repertoire by suppressing JunB mRNA expression and by inducing Fra-2 ubiquitination and degradation; loss of MEKK1 results in elevated JunB that forms an inhibitory AP-1 complex suppressing uPA transcription. MEKK1-/- cells; RT-PCR for JunB mRNA; Fra-2 ubiquitination assay; AP-1 reporter assay; uPA promoter analysis Oncogene Medium 15558021
2007 MEKK1 mediates eyelid closure morphogenesis through differential phosphorylation of JNK1 and JNK2; JNK1 (possessing unique Gly177 and Ser179 residues) is phosphorylated more efficiently than JNK2 by the MEKK1-MKK4 pathway activated by activin B, controlling downstream c-Jun phosphorylation and PAI1 expression. Mekk1/Jnk1/Jnk2 compound mutant mice; JNK phosphorylation assays; c-Jun phosphorylation; PAI1 expression; eyelid closure phenotype scoring Development (Cambridge, England) High 18032450
2007 STK38 (NDR kinase) physically interacts with the catalytic domain of MEKK1 and negatively regulates MEKK1 activity by converting it from its phosphorylated to non-phosphorylated form, suppressing MEKK1 autophosphorylation and downstream signaling. Co-immunoprecipitation; in vitro kinase assay; shRNA knockdown of STK38; autophosphorylation assay Oncogene Medium 17906693
2008 TRAF6 and MEKK1 act downstream of IPS-1 in the RIG-I/MDA5 antiviral pathway; MEKK1 (but not TAK1) is required for IFN-β induction in response to poly(I:C) and VSV, and co-expression of MEKK1 with IRF3 is sufficient to induce IFN-β. TRAF6-/- and TAK1-/- MEFs; siRNA knockdown of MEKK1; overexpression of MEKK1+IRF3; NF-κB, JNK, p38 activation assays; IFN-β reporter assay The Journal of biological chemistry High 18984593
2010 Mutations in MAP3K1 causing 46,XY disorders of sex development (DSD) alter phosphorylation of downstream targets p38 and ERK1/2, and enhance binding of RHOA to the MAP3K1 complex in patient-derived lymphoblastoid cells, implicating MAP3K1 in testis determination via MAPK signaling. Linkage analysis; sequencing of patient samples; phospho-p38 and phospho-ERK1/2 assays in patient lymphoblastoid cells; co-immunoprecipitation for RHOA binding American journal of human genetics High 21129722
2010 MAP3K1 functionally interacts with Axin1; this interaction is induced by Wnt stimulation; MAP3K1's E3 ubiquitin ligase activity (but not kinase activity) is required for TCF/LEF-driven transcription and Wnt target gene expression. Immunoprecipitation-coupled proteomics; co-immunoprecipitation with Wnt stimulation; siRNA knockdown; ubiquitin ligase mutant and kinase mutant expression; TCF/LEF luciferase reporter assay Biological chemistry High 20128690
2010 MAP3K1 mutations causing 46,XY DSD enhance binding of RHOA, MAP3K4, and FRAT1 while reducing RAC1 binding; these mutations tilt signaling toward WNT/β-catenin/FOXL2 and away from SOX9/FGF9 pathways; overexpressing RHOA or reducing MAP3K4 phenocopies the mutations. Transfection of wild-type and mutant MAP3K1 in NT2/D1 cells; co-immunoprecipitation; phosphorylation assays; siRNA knockdown of RHOA/MAP3K4; reporter assays for WNT/β-catenin and SOX9/FGF9 Human molecular genetics High 24135036
2010 MEKK1 activation by IL-1β mediates canonical NF-κB pathway activation, which is required for IL-1β-induced increase in intestinal tight junction permeability; MEKK1 also plays an essential role in MLCK gene activation downstream of IL-1β. siRNA knockdown of MEKK1 and NIK in Caco-2 monolayers; transepithelial resistance measurement; NF-κB pathway activation assays; MLCK promoter assay The American journal of pathology Medium 21048223
2011 MAP3K1 deficiency leads to increased proliferation, apoptosis, and Müller glial overproduction in developing retinas; this retinal defect is independent of the eye-open-at-birth phenotype and of JNK, but involves cyclin D1/CDK4/6-RB-E2F signaling. Map3k1 knockout mice; BrdU incorporation; TUNEL apoptosis assay; immunostaining for cell-type markers; compound mutant analysis with Jnk1-/- and Jnk1/2 hemizygotes; tarsorrhaphy control Development (Cambridge, England) High 21862560
2005 MEKK1 controls neurite regrowth after injury by simultaneously activating both ERK1/2 (via MEK1) and JNK2 (via MKK7); MEK1 and MKK7 compete for binding to MEKK1, creating a pathway cross-talk. RNAi knockdown of MEKK1 abolishes both ERK and JNK phosphorylation. RNAi knockdown; co-immunoprecipitation of MEK1 and MKK7 with MEKK1; ERK/JNK phosphorylation assays; neurite regrowth assay in PC12 cells Molecular and cellular neurosciences Medium 16006144
2003 Axin binds MEKK1 to activate JNK; Axin also binds MEKK4 at a distinct domain, and MEKK4 can mediate Axin-induced JNK activation in MEKK1-/- cells; MEKK1 and MEKK4 compete for Axin binding. Co-immunoprecipitation; MEKK1-/- MEFs; siRNA against MEKK4; JNK activation assay The Journal of biological chemistry Medium 12878610
2002 p115 Rho GTPase-activating protein (p115 RhoGAP) binds to the N-terminal regulatory domain of MEKK1 via the RhoGAP SH3 domain; this interaction reduces MEKK1-induced AP-1 signaling, linking MEKK1 to cytoskeletal Rho regulation. Yeast two-hybrid screen; in vitro binding; co-immunoprecipitation; AP-1 reporter assay; SH3 deletion mutant Journal of cellular physiology Medium 12115726
2007 Dietary isothiocyanates (ITCs) directly and covalently modify a specific cysteine residue in the ATP binding pocket of MEKK1, irreversibly inhibiting its kinase activity; this correlates with specific inhibition of SAPK/JNK but not parallel MAPK pathways. In vitro kinase assay; affinity reagent for ITC modification; cysteine-mutant MEKK1; kinase assay of endogenous immunopurified MEKK1; phospho-specific immunoblotting BMC cancer High 17894894
2018 MAP3K1 deficiency in PIK3CA-mutant breast cancer cells enhances AKT phosphorylation and downstream signaling by impairing MAP3K1-JNK signaling that normally promotes IRS-1 degradation; MAP3K1 loss increases IRS-1 stability and IRS-1/p85 binding, enhancing PI3Kα activity. CRISPR knockout of MAP3K1; phospho-AKT/IRS-1 immunoblotting; co-immunoprecipitation of IRS-1/p85; 3D acinar growth assay; in vivo xenograft efficacy studies Oncotarget High 29765551
2019 MAP3K1 mutations causing 46,XY DSD cluster in three structural domains: an N-terminal GEF-homology domain (Met164–Glu231), PHD domain (Met442–Trp495), and ARMadillo repeat domain (Met566–Glu862); mutations differentially increase binding of RHOA, MAP3K4, and FRAT1 and decrease RAC1 binding depending on domain location. Structural modeling; co-immunoprecipitation for binding partners; downstream phosphorylation assays; patient mutation functional analysis Human molecular genetics Medium 30608580

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1. Nature 717 7997270
1997 The regulation of anoikis: MEKK-1 activation requires cleavage by caspases. Cell 466 9244305
1998 MEKK1/JNK signaling stabilizes and activates p53. Proceedings of the National Academy of Sciences of the United States of America 456 9724739
2002 The PHD domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2. Molecular cell 268 12049732
1998 Intramolecular masking of nuclear import signal on NF-AT4 by casein kinase I and MEKK1. Cell 266 9630228
2009 A major role of the MEKK1-MKK1/2-MPK4 pathway in ROS signalling. Molecular plant 189 19529823
2003 Mitogenic effect of orphan receptor TR3 and its regulation by MEKK1 in lung cancer cells. Molecular and cellular biology 172 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
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
2002 The MEKK1-JNK pathway plays a protective role in pressure overload but does not mediate cardiac hypertrophy. The Journal of clinical investigation 136 12122119
2010 Mutations in MAP3K1 cause 46,XY disorders of sex development and implicate a common signal transduction pathway in human testis determination. American journal of human genetics 135 21129722
2007 Arabidopsis MEKK1 can take a short cut: it can directly interact with senescence-related WRKY53 transcription factor on the protein level and can bind to its promoter. Plant molecular biology 135 17587183
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
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 115 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 111 10212239
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
2000 MEKK1 binds raf-1 and the ERK2 cascade components. The Journal of biological chemistry 100 10969079
1998 Heat stress activates fission yeast Spc1/StyI MAPK by a MEKK-independent mechanism. Molecular biology of the cell 100 9614178
1998 Functional binding between Gbeta and the LIM domain of Ste5 is required to activate the MEKK Ste11. Current biology : CB 98 9501067
1997 MEKK1 binds directly to the c-Jun N-terminal kinases/stress-activated protein kinases. The Journal of biological chemistry 98 9405400
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
2006 Convergence of Itch-induced ubiquitination with MEKK1-JNK signaling in Th2 tolerance and airway inflammation. The Journal of clinical investigation 84 16557301
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
2001 A Drosophila MAPKKK, D-MEKK1, mediates stress responses through activation of p38 MAPK. The EMBO journal 82 11574474
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
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
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
2013 Mutations in MAP3K1 tilt the balance from SOX9/FGF9 to WNT/β-catenin signaling. Human molecular genetics 70 24135036
2003 RhoA binds to the amino terminus of MEKK1 and regulates its kinase activity. The Journal of biological chemistry 67 14581471
2013 Phosphorylation of Arabidopsis thaliana MEKK1 via Ca(2+) signaling as a part of the cold stress response. Journal of plant research 66 23857079
2007 Clinical correlates of low-risk variants in FGFR2, TNRC9, MAP3K1, LSP1 and 8q24 in a Dutch cohort of incident breast cancer cases. Breast cancer research : BCR 66 17997823
1997 Regulation of the activity of MEK kinase 1 (MEKK1) by autophosphorylation within the kinase activation domain. The Biochemical journal 65 9078260
2006 MEKK1 mediates the ubiquitination and degradation of c-Jun in response to osmotic stress. Molecular and cellular biology 64 17101801
2014 Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1. American journal of human genetics 62 25529635
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
2011 Minor abnormalities of testis development in mice lacking the gene encoding the MAPK signalling component, MAP3K1. PloS one 57 21559298
2008 DJ-1 modulates UV-induced oxidative stress signaling through the suppression of MEKK1 and cell death. Cell death and differentiation 57 18309325
2006 MEKK1 controls matrix degradation and tumor cell dissemination during metastasis of polyoma middle-T driven mammary cancer. Oncogene 57 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
2013 Glutamate signalling via a MEKK1 kinase-dependent pathway induces changes in Arabidopsis root architecture. The Plant journal : for cell and molecular biology 55 23574009
2001 Intracellular aggregation of polypeptides with expanded polyglutamine domain is stimulated by stress-activated kinase MEKK1. The Journal of cell biology 51 11352944
2005 MEKK1 controls neurite regrowth after experimental injury by balancing ERK1/2 and JNK2 signaling. Molecular and cellular neurosciences 50 16006144
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 49 29344125
2001 Stimulation of p300-mediated transcription by the kinase MEKK1. The Journal of biological chemistry 49 11278389
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 47 34195198
2004 Negative regulation of MEKK1-induced signaling by glutathione S-transferase Mu. The Journal of biological chemistry 47 15299005
2002 Dominant negative MEKK1 inhibits survival of pancreatic cancer cells. Oncogene 46 12185592
2008 Elucidation of the signaling network of COX-2 induction in sheared chondrocytes: COX-2 is induced via a Rac/MEKK1/MKK7/JNK2/c-Jun-C/EBPbeta-dependent pathway. American journal of physiology. Cell physiology 44 18367585
2022 The MEKK1-MKK1/2-MPK4 cascade phosphorylates and stabilizes STOP1 to confer aluminum resistance in Arabidopsis. Molecular plant 43 36419357
2019 Disruption of the MAMP-Induced MEKK1-MKK1/MKK2-MPK4 Pathway Activates the TNL Immune Receptor SMN1/RPS6. Plant & cell physiology 43 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) 42 18032450
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
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 40 25613373
2018 Functional significance of co-occurring mutations in PIK3CA and MAP3K1 in breast cancer. Oncotarget 39 29765551
2002 Binding of JNK/SAPK to MEKK1 is regulated by phosphorylation. The Journal of biological chemistry 38 12228228
2017 MAP3K1-related gonadal dysgenesis: Six new cases and review of the literature. American journal of medical genetics. Part C, Seminars in medical genetics 37 28504475
2000 Vasoactive intestinal peptide and pituitary adenylate cyclase activating polypeptide inhibit the MEKK1/MEK4/JNK signaling pathway in LPS-stimulated macrophages. Journal of neuroimmunology 37 11024538
2015 MiR-451 inhibits proliferation of esophageal carcinoma cell line EC9706 by targeting CDKN2D and MAP3K1. World journal of gastroenterology 36 26019450
2020 LncRNA NEAT1 promotes malignant phenotypes and TMZ resistance in glioblastoma stem cells by regulating let-7g-5p/MAP3K1 axis. Bioscience reports 35 33057597
2023 Resveratrol inhibits autophagy against myocardial ischemia-reperfusion injury through the DJ-1/MEKK1/JNK pathway. European journal of pharmacology 34 37149277
2019 A role for peroxiredoxins in H2O2- and MEKK-dependent activation of the p38 signaling pathway. Redox biology 34 31629169
2002 Apoptosis stimulated by the 91-kDa caspase cleavage MEKK1 fragment requires translocation to soluble cellular compartments. The Journal of biological chemistry 32 11782455
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
2010 MAP3K1 functionally interacts with Axin1 in the canonical Wnt signalling pathway. Biological chemistry 30 20128690
2007 The isothiocyanate class of bioactive nutrients covalently inhibit the MEKK1 protein kinase. BMC cancer 30 17894894
2016 MAP3K1-targeting therapeutic artificial miRNA suppresses the growth and invasion of breast cancer in vivo and in vitro. SpringerPlus 29 26759750
2005 MEKK1 regulates the AP-1 dimer repertoire via control of JunB transcription and Fra-2 protein stability. Oncogene 29 15558021
2001 Role of receptor-interacting protein in tumor necrosis factor-alpha -dependent MEKK1 activation. The Journal of biological chemistry 29 11369754
2002 Regulation of c-myc stability by selective stress conditions and by MEKK1 requires aa 127-189 of c-myc. Oncogene 28 12080469
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
2015 BAALC potentiates oncogenic ERK pathway through interactions with MEKK1 and KLF4. Leukemia 27 26050649
2008 Simulation of crosstalk between small GTPase RhoA and EGFR-ERK signaling pathway via MEKK1. Bioinformatics (Oxford, England) 27 19074159
2007 Negative regulation of MEKK1/2 signaling by serine-threonine kinase 38 (STK38). Oncogene 27 17906693
2002 p115 Rho GTPase activating protein interacts with MEKK1. Journal of cellular physiology 27 12115726
2011 Loss of MAP3K1 enhances proliferation and apoptosis during retinal development. Development (Cambridge, England) 26 21862560
2018 MEKK1, JNK, and SMAD3 mediate CXCL12-stimulated connective tissue growth factor expression in human lung fibroblasts. Journal of biomedical science 25 29499695
2004 Differential binding of ceramide to MEKK1 in glomerular endothelial and mesangial cells. Biochimica et biophysica acta 25 15164763
2003 Involvement of MEKK1/ERK/P21Waf1/Cip1 signal transduction pathway in inhibition of IGF-I-mediated cell growth response by methylglyoxal. Journal of cellular biochemistry 25 12647305
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
2009 Depleting MEKK1 expression inhibits the ability of invasion and migration of human pancreatic cancer cells. Journal of cancer research and clinical oncology 24 19513748
2001 Expression of Galpha 13 (Q226L) induces P19 stem cells to primitive endoderm via MEKK1, 2, or 4. The Journal of biological chemistry 23 11700306
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
2016 Induction of Connective Tissue Growth Factor Expression by Hypoxia in Human Lung Fibroblasts via the MEKK1/MEK1/ERK1/GLI-1/GLI-2 and AP-1 Pathways. PloS one 22 27486656
2002 Opposing roles of serine/threonine kinases MEKK1 and LOK in regulating the CD28 responsive element in T-cells. The Biochemical journal 21 11903060
2020 Long noncoding RNA FOXD2-AS1 aggravates hepatocellular carcinoma tumorigenesis by regulating the miR-206/MAP3K1 axis. Cancer medicine 20 32558350
1999 Characterisation of novel plant genes encoding MEKK/STE11 and RAF-related protein kinases. Gene 20 10095117