Affinage

MAP2K1

Dual specificity mitogen-activated protein kinase kinase 1 · UniProt Q02750

Length
393 aa
Mass
43.4 kDa
Annotated
2026-06-10
100 papers in source corpus 24 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAP2K1 (MEK1) is a dual-specificity protein kinase that occupies the central tier of the RAF-MEK-ERK cascade, transducing upstream RAF activity into ERK1/2 phosphorylation to control proliferation, cell-cycle progression, and tissue-specific signaling outcomes (PMID:30377225, PMID:9582373). In the resting state MEK1 is held in an autoinhibited BRAF-MEK1 complex restrained by a 14-3-3 dimer; release of these inhibitory interactions permits a single 14-3-3 dimer to bridge two BRAF molecules into an active back-to-back dimer that activates MEK1 (PMID:31581174). Activation proceeds through RAF-catalyzed phosphorylation of Ser218 and Ser222 in the activation segment, a step that also requires the KSR scaffold, while activated ERK imposes feedback inhibition by phosphorylating MEK1 at Thr292 (PMID:22177953). MEK1 dimerization is itself required both for RAF-mediated activation and for catalytic activity toward ERK, and oncogenic mutations act either by relieving helix-A autoinhibition or by enhancing homodimerization to drive intradimer cross-phosphorylation, the latter conferring resistance to allosteric MEK inhibitors (PMID:30377225). MEK1 is the dominant rheostat of pathway duration: it heterodimerizes with MEK2, and ERK-driven phosphorylation of the MEK1-specific Thr292 negatively regulates this heterodimer, such that loss of MEK1 stabilizes MEK2 and ERK phosphorylation (PMID:19219045). Beyond catalysis, MEK1 activity is tuned by inhibitory phosphorylation at Thr286/Thr292 by p34cdc2, Cdk5, ERK, and Cdk1 (PMID:8114697, PMID:25971971), and by post-translational modifications including Cys341 S-sulfhydration that promotes nuclear ERK/PARP-1-dependent DNA repair (PMID:24778456) and Lys175 acetylation controlled by SIRT2 that links MEK1-ERK to DRP1-driven mitochondrial fission (PMID:34965411). Functionally MEK1 is non-redundant with MEK2: it drives the G1/S transition through cyclin D1 induction and p27/p21 control (PMID:9582373, PMID:15284233), promotes epidermal proliferation in part through a kinase-independent mechanism (PMID:15342384), confers cardioprotection against ischemia-reperfusion injury via ERK2 (PMID:15096454), and limits the duration of macrophage proinflammatory ERK signaling to promote resolution of lung injury (PMID:31801908, PMID:28003382). Recurrent activating MAP2K1 mutations cause constitutive ERK activation and MEK-inhibitor resistance in Langerhans cell histiocytosis and other cancers (PMID:25899310, PMID:31227518).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1994 High

    Established that MEK1 is not only activated by upstream kinases but is also negatively controlled, defining a cell-cycle-linked inhibitory mechanism.

    Evidence In vitro kinase assay with p34cdc2 plus in vivo phosphorylation mapping and mutagenesis of Thr286/Thr292

    PMID:8114697

    Open questions at the time
    • Did not resolve how inhibitory phosphorylation is reversed
    • Functional consequence for ERK output not quantified in this study
  2. 1998 Medium

    Demonstrated that MEK1 activity is sufficient to drive proliferation and transformation, linking the kinase directly to cell-cycle machinery.

    Evidence Inducible constitutively active MEK1-ER fusion in NIH-3T3 cells with cell-cycle, cyclin D1/p27, and transformation assays

    PMID:9582373

    Open questions at the time
    • Whether endogenous MEK1 sets the same thresholds was untested
    • Does not distinguish MEK1 from MEK2 contributions
  3. 1999 Medium

    Showed that MEK1 subcellular distribution is regulated, addressing where MEK1 acts during the cell cycle.

    Evidence Fluorescence microscopy of NES- and activation-site-mutant MEK1 constructs with inhibitor and synchronization in cultured cells

    PMID:10037701

    Open questions at the time
    • Nuclear substrates of MEK1 not identified
    • Single-lab localization study
  4. 2002 Medium

    Defined an upstream regulatory input by showing MEKK1 autoubiquitylation gates its ability to phosphorylate MKK1.

    Evidence In vitro kinase and ubiquitylation assays with MEKK1 PHD-domain mutagenesis

    PMID:12456688

    Open questions at the time
    • Physiological contexts where MEKK1 controls MEK1 unclear
    • Did not map MEK1 phosphosites targeted by MEKK1
  5. 2004 Medium

    Resolved that MEK1 and MEK2 have non-redundant roles, with MEK1 specifically required to restrain G1/S progression and prevent senescence.

    Evidence Isoform-specific RNAi knockdown with cell-cycle, cyclin D1/p21, and colony-formation readouts; transgenic epidermal and cardiac models

    PMID:15096454 PMID:15284233 PMID:15342384

    Open questions at the time
    • Molecular basis of MEK1 vs MEK2 substrate/output divergence not defined
    • Kinase-independent epidermal function mechanism unresolved
  6. 2007 Medium

    Identified WNK2 as an upstream negative regulator acting at the MEK1 level, expanding the network controlling pathway suppression.

    Evidence RNAi knockdown and kinase-dead WNK2 mutant with pMEK1(S298)/pERK readouts in HeLa and HT29 cells

    PMID:17667937

    Open questions at the time
    • Whether WNK2 acts directly on MEK1 not shown
    • Mechanism connecting WNK2 to Ser298 phosphorylation unknown
  7. 2009 High

    Discovered the MEK1-MEK2 heterodimer and established MEK1 as the master modulator of pathway duration through Thr292 feedback.

    Evidence Reciprocal Co-IP, phosphosite mutagenesis, and MEK1 knockout mouse with in vivo ERK/MEK phosphorylation assays

    PMID:19219045

    Open questions at the time
    • Structural geometry of the heterodimer not resolved
    • Quantitative contribution of heterodimer vs homodimer to ERK output unclear
  8. 2011 Medium

    Consolidated the activating and inhibitory phosphosite map and the KSR scaffold requirement into a coherent activation model.

    Evidence Synthesis of phosphosite mapping, kinase assay, and mutagenesis data (review)

    PMID:22177953

    Open questions at the time
    • Review-level synthesis rather than new primary data
    • Dynamic interplay among phosphosites not quantified
  9. 2014 Medium

    Revealed a redox-sensing modification on MEK1 that couples H2S signaling to nuclear ERK-dependent DNA repair.

    Evidence S-sulfhydration assay, Cys341 mutagenesis, MEK1-PARP-1 Co-IP, nuclear ERK immunofluorescence, and DNA damage assays

    PMID:24778456

    Open questions at the time
    • Single-lab finding without independent replication
    • Stoichiometry and physiological H2S thresholds undefined
  10. 2016 Medium

    Defined a tissue-specific MEK1 role in restraining macrophage M2 polarization and efferocytosis, separable from STAT6.

    Evidence Conditional Mek1 knockout, pharmacological MEKi, STAT6 KO epistasis, and in vivo efferocytosis and lung injury models

    PMID:28003382

    Open questions at the time
    • MEK1 substrates governing efferocytosis genes not identified
    • STAT6-independent efferocytosis mechanism unresolved
  11. 2018 High

    Classified oncogenic MEK1 mutations by mechanism and established dimerization as essential for both activation and catalysis.

    Evidence In vitro kinase and dimerization assays, mutagenesis, inhibitor-sensitivity assays, and xenograft models

    PMID:30377225

    Open questions at the time
    • Structural basis of homodimer cross-phosphorylation not directly visualized
    • In vivo prevalence of each mutation class not addressed
  12. 2019 High

    Provided the structural basis for MEK1 autoinhibition and activation within the 14-3-3-cradled BRAF complex.

    Evidence Cryo-EM of full-length BRAF-MEK1-14-3-3 complexes in autoinhibited and active states

    PMID:31581174

    Open questions at the time
    • MEK1 catalytic transition state not captured
    • Role of MEK2 in analogous complexes not addressed
  13. 2019 Medium

    Characterized a clinically acquired gatekeeper mutation that uncouples MEK1 from allosteric inhibition while retaining ATP-competitive vulnerability.

    Evidence Whole-genome sequencing of patient tumor with MEK1 kinase, drug-affinity, and in vivo sensitivity assays for V211D

    PMID:31227518

    Open questions at the time
    • Generality across other allosteric inhibitors beyond those tested
    • Resistance evolution dynamics in patients not tracked
  14. 2021 High

    Mapped how arrestin-2 scaffolds the cRAF-MEK1-ERK2 cascade and how MEK1 nucleotide state gates the interaction.

    Evidence HDX-MS, tryptophan-induced bimane fluorescence quenching, and NMR interface mapping

    PMID:34507982

    Open questions at the time
    • Cellular consequences of scaffolded geometry not quantified
    • Whether MEK2 is similarly scaffolded unknown
  15. 2021 Medium

    Extended MEK1 regulation to acetylation, linking SIRT2-MEK1-ERK to DRP1-driven mitochondrial dynamics.

    Evidence Acetylation mass spectrometry, Lys175 site identification, and ERK/DRP1 phosphorylation with mitochondrial imaging upon SIRT2 perturbation

    PMID:34965411

    Open questions at the time
    • Single-lab finding
    • Acetyltransferase opposing SIRT2 not identified
  16. 2021 Medium

    Demonstrated in vivo that MEK1 limits the duration of macrophage proinflammatory ERK signaling to enable resolution of lung injury.

    Evidence Conditional LysMCre Mek1 knockout in LPS-induced acute lung injury with macrophage MEK2/ERK phosphorylation readouts

    PMID:31801908

    Open questions at the time
    • Mechanistic link between MEK1 loss and failed resolution incompletely defined
    • Relative roles of MEK2 derepression vs direct MEK1 loss unclear
  17. 2021 Low

    Proposed SUMOylation as an additional negative regulatory modification of MEK1.

    Evidence SUMOylation assays and proliferation/invasion readouts in ovarian cancer cells and xenografts after monensin treatment

    PMID:34650638

    Open questions at the time
    • SUMO acceptor sites and responsible E3 ligase not identified
    • Correlative rather than direct causal evidence
  18. 2022 Low

    Offered an atomistic rationale for how BRAF versus KSR1 differentially position the MEK1 activation loop for phosphorylation.

    Evidence Molecular dynamics simulations of B-Raf/MEK1 and KSR1/MEK1 heterodimers

    PMID:35508574

    Open questions at the time
    • Computational only, no experimental validation in this study
    • Predicted P-rich loop role not tested by mutagenesis

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the many regulatory inputs on MEK1 — activating and inhibitory phosphorylation, S-sulfhydration, acetylation, SUMOylation, dimerization state, and scaffold occupancy — are integrated dynamically to set ERK signal amplitude and duration in a given cell type remains unresolved.
  • No unified quantitative model integrating MEK1 PTMs and dimerization
  • Cell-type-specific weighting of regulatory inputs undefined
  • Structural state of catalytically active MEK1 toward ERK not captured

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5 GO:0016740 transferase activity 3 GO:0140657 ATP-dependent activity 1
Localization
GO:0005634 nucleus 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 4 R-HSA-1640170 Cell Cycle 3 R-HSA-1643685 Disease 3 R-HSA-168256 Immune System 2
Partners
ARRB1BRAFKSR1MAP2K2MAPK1PARP1RAF1SIRT2
Complex memberships
BRAF-MEK1-14-3-3 complexMEK1-MEK2 heterodimercRAF-MEK1-ERK2 arrestin-2 scaffold complex

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 Cryo-EM structures of full-length BRAF in complex with MEK1 and a 14-3-3 dimer revealed that in the autoinhibited state, MEK1 is held in an inactive BRAF-MEK1 complex restrained in a cradle formed by the 14-3-3 dimer binding phosphorylated S365 and S729 of BRAF. The 14-3-3 cradle maintains autoinhibition by sequestering the BRAF cysteine-rich domain and blocking BRAF kinase domain dimerization. In the active state, inhibitory interactions are released and a single 14-3-3 dimer bridges two BRAFs via C-terminal pS729 sites, driving formation of an active back-to-back BRAF dimer that activates MEK1. Cryo-electron microscopy of full-length protein complexes Nature High 31581174
2009 MEK1 forms a previously undiscovered heterodimer with MEK2. ERK-mediated phosphorylation of MEK1 at Thr292 (a residue absent in MEK2) negatively regulates the MEK1-MEK2 heterodimer, thereby downregulating MEK2-dependent ERK signaling. Loss of MEK1 (knockout embryos and mice) stabilizes phosphorylation of both MEK2 and ERK, demonstrating that MEK1 is the crucial modulator of MEK/ERK signaling duration and strength. Co-immunoprecipitation, MEK1 knockout mouse model, phosphosite mutagenesis, in vivo ERK/MEK phosphorylation assays Nature structural & molecular biology High 19219045
1994 MEK1 (MKK1) is negatively regulated by phosphorylation of Thr286 and Thr292 in vitro and in vivo. p34cdc2 catalyzes phosphorylation of both threonine residues and inactivates MEK1 enzymatic activity, providing a mechanism for cell-cycle-dependent downregulation of MEK1. In vitro kinase assay with p34cdc2, in vivo phosphorylation mapping, site-directed mutagenesis Molecular and cellular biology High 8114697
2011 MEK1 is activated by RAF-catalyzed phosphorylation of S218 and S222 in its activation segment. Phosphorylation of S212 in the activation segment is inhibitory. Active ERK catalyzes a feedback inhibitory phosphorylation of MEK1 at T292, serving to downregulate the pathway. The KSR scaffold is required both structurally and catalytically for MEK activation. Biochemical analysis, phosphosite mapping, review of kinase assay and mutagenesis data from multiple studies Biochemical and biophysical research communications Medium 22177953
1999 Nuclear localization of MEK1 is promoted by serum stimulation and by G2-M progression. Nuclear uptake requires phosphorylation (or negatively charged residues) at the activation lip (Ser218, Ser222) but not catalytic activity. Disruption of the MEK1 nuclear export signal (NES, residues 32–37) enhances nuclear accumulation. Signaling downstream of MEK (ERK activation) is also necessary for nuclear translocation. Fluorescence microscopy of NES-mutant and activation-site-mutant MEK1 constructs in transfected cells, pharmacological inhibitor (UO126) treatment, cell-cycle synchronization The Journal of biological chemistry Medium 10037701
2014 H2S S-sulfhydrates MEK1 at Cys341, which activates ERK1/2 phosphorylation and promotes nuclear translocation of phospho-ERK1/2. Nuclear ERK1/2 then directly interacts with and activates PARP-1, which recruits XRCC1 and DNA ligase III to DNA breaks. Mutation of MEK1 Cys341 abolishes ERK phosphorylation and PARP-1 activation, linking H2S-induced MEK1 S-sulfhydration to DNA damage repair. S-sulfhydration assay, site-directed mutagenesis (C341), Co-IP of MEK1 with PARP-1, immunofluorescence of nuclear ERK, comet/DNA damage assays EMBO reports Medium 24778456
2021 SIRT2 deacetylase downregulation increases acetylation of MEK1 at Lys175, resulting in ERK activation and subsequent activation of the pro-fission factor DRP1, linking SIRT2-MEK1-ERK-DRP1 axis to mitochondrial dynamics and somatic cell reprogramming (Warburg effect). Acetylation mass spectrometry, MEK1-K175 acetylation site identification, ERK and DRP1 phosphorylation assays upon SIRT2 knockdown/overexpression, mitochondrial morphology imaging Cell reports Medium 34965411
2021 Arrestin-2 scaffolds the cRAF-MEK1-ERK2 signaling cascade. Basal and active arrestin-2 interact with cRAF, whereas only active arrestin-2 interacts with MEK1 and ERK2. The ATP-binding status of MEK1 affects arrestin-2 interaction: ATP-bound MEK1 interacts with arrestin-2, while only empty ERK2 binds arrestin-2. The relative positions of cRAF, MEK1, and ERK2 on arrestin-2 facilitate sequential phosphorylation. Hydrogen/deuterium exchange-mass spectrometry, tryptophan-induced bimane fluorescence quenching, NMR; binding interface mapping Proceedings of the National Academy of Sciences of the United States of America High 34507982
2018 Cancer-associated activating mutations in MEK1 fall into two mechanistic classes: (1) mutations that relieve inhibitory interactions with the helix A region (sensitive to traditional allosteric MEK inhibitors), and (2) in-frame deletions of the β3-αC loop that enhance MEK1 homodimerization, promoting intradimer cross-phosphorylation of the activation loop and conferring resistance to allosteric MEK inhibitors. MEK1 dimerization is required both for its activation by RAF and for its catalytic activity toward ERK. In vitro kinase assays, MEK1 dimerization assays, mutagenesis, in vivo tumor xenograft models, inhibitor sensitivity assays Science signaling High 30377225
2022 Molecular dynamics simulations clarified how B-Raf and KSR1 activate MEK1: the proline-rich (P-rich) loop of MEK1 plays a decisive role in MEK1 activation loop (A-loop) phosphorylation. In inactive B-Raf/MEK1 heterodimer, B-Raf's collapsed A-loop interacts with the P-rich loop and A-loop of MEK1 to minimize MEK1 A-loop fluctuation. In the active B-Raf/MEK1 heterodimer, P-rich loop movement reduces interactions with MEK1 A-loop, increasing flexibility and bringing Ser222 closer to ATP. B-Raf αG-helix Arg662 orients Ser218 toward ATP; KSR1 has Ala826 at the equivalent position, resulting in a more flexible MEK1 A-loop. Molecular dynamics simulations of B-Raf/MEK1 and KSR1/MEK1 complexes Cellular and molecular life sciences : CMLS Low 35508574
2007 WNK2 inhibits cell proliferation by negatively modulating MEK1 activity. WNK2 depletion activates ERK1/2 via MEK1 phosphorylation at Ser298, an effect that occurs downstream of Raf kinases. A kinase-dead WNK2-K207M mutant also activates ERK1/2, indicating WNK2 catalytic activity is required for suppression of the MEK1/ERK1/2 pathway. RNAi knockdown, kinase-dead mutant expression, Western blot for pMEK1(S298) and pERK1/2 in HeLa and HT29 cells Oncogene Medium 17667937
2015 Polo-like kinase 1 (Plk1) controls MEK1/2 phosphorylation and ERK1/2 activation downstream of PDGF in airway smooth muscle cells. Plk1 knockdown attenuates PDGF-induced MEK1/2 and ERK1/2 phosphorylation without affecting Raf-1 or AKT phosphorylation. Expression of non-phosphorylatable T210A-Plk1 also inhibits MEK1/2 phosphorylation, indicating Plk1 kinase activity is required upstream of MEK1/2. Stable Plk1 knockdown cells, non-phosphorylatable Plk1 mutant (T210A), immunoblot for pMEK1/2 and pERK1/2 Respiratory research Low 26242183
2002 MEKK1 ubiquitylation (via its PHD/E3 ligase domain) inhibits MEKK1's ability to phosphorylate MKK1 and MKK4, resulting in suppressed ERK1/2 and JNK activation. Mutation of Cys441 in the MEKK1 PHD domain blocks ubiquitylation and preserves MEKK1-catalyzed MKK1/MKK4 phosphorylation. MEKK1 kinase activity is required for its own ubiquitylation. In vitro kinase assay, ubiquitylation assay, site-directed mutagenesis (C441A), ERK1/2 and JNK activation assays The Journal of biological chemistry Medium 12456688
2015 MAP2K1 mutations identified in LCH (C121S, C121S/G128D, 56_61QKQKVG>R deletion) constitutively phosphorylate ERK in in vitro kinase assays. The C121S/G128D and 56_61QKQKVG>R variants were resistant to the MEK inhibitor trametinib in vitro, establishing that specific MAP2K1 mutations confer both constitutive ERK activation and MEK inhibitor resistance. In vitro kinase assay, trametinib resistance assay, targeted next-generation sequencing Genes, chromosomes & cancer Medium 25899310
2019 MEK1 V211D gatekeeper mutation, acquired during clinical treatment with allosteric MEK inhibitor binimetinib, causes RAF-independent MEK1 activity, increases MEK1 catalytic activity, and reduces MEK1 affinity for binimetinib and all tested allosteric MEK inhibitors. V211D MEK1 remains regulated by RAF but is sensitive to ATP-competitive MEK inhibitors. Whole-genome sequencing of patient tumor, MEK1 kinase activity assays, drug-binding affinity assays, drug sensitivity assays in vitro and in vivo Cancer discovery Medium 31227518
2004 In transgenic murine and human epidermis, MEK1 (but not MEK2) recapitulated RAS/RAF effects—increasing proliferation, integrin expression, and suppressing differentiation. A kinase-dead MEK1 mutant incapable of phosphorylating ERK retained the ability to mediate MEK1-driven epidermal proliferation, indicating MEK1 promotes the proliferative epithelial phenotype partly through a kinase-independent mechanism. Transgenic mouse and human epidermal tissue models with inducible MEK1/MEK2 and kinase-dead MEK1 (K97R) constructs; ERK phosphorylation, proliferation, and differentiation assays Cancer research Medium 15342384
1998 Constitutively active MEK1 (fused to estrogen receptor hormone-binding domain) drives S-phase entry, proliferation in low serum, morphological transformation, and anchorage-independent growth in NIH-3T3 cells. Activated MEK1 induces upregulation of cyclin D1 and downregulation of p27(Kip1), establishing a direct link between MEK1 activity and cell cycle machinery. Inducible constitutively active MEK1-ER fusion in NIH-3T3 cells; cell cycle analysis, cyclin D1/p27 Western blots, transformation assays The Journal of biological chemistry Medium 9582373
2004 MEK1 knockdown by RNAi leads to p21(cip1) induction and a senescence-like phenotype, and permanent MEK1 ablation reduces colony formation. In contrast, MEK2 deficiency induces cyclin D1 overexpression and CDK4/6 activation leading to nucleophosmin hyperphosphorylation and centrosome over-amplification. MEK1 and MEK2 thus differentially control the G1/S transition. RNA interference knockdown of MEK1 and MEK2 separately in human cells; cell cycle analysis, cyclin D1 and p21 immunoblots, colony formation assays The Journal of biological chemistry Medium 15284233
2017 Activating variants at MEK1 Phe53 are phosphorylated by RAF faster than wild-type MEK1 and show constitutive activity, but the maximal activities of fully phosphorylated wild-type and mutant enzymes are indistinguishable. The activating substitutions destabilize the inactive conformation of MEK1, increasing susceptibility to RAF-mediated phosphorylation. In zebrafish, developmental effects of activating variants reflect joint control by the negative regulatory region and activating phosphorylation. In vitro Raf phosphorylation kinetics assay, MEK1 kinase activity assay, zebrafish developmental assays with activating MEK1 variants The Journal of biological chemistry Medium 29018093
2015 Cdk5 phosphorylates MEK1 only at Thr292, whereas ERK and Cdk1 phosphorylate both Thr292 and Thr286. Both sites interact in a kinase-specific manner to inhibit MEK1's ability to activate ERK. Thr292 phosphorylation is regulated by cAMP-dependent signaling in mouse striatum consistent with negative feedback inhibition following ERK activation. Protein phosphatase 1 and 2A contribute to basal phosphorylation at both sites. In vitro kinase assays with Cdk5, ERK, Cdk1 and MEK1; phosphosite mapping; immunoprecipitation from mouse brain tissue; pharmacological inhibitor studies The Journal of biological chemistry Medium 25971971
2021 MEK1 deletion (LysMCre × Mek1fl) in myeloid cells results in failure to resolve LPS-induced acute lung injury, with alveolar macrophages lacking MEK1 showing increased MEK2 and ERK1/2 activation on day 4 of injury, demonstrating that MEK1 specifically limits the duration of macrophage proinflammatory ERK signaling to promote resolution. Conditional Mek1 knockout mice (LysMCre), LPS-induced acute lung injury model, ERK1/2 and MEK2 phosphorylation assays in alveolar macrophages JCI insight Medium 31801908
2016 Genetic deletion of MEK1 in macrophages (LysMCre+/+Mek1fl/fl) significantly increases expression of IL-4/IL-13 (M2)-responsive genes and enhances macrophage efferocytosis of apoptotic cells, associated with increased expression of Mertk, Tyro3, and Abca1. MEK1 deletion-enhanced M2 polarization is dependent on STAT6 signaling (MEKi enhanced STAT6 phosphorylation), while enhanced efferocytosis is independent of polarization and STAT6. Conditional Mek1 KO (LysMCre), pharmacological MEKi, STAT6 knockout validation, in vivo peritoneal efferocytosis assay, LPS lung injury model Journal of immunology Medium 28003382
2021 MEK1 SUMOylation is enhanced by monensin treatment in ovarian cancer cells. Increased MEK1 SUMOylation correlates with suppression of the MEK-ERK pathway and inhibition of cell proliferation and invasion both in vitro and in xenograft models. SUMOylation assay in vitro and in vivo, xenograft tumor model, proliferation/invasion assays Experimental and therapeutic medicine Low 34650638
2004 Transgenic mice with cardiac-specific activated MEK1-ERK1/2 signaling are largely resistant to ischemia-reperfusion injury (reduced DNA laddering, TUNEL-positive cells, preserved hemodynamic function). Erk2+/- mice showed enhanced infarction and apoptosis, establishing that MEK1-ERK2 signaling is causally required for cardioprotection against ischemia-reperfusion injury. MEK1 cardiac transgenic mice, Erk1 null and Erk2 heterozygous knockout mice, ischemia-reperfusion model, TUNEL, DNA laddering, pressure-volume loops Circulation Medium 15096454

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2015 MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road. Nature reviews. Cancer 495 26399658
1999 MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia. Proceedings of the National Academy of Sciences of the United States of America 409 10536014
2011 Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma. Nature genetics 339 22197931
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
2014 High prevalence of somatic MAP2K1 mutations in BRAF V600E-negative Langerhans cell histiocytosis. Blood 277 24982505
1993 MKK1 and MKK2, which encode Saccharomyces cerevisiae mitogen-activated protein kinase-kinase homologs, function in the pathway mediated by protein kinase C. Molecular and cellular biology 274 8386320
2019 Architecture of autoinhibited and active BRAF-MEK1-14-3-3 complexes. Nature 241 31581174
2011 MEK1/2 dual-specificity protein kinases: structure and regulation. Biochemical and biophysical research communications 215 22177953
2004 MEK1-ERK2 signaling pathway protects myocardium from ischemic injury in vivo. Circulation 203 15096454
2017 Mutually exclusive recurrent KRAS and MAP2K1 mutations in Rosai-Dorfman disease. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 201 28664935
2009 A major role of the MEKK1-MKK1/2-MPK4 pathway in ROS signalling. Molecular plant 191 19529823
2015 MAP2K1 and MAP3K1 mutations in Langerhans cell histiocytosis. Genes, chromosomes & cancer 162 25899310
2009 A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal. Nature structural & molecular biology 139 19219045
2014 S-sulfhydration of MEK1 leads to PARP-1 activation and DNA damage repair. EMBO reports 128 24778456
2014 MAP2K1 (MEK1) Mutations Define a Distinct Subset of Lung Adenocarcinoma Associated with Smoking. Clinical cancer research : an official journal of the American Association for Cancer Research 113 25351745
2000 IL-2 activation of NK cells: involvement of MKK1/2/ERK but not p38 kinase pathway. Journal of immunology (Baltimore, Md. : 1950) 110 10843677
2015 MEK1/2 Inhibitors: Molecular Activity and Resistance Mechanisms. Seminars in oncology 106 26615130
2004 MEK1 and MEK2, different regulators of the G1/S transition. The Journal of biological chemistry 97 15284233
2016 Allosteric MEK1/2 inhibitors including cobimetanib and trametinib in the treatment of cutaneous melanomas. Pharmacological research 95 27956260
2015 A Phosphoproteomic Comparison of B-RAFV600E and MKK1/2 Inhibitors in Melanoma Cells. Molecular & cellular proteomics : MCP 89 25850435
2021 Dual Inhibition of DKC1 and MEK1/2 Synergistically Restrains the Growth of Colorectal Cancer Cells. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 84 34026451
2014 MEK1/2 inhibitors in the treatment of gynecologic malignancies. Gynecologic oncology 84 24434059
2002 Ubiquitylation of MEKK1 inhibits its phosphorylation of MKK1 and MKK4 and activation of the ERK1/2 and JNK pathways. The Journal of biological chemistry 78 12456688
1994 Mitogen-activated protein kinase kinase 1 (MKK1) is negatively regulated by threonine phosphorylation. Molecular and cellular biology 78 8114697
2020 Phytophthora infestans RXLR effector PITG20303 targets a potato MKK1 protein to suppress plant immunity. The New phytologist 76 32772378
2016 Chromosome Synapsis Alleviates Mek1-Dependent Suppression of Meiotic DNA Repair. PLoS biology 75 26870961
2023 Erianin suppresses constitutive activation of MAPK signaling pathway by inhibition of CRAF and MEK1/2. Signal transduction and targeted therapy 74 36872366
2001 The role of MKK1/2 kinase activity in human cytomegalovirus infection. The Journal of general virology 73 11172089
1998 An analysis of Mek1 signaling in cell proliferation and transformation. The Journal of biological chemistry 71 9582373
1999 Nuclear localization of mitogen-activated protein kinase kinase 1 (MKK1) is promoted by serum stimulation and G2-M progression. Requirement for phosphorylation at the activation lip and signaling downstream of MKK. The Journal of biological chemistry 70 10037701
2011 MicroRNA-1826 targets VEGFC, beta-catenin (CTNNB1) and MEK1 (MAP2K1) in human bladder cancer. Carcinogenesis 69 22049531
2007 Protein kinase WNK2 inhibits cell proliferation by negatively modulating the activation of MEK1/ERK1/2. Oncogene 69 17667937
2004 Mek1 alters epidermal growth and differentiation. Cancer research 69 15342384
2009 Spectrum of MEK1 and MEK2 gene mutations in cardio-facio-cutaneous syndrome and genotype-phenotype correlations. European journal of human genetics : EJHG 67 19156172
2017 Mutations of MAP2K1 are frequent in pediatric-type follicular lymphoma and result in ERK pathway activation. Blood 65 28533310
2000 Wnt1 and MEK1 cooperate to promote cyclin D1 accumulation and cellular transformation. The Journal of biological chemistry 65 10748202
2016 BRAF and MAP2K1 mutations in Langerhans cell histiocytosis: a study of 50 cases. Human pathology 64 26980021
2014 The mitogen-activated protein kinase cascade MKK1-MPK4 mediates salt signaling in rice. Plant science : an international journal of experimental plant biology 64 25219319
1996 Constitutively active mitogen-activated protein kinase kinase 1 (MAPKK1) and MAPKK2 mediate similar transcriptional and morphological responses. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 63 8822208
2022 CircNFIB inhibits tumor growth and metastasis through suppressing MEK1/ERK signaling in intrahepatic cholangiocarcinoma. Molecular cancer 61 35039066
2019 YAP1 Mediates Resistance to MEK1/2 Inhibition in Neuroblastomas with Hyperactivated RAS Signaling. Cancer research 58 31672841
2021 SIRT2 regulates mitochondrial dynamics and reprogramming via MEK1-ERK-DRP1 and AKT1-DRP1 axes. Cell reports 56 34965411
2013 Increased AKT or MEK1/2 activity influences progesterone receptor levels and localization in endometriosis. The Journal of clinical endocrinology and metabolism 56 24064688
2011 MicroRNA-1826 directly targets beta-catenin (CTNNB1) and MEK1 (MAP2K1) in VHL-inactivated renal cancer. Carcinogenesis 54 22180573
2019 Disruption of the MAMP-Induced MEKK1-MKK1/MKK2-MPK4 Pathway Activates the TNL Immune Receptor SMN1/RPS6. Plant & cell physiology 45 30590768
2018 Activating mutations in MEK1 enhance homodimerization and promote tumorigenesis. Science signaling 45 30377225
2005 Effects of active MEK1 expression in vivo. Cancer letters 44 16253755
2020 Chloroquine Sensitizes GNAQ/11-mutated Melanoma to MEK1/2 Inhibition. Clinical cancer research : an official journal of the American Association for Cancer Research 43 32933997
2019 The meiotic-specific Mek1 kinase in budding yeast regulates interhomolog recombination and coordinates meiotic progression with double-strand break repair. Current genetics 43 30671596
2021 Ethylene-induced stomatal closure is mediated via MKK1/3-MPK3/6 cascade to EIN2 and EIN3. Journal of integrative plant biology 42 33605510
2021 Scaffolding mechanism of arrestin-2 in the cRaf/MEK1/ERK signaling cascade. Proceedings of the National Academy of Sciences of the United States of America 42 34507982
2019 Trametinib in the treatment of multiple malignancies harboring MEK1 mutations. Cancer treatment reviews 42 31715422
2019 Intramuscular fast-flow vascular anomaly contains somatic MAP2K1 and KRAS mutations. Angiogenesis 41 31486960
1999 Mitogen-activated protein kinase cascade and transcription factors: the opposite role of MKK3/6-p38K and MKK1-MAPK. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association 41 10048449
2021 Research progress of MEK1/2 inhibitors and degraders in the treatment of cancer. European journal of medicinal chemistry 40 33774345
2015 MiR-449a suppresses cell invasion by inhibiting MAP2K1 in non-small cell lung cancer. American journal of cancer research 39 26609480
2012 Cot/tpl2-MKK1/2-Erk1/2 controls mTORC1-mediated mRNA translation in Toll-like receptor-activated macrophages. Molecular biology of the cell 39 22675026
2019 V211D Mutation in MEK1 Causes Resistance to MEK Inhibitors in Colon Cancer. Cancer discovery 37 31227518
2016 MEK1/2 Inhibition Promotes Macrophage Reparative Properties. Journal of immunology (Baltimore, Md. : 1950) 37 28003382
2017 Combined kinase inhibitors of MEK1/2 and either PI3K or PDGFR are efficacious in intracranial triple-negative breast cancer. Neuro-oncology 35 28486691
2007 Retrophosphorylation of Mkk1 and Mkk2 MAPKKs by the Slt2 MAPK in the yeast cell integrity pathway. The Journal of biological chemistry 35 17711850
1995 Characterization of domains in the yeast MAP kinase Slt2 (Mpk1) required for functional activity and in vivo interaction with protein kinases Mkk1 and Mkk2. Molecular microbiology 35 8596433
2019 miR-330-3p suppresses liver cancer cell migration by targeting MAP2K1. Oncology letters 34 31289502
2010 Mek1 kinase governs outcomes of meiotic recombination and the checkpoint response. Current biology : CB 32 20888230
2021 The CaM1-associated CCaMK-MKK1/6 cascade positively affects lateral root growth via auxin signaling under salt stress in rice. Journal of experimental botany 30 34129028
2018 Distinct Clinical and Pathological Features of Melorheostosis Associated With Somatic MAP2K1 Mutations. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 29 30138550
2016 BRAFV600E and MAP2K1 mutations in Langerhans cell histiocytosis occur predominantly in children. Hematological oncology 29 27597420
2020 Endothelial MAP2K1 mutations in arteriovenous malformation activate the RAS/MAPK pathway. Biochemical and biophysical research communications 28 32703450
2017 miR-322 stabilizes MEK1 expression to inhibit RAF/MEK/ERK pathway activation in cartilage. Development (Cambridge, England) 28 28851708
2022 The mechanism of activation of MEK1 by B-Raf and KSR1. Cellular and molecular life sciences : CMLS 27 35508574
2022 Cellular and Molecular Mechanisms of MEK1 Inhibitor-Induced Cardiotoxicity. JACC. CardioOncology 27 36444237
2019 MEK1 regulates pulmonary macrophage inflammatory responses and resolution of acute lung injury. JCI insight 27 31801908
2023 High-Throughput Functional Evaluation of MAP2K1 Variants in Cancer. Molecular cancer therapeutics 26 36442478
2015 Plk1 regulates MEK1/2 and proliferation in airway smooth muscle cells. Respiratory research 26 26242183
2015 Wide-Ranging Effects of the Yeast Ptc1 Protein Phosphatase Acting Through the MAPK Kinase Mkk1. Genetics 26 26546002
2022 Selumetinib: a selective MEK1 inhibitor for solid tumor treatment. Clinical and experimental medicine 25 35171389
2020 Melanocytic Neoplasms With MAP2K1 in Frame Deletions and Spitz Morphology. The American Journal of dermatopathology 25 33289976
2018 The MEK1/2-ERK Pathway Inhibits Type I IFN Production in Plasmacytoid Dendritic Cells. Frontiers in immunology 24 29535732
2021 Monensin suppresses cell proliferation and invasion in ovarian cancer by enhancing MEK1 SUMOylation. Experimental and therapeutic medicine 22 34650638
2014 Intrinsic and acquired resistance to MEK1/2 inhibitors in cancer. Biochemical Society transactions 22 25109957
2024 Activation of endogenous retroviruses and induction of viral mimicry by MEK1/2 inhibition in pancreatic cancer. Science advances 21 38536927
2020 Bta-miR-34b inhibits proliferation and promotes apoptosis via the MEK/ERK pathway by targeting MAP2K1 in bovine primary Sertoli cells. Journal of animal science 20 32954430
2018 Mek1Y130C mice recapitulate aspects of human cardio-facio-cutaneous syndrome. Disease models & mechanisms 20 29590634
2012 Tumour cell responses to MEK1/2 inhibitors: acquired resistance and pathway remodelling. Biochemical Society transactions 20 22260668
2021 MAP2K1-Mutated Melanocytic Neoplasms With a SPARK-Like Morphology. The American Journal of dermatopathology 19 33264134
2015 Regulation of ERK Kinase by MEK1 Kinase Inhibition in the Brain. The Journal of biological chemistry 19 25971971
2017 How activating mutations affect MEK1 regulation and function. The Journal of biological chemistry 18 29018093
2016 Allosteric modulators of MEK1: drug design and discovery. Chemical biology & drug design 18 27115708
2023 Tumor Cell Resistance to the Inhibition of BRAF and MEK1/2. International journal of molecular sciences 17 37834284
2020 Circular RNA DHX33 promotes malignant behavior in ccRCC by targeting miR-489-3p/MEK1 axis. Aging 17 32717723
2018 Frequency of MAP2K1, TP53, and U2AF1 Mutations in BRAF-mutated Langerhans Cell Histiocytosis: Further Characterizing the Genomic Landscape of LCH. The American journal of surgical pathology 17 29649018
2023 Banana MKK1 modulates fruit ripening via the MKK1-MPK6-3/11-4-bZIP21 module. Cell reports 16 37498740
2022 Discovery of Coumarin-Based MEK1/2 PROTAC Effective in Human Cancer Cells. ACS medicinal chemistry letters 16 36655129
2015 Direct interaction of Ste11 and Mkk1/2 through Nst1 integrates high-osmolarity glycerol and pheromone pathways to the cell wall integrity MAPK pathway. FEBS letters 16 26787465
2013 MEK1 and MEK2 differentially control the duration and amplitude of the ERK cascade response. Physical biology 16 23735655
2007 MEK1 and protein phosphatase 4 coordinate Dictyostelium development and chemotaxis. Molecular and cellular biology 16 17353263
2023 Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer. Nature communications 15 37816716
2021 Recurrent Somatic MAP2K1 Mutations in Papillary Thyroid Cancer and Colorectal Cancer. Frontiers in oncology 15 34046359
2019 MAP2K1 is a potential therapeutic target in erlotinib resistant head and neck squamous cell carcinoma. Scientific reports 15 31827134
2016 Variability in clinical and neuropsychological features of individuals with MAP2K1 mutations. American journal of medical genetics. Part A 15 27862862

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