Affinage

MAP2K1

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

Length
393 aa
Mass
43.4 kDa
Annotated
2026-04-28
100 papers in source corpus 32 papers cited in narrative 32 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAP2K1 (MEK1) is the central dual-specificity kinase of the RAS-RAF-MEK-ERK cascade, serving as a signaling bottleneck that integrates upstream activating signals and negative feedback to control cell proliferation, differentiation, survival, and tissue-specific morphogenesis. RAF kinases phosphorylate MEK1 at S218 and S222 on a KSR scaffold to activate it, whereupon MEK1 phosphorylates its sole substrates ERK1/2; MEK1 activity is further tuned by activating modifications including PAK1-mediated S298 phosphorylation, acetylation at K175 (reversed by SIRT2), S-sulfhydration at C341, and copper delivery by the chaperone CCS, while inhibitory phosphorylation at T292 (by ERK, Cdk5) and T286 (by ERK, Cdk1) provides negative feedback (PMID:8090753, PMID:22177953, PMID:25971971, PMID:34965411, PMID:24778456, PMID:34715128, PMID:12876277). MEK1 heterodimerizes with MEK2 and uniquely restrains MEK2-ERK signaling through the T292 feedback site absent in MEK2, a mechanism essential for resolution of inflammation and proper placental development (PMID:19219045, PMID:31801908, PMID:16887817). Somatic gain-of-function MAP2K1 mutations in the negative-regulatory helix A or β3-αC loop drive constitutive ERK activation and are causative in melorheostosis and recurrent across cancers, with specific mutations conferring resistance to allosteric MEK inhibitors (PMID:29643386, PMID:30377225, PMID:19915144).

Mechanistic history

Synthesis pass · year-by-year structured walk · 15 steps
  1. 1994 High

    Establishing that S218/S222 phosphorylation is the activating switch for MEK1 kinase activity resolved how RAF transmits signal to the MAPK cascade.

    Evidence Phosphomimetic mutagenesis (S218D/S222D) in vitro and in COS-7 cells showed >100-fold activation of MAP kinase phosphorylation

    PMID:8090753

    Open questions at the time
    • Upstream kinase specificity (which RAF isoform) not resolved
    • Scaffold requirements for activation not addressed
  2. 1998 High

    Demonstrating that MEK1 activation is sufficient to drive S-phase entry and transformation through cyclin D1 upregulation and p27 downregulation linked MEK1 directly to cell cycle control.

    Evidence Inducible MEK1-ER fusion in NIH-3T3 fibroblasts drove proliferation, anchorage-independent growth, and cell cycle protein changes

    PMID:10748202 PMID:9124614 PMID:9582373

    Open questions at the time
    • Whether MEK1 acts through ERK-dependent transcription of cyclin D1 versus post-translational stabilization not fully resolved
    • Wnt1 cooperation mechanism only partially defined
  3. 2000 High

    Cardiac-specific activated MEK1 in mice revealed that MEK1-ERK signaling drives compensated hypertrophy and cardioprotection, establishing a tissue-specific pro-survival role distinct from oncogenic transformation.

    Evidence Transgenic mice with cardiac-restricted activated MEK1; echocardiography, isolated hearts, TUNEL assays; confirmed by ischemia-reperfusion protection

    PMID:11101507 PMID:15096454

    Open questions at the time
    • Downstream ERK substrates mediating cardioprotection not identified
    • Whether anti-apoptotic effect is direct or secondary to hypertrophy unclear
  4. 2003 High

    Identification of PAK1 as a kinase that primes MEK1 at S298 upon integrin engagement revealed how adhesion signals converge on the MAPK cascade at the level of MEK1.

    Evidence Phospho-specific antibodies, dominant-negative PAK1, fibronectin adhesion assays, and localization to adhesion structures

    PMID:12876277

    Open questions at the time
    • Whether S298 phosphorylation alters MEK1 conformation or simply scaffold recruitment not determined
    • Contribution in non-adherent cells unknown
  5. 2004 High

    Discovery that MEK1 promotes mitotic Golgi fragmentation through Plk3 activation and that kinase-dead MEK1 retains epidermal proliferative activity revealed kinase-dependent and kinase-independent functions of MEK1.

    Evidence Plk3-MEK1 pull-down with kinase-dead mutant epistasis; MEK1/MEK2 transgenic epidermis showing kinase-dead MEK1 retains proliferative capacity

    PMID:15021912 PMID:15342384

    Open questions at the time
    • Identity of kinase-independent MEK1 interactors in epidermis unknown
    • Whether Plk3 is a direct MEK1 substrate not definitively shown
  6. 2006 High

    Map2k1 knockout revealed an essential, non-redundant role for MEK1 in extra-embryonic ectoderm for placental development, separating it functionally from MEK2.

    Evidence Map2k1 null mice with tetraploid rescue and embryo-specific Cre deletion

    PMID:16887817

    Open questions at the time
    • Whether MEK2 cannot compensate due to expression level or unique MEK1 interactions not resolved
  7. 2009 High

    The MEK1-MEK2 heterodimer and the unique T292 feedback phosphorylation site on MEK1 established that MEK1 acts as a negative regulator of MEK2-ERK signaling, resolving why MEK1 and MEK2 are non-interchangeable.

    Evidence Mek1 KO embryos and mice; T292 phospho-mutants; reciprocal Co-IP and signaling assays

    PMID:19219045

    Open questions at the time
    • Structural basis of heterodimer-mediated MEK2 suppression not defined
    • Whether MEK1-MEK2 stoichiometry varies across tissues not addressed
  8. 2009 High

    Systematic mutagenesis of MEK1's allosteric pocket identified resistance mutations to MEK and BRAF inhibitors, defining the drug-binding mechanism and clinical escape routes.

    Evidence Random mutagenesis screen with massively parallel sequencing; AZD6244 and PLX4720 resistance assays

    PMID:19915144

    Open questions at the time
    • Whether all resistance mutations act through the same conformational change unclear
    • In vivo confirmation in patient cohorts limited at this stage
  9. 2014 High

    Discovery that H2S S-sulfhydrates MEK1 at C341 to activate ERK nuclear translocation and PARP-1-dependent DNA repair identified a novel gasotransmitter-regulated PTM linking MEK1 to the DNA damage response.

    Evidence S-sulfhydration assay; C341 mutagenesis; ERK-PARP-1 co-IP; DNA repair assays in endothelial cells

    PMID:24778456

    Open questions at the time
    • Physiological contexts where H2S-MEK1 signaling dominates not established
    • Whether C341 modification affects MEK1-ERK binding kinetics unknown
  10. 2015 High

    Mapping of Cdk5/Cdk1/ERK-mediated inhibitory phosphorylation at T286 and T292 and their regulation by PP1/PP2A in brain tissue established a multi-kinase negative feedback architecture for MEK1 in neurons.

    Evidence In vitro kinase reconstitution with Cdk5, ERK, Cdk1; phospho-specific antibodies in brain fractions; PP1/PP2A inhibitors

    PMID:25971971

    Open questions at the time
    • Whether T286 and T292 phosphorylation are independent or cooperative events not resolved
    • Behavioral consequences of specifically blocking these sites not tested
  11. 2018 High

    Classification of cancer-associated MEK1 mutations into helix-A and β3-αC-loop-deletion classes, and demonstration that loop deletions enhance homodimerization and intradimer cross-phosphorylation, revealed the structural basis for oncogenic MEK1 activation and explained differential inhibitor sensitivity.

    Evidence Structural/biochemical analysis with dimerization mutants; in vitro kinase assays; trametinib sensitivity

    PMID:25899310 PMID:29018093 PMID:30377225

    Open questions at the time
    • Crystal structure of the activated homodimer not available
    • Whether homodimer-driven activation occurs physiologically or only in mutant contexts unknown
  12. 2018 High

    Identification of somatic MAP2K1 mutations (Q56P, K57E, K57N) as the cause of melorheostosis established the first Mendelian bone disease driven by activating MEK1 variants.

    Evidence Whole exome sequencing of affected bone; patient-derived osteoblast cultures with elevated p-ERK and impaired mineralization

    PMID:29643386

    Open questions at the time
    • Why bone overgrowth is mosaic and regional not explained mechanistically
    • Whether MEK inhibitor therapy can reverse established lesions untested
  13. 2019 High

    Cryo-EM structures of the full-length BRAF-MEK1-14-3-3 complex revealed the autoinhibited and active conformations, showing how 14-3-3 controls BRAF dimerization and MEK1 access.

    Evidence Cryo-EM of BRAF-MEK1-14-3-3 complexes at near-atomic resolution with phosphosite mapping

    PMID:31581174

    Open questions at the time
    • Whether MEK1 undergoes conformational change upon release from autoinhibited complex not resolved
    • Dynamics of complex assembly/disassembly in living cells unknown
  14. 2019 High

    Demonstrating that myeloid MEK1 deletion impairs resolution of lung inflammation by derepressing MEK2-ERK signaling confirmed the MEK1-as-brake model in an immune context in vivo.

    Evidence Conditional myeloid Mek1 KO with LPS-induced lung injury; phospho-ERK and phospho-MEK2 analysis in alveolar macrophages

    PMID:31801908

    Open questions at the time
    • Whether pharmacologic MEK1-selective activation could accelerate inflammation resolution not tested
    • Downstream transcriptional targets of derepressed MEK2 in macrophages not identified
  15. 2021 High

    Multiple discoveries in 2021 expanded the regulatory landscape of MEK1: CCS was identified as the copper chaperone delivering Cu to MEK1, SIRT2 was shown to deacetylate K175 to restrain ERK activation, and arrestin-2 was mapped as a scaffold that recruits MEK1 in its ATP-bound form for sequential MAPK cascade activation.

    Evidence SPR/BioID for CCS-MEK1 binding; SIRT2 KO with K175 mutagenesis; HDX-MS/NMR for arrestin-2-MEK1 interface

    PMID:34507982 PMID:34715128 PMID:34965411

    Open questions at the time
    • Whether copper binding and K175 acetylation are coordinated or independent regulatory inputs unknown
    • Stoichiometry of arrestin-2/MEK1 complex in native GPCR signaling not determined

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural basis of MEK1-MEK2 heterodimer-mediated suppression, the full inventory of kinase-independent MEK1 functions, and how tissue-specific PTM combinations (sulfhydration, acetylation, copper binding, SUMOylation) are integrated to tune ERK output in different physiological contexts.
  • No high-resolution structure of MEK1-MEK2 heterodimer available
  • Kinase-independent interaction partners not identified
  • Quantitative models of multi-PTM regulation lacking

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
Localization
GO:0005829 cytosol 2 GO:0005794 Golgi apparatus 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 6 R-HSA-1266738 Developmental Biology 2 R-HSA-1640170 Cell Cycle 2 R-HSA-168256 Immune System 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-73894 DNA Repair 1
Partners
ARRB1BRAFCCSMAP2K2MAPK1MAPK3PAK1RAF1
Complex memberships
Arrestin-2-cRaf-MEK1-ERK2BRAF-MEK1-14-3-3MEK1-MEK2 heterodimer

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 MEK1 (MAP2K1) is constitutively activated by introducing negatively charged residues (aspartate/glutamate) at phosphorylation sites S218 and S222, mimicking phosphorylation by Raf-1; S218D substitution alone activated MEK1 capacity to phosphorylate MAP kinase by >100-fold, and expression in COS-7 cells led to MAP kinase activation and increased cell mass. Site-directed mutagenesis of phosphorylation sites; in vitro kinase assay; transfection in COS-7 cells Proceedings of the National Academy of Sciences of the United States of America High 8090753
1997 MEK1 is required and sufficient for PDGF-induced ERK2 activation and DNA synthesis in airway smooth muscle cells; dominant-negative MEK1 inhibited PDGF-induced ERK2 activation and the MEK inhibitor PD-98059 blocked MEK1/ERK activation and reduced [3H]thymidine incorporation. Dominant-negative and constitutively active MEK1 transfection; in vitro kinase assay; pharmacologic inhibition with PD-98059; [3H]thymidine incorporation assay The American journal of physiology High 9124614
1998 Constitutively active MEK1 (Mek-ER fusion) drives S-phase entry, proliferation in low serum, morphological transformation, anchorage-independent growth, upregulation of cyclin D1, and downregulation of p27Kip1 in NIH-3T3 fibroblasts, establishing a direct link between MEK1 activity and the cell cycle machinery. Inducible constitutively active Mek1-ER fusion; ERK phosphorylation assay; cell proliferation and transformation assays; immunoblot for cyclin D1 and p27 The Journal of biological chemistry High 9582373
2000 Cardiac-restricted expression of activated MEK1 in transgenic mice activates ERK1/2 (but not p38 or JNK), induces compensated concentric hypertrophy with augmented cardiac function, and confers partial resistance to apoptotic stimuli, establishing MEK1-ERK1/2 as a pathway promoting physiologic hypertrophy. Transgenic mouse model with cardiac-restricted activated MEK1; echocardiography; isolated working heart preparation; adenovirus-infected neonatal cardiomyocytes; TUNEL/apoptosis assays The EMBO journal High 11101507
2003 PAK1 phosphorylates MEK1 at S298 upon fibronectin-mediated cell adhesion, and this phosphorylation is necessary for efficient MEK1 activation and subsequent ERK/MAPK activation; this event depends on FAK/Src signaling and localizes active Raf-MEK1-MAPK complexes to peripheral adhesion structures. Phospho-specific antibodies; dominant-negative PAK1; fibronectin adhesion assays; immunofluorescence localization; immunoprecipitation The Journal of cell biology High 12876277
2004 MEK1-ERK1/2 signaling protects the myocardium from ischemia-reperfusion injury in vivo; MEK1 transgenic mice were largely resistant to ischemia-reperfusion injury whereas Erk2+/− mice showed enhanced infarction and apoptosis. Genetic mouse models (MEK1 transgenic, Erk1 null, Erk2 heterozygous); ischemia-reperfusion surgery; TUNEL; DNA laddering; pressure-volume loop hemodynamics Circulation High 15096454
2004 MEK1 (but not MEK2) stimulates epidermal proliferation, increases integrin expression, and suppresses differentiation in transgenic mouse and human epidermis, partially through a kinase-independent mechanism (kinase-dead MEK1 retains ability to promote proliferation). Inducible MEK1/MEK2 transgenic murine and human epidermis; ERK phosphorylation assays; kinase-dead MEK1 mutant; proliferation and differentiation markers Cancer research High 15342384
2006 Map2k1 (MEK1) is required in extra-embryonic ectoderm for placental development; Map2k1-null embryos show labyrinthine hypoproliferation, apoptosis, hypovascularization, and abnormal syncytiotrophoblast localization. Embryo-specific Map2k1 deletion results in viable mice, demonstrating the placenta-specific essential role. Map2k1 knockout mice; tetraploid complementation rescue; embryo-specific Cre deletion; immunohistochemistry for ERK/MAPK activation Development (Cambridge, England) High 16887817
2009 MEK1 forms a heterodimer with MEK2, and Mek1 negatively regulates MEK2-dependent ERK signaling via ERK-mediated feedback phosphorylation of MEK1 on Thr292 (absent in MEK2). Loss of MEK1 stabilizes MEK2 and ERK phosphorylation, demonstrating that MEK1 and MEK2 have non-interchangeable roles in ERK signaling. Mek1 knockout embryos and mice; Thr292 phospho-specific mutants; reciprocal Co-IP; cell signaling assays; in vivo phosphorylation analysis Nature structural & molecular biology High 19219045
2009 Mutations in MEK1 that populate the allosteric drug-binding pocket or alpha-helix C, or disrupt the N-terminal negative regulatory helix A (e.g., P124L, Q56P), confer resistance to allosteric MEK inhibitors and cross-resistance to B-RAF inhibitors in melanoma. Random mutagenesis screen; massively parallel sequencing of resistant clones; in vitro resistance assays with AZD6244 and PLX4720; clinical tumor sequencing Proceedings of the National Academy of Sciences of the United States of America High 19915144
2011 MEK1 (MAP2K1) is activated by S218 and S222 phosphorylation by RAF kinases via a KSR scaffold. Phosphorylation of S212 in the activation segment is inhibitory. Active ERK catalyzes feedback inhibitory phosphorylation of MEK1 at T292, downregulating the pathway. Biochemical review integrating phosphorylation site mutagenesis, structural data, and kinase assays from primary literature Biochemical and biophysical research communications High 22177953
2014 H2S S-sulfhydrates MEK1 at cysteine 341, which activates ERK1/2 phosphorylation and facilitates its nuclear translocation where ERK directly activates PARP-1, leading to recruitment of XRCC1 and DNA ligase III for DNA damage repair. Mutation of MEK1 C341 abolishes these effects. S-sulfhydration assay; site-directed mutagenesis (C341); co-IP of ERK with PARP-1; nuclear translocation assays; DNA damage repair assays in human endothelial cells EMBO reports High 24778456
2015 MAP2K1 mutations including C121S, C121S/G128D, and an in-frame deletion (56_61QKQKVG>R) constitutively phosphorylate ERK in in vitro kinase assays; the C121S/G128D and deletion variants confer resistance to the MEK inhibitor trametinib in vitro. In vitro kinase assay of MAP2K1 mutants; trametinib resistance testing; targeted massively parallel sequencing Genes, chromosomes & cancer High 25899310
2018 Somatic MAP2K1 activating mutations (Q56P, K57E, K57N) cluster in the MEK1 negative regulatory domain, cause increased p-ERK1/2 in osteoblasts, enhanced cell proliferation, but inhibit BMP2-mediated osteoblast mineralization and differentiation, causing bone overgrowth in melorheostosis. Whole exome sequencing; osteoblast culture from affected/unaffected bone; flow cytometry for p-ERK1/2; BMP2-induced mineralization assays; immunohistochemistry Nature communications High 29643386
2018 Cancer-related activating MEK1 mutations fall into two groups: helix A-associated mutants that relieve inhibitory interactions, and in-frame β3-αC loop deletions that enhance MEK1 homodimerization and intradimer cross-phosphorylation of the activation loop. MEK1 dimerization is required both for RAF-mediated activation and for MEK1 catalytic activity toward ERK. Structural and biochemical analysis; in vitro kinase assays; MEK1 dimerization mutants; RAF activation assays; in vitro and in vivo resistance to MEK inhibitors Science signaling High 30377225
2019 Cryo-EM structures of full-length BRAF in complex with MEK1 and a 14-3-3 dimer reveal an autoinhibited state where the 14-3-3 cradle (binding pS365 and pS729 on BRAF) sequesters the BRAF cysteine-rich domain and blocks BRAF kinase domain dimerization. In the active state, a single 14-3-3 dimer bridges C-terminal pS729 sites of two BRAFs to drive back-to-back dimerization and MEK1 activation. Cryo-electron microscopy of full-length BRAF-MEK1-14-3-3 complexes; phosphoproteomic mapping Nature High 31581174
2019 MEK1 V211D gatekeeper mutation confers resistance to allosteric MEK inhibitors by increasing MEK1 catalytic activity and reducing drug affinity while remaining sensitive to ATP-competitive MEK inhibitors; the mutant is RAF-independent in activity but remains regulated by RAF. Patient tumor sequencing; in vitro kinase activity assays; drug binding affinity studies; cell line resistance experiments Cancer discovery High 31227518
2019 Myeloid MEK1 deletion 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, demonstrating that MEK1 restrains MEK2-ERK1/2 signaling during resolution of lung inflammation. Conditional myeloid Mek1 knockout (LysMCre × Mekfl); LPS-induced acute lung injury model; phospho-ERK and phospho-MEK2 immunoblots; alveolar macrophage analysis JCI insight High 31801908
2021 The copper chaperone CCS selectively binds to and facilitates copper transfer to MEK1; CCS mutants disrupting Cu(I) acquisition/exchange or a CCS small-molecule inhibitor reduce copper-stimulated MEK1 kinase activity, identifying CCS as the delivery mechanism for copper to MEK1 active site. Surface plasmon resonance; proximity-dependent biotin ligase (BioID); CCS mutagenesis; in vitro MEK1 kinase assays with Cu supplementation The Journal of biological chemistry High 34715128
2021 SIRT2 deacetylates MEK1 at Lys175; SIRT2 downregulation during somatic reprogramming increases MEK1 Lys175 acetylation, activating ERK and subsequently activating DRP1 to promote mitochondrial fission and metabolic reprogramming. Acetylation mapping by MS; SIRT2 KO/knockdown; MEK1 K175 mutants; ERK and DRP1 activation assays; mitochondrial morphology imaging Cell reports High 34965411
2021 Arrestin-2 scaffolds cRaf, MEK1, and ERK2 in a sequential manner: basal and active arrestin-2 interact with cRaf, while only active arrestin-2 interacts with MEK1 (in its ATP-bound form) and empty ERK2, facilitating sequential phosphorylation in the MAP kinase cascade. Hydrogen/deuterium exchange-mass spectrometry; tryptophan-induced bimane fluorescence quenching; NMR; nucleotide-state-dependent binding experiments Proceedings of the National Academy of Sciences of the United States of America High 34507982
2021 miR-322 stabilizes Mek1 mRNA in chondrocytes, raising MEK1 protein levels and dampening ERK1/2 phosphorylation; cartilage-specific loss of miR-322 in mice decreases MEK1 protein and increases RAF/MEK/ERK pathway activation, resulting in perinatal lethality from tracheal restriction. Transcriptome profiling; miR-322 target validation; cartilage-specific miR-322 knockout mice; MEK1 protein/mRNA analysis; ERK phosphorylation assays Development (Cambridge, England) High 28851708
2000 MEK1 cooperates with Wnt1 to promote cyclin D1 accumulation and S-phase entry in the absence of serum; activated MEK1 alone upregulates cyclin D1 and drives cellular transformation, and dominant-negative cyclin D1 inhibits Wnt1/MEK1-dependent S-phase entry. Co-expression of Wnt1 and activated MEK1 in NIH-3T3 cells; cyclin D1 immunoblot; GSK-3β activity assay; [3H]thymidine S-phase entry; dominant-negative cyclin D1 mutant The Journal of biological chemistry High 10748202
2010 Trib1 interacts with MEK1 via a conserved C-terminal ILLHPWF motif, enhancing ERK phosphorylation and promoting leukemogenesis; Trib1/MEK1 interaction is also required for Trib1-induced C/EBPα degradation, which is suppressed by ERK inhibition. Co-immunoprecipitation; motif mutagenesis; ERK phosphorylation assays; bone marrow colony-forming assays; leukemia transplantation model Blood High 20610816
2004 MEK1 promotes Golgi fragmentation during mitosis partly through physical interaction with and activation of Polo-like kinase 3 (Plk3); Plk3 activation by MEK1 requires MEK1 kinase activity (kinase-dead MEK1 does not stimulate Plk3), and MEK inhibitors reduce Plk3-induced Golgi breakdown. Pull-down assays showing Plk3-MEK1 interaction; MEK-specific inhibitors (PD98059, U0126); transfection of activated/kinase-dead MEK1; kinase activity assays; Golgi fragmentation imaging; Plk3-/- MEF analysis Oncogene High 15021912
2012 The MEK1-RSK2 cascade stabilizes GLI2 transcription factor by inhibiting GSK-3β-mediated phosphorylation and ubiquitination of GLI2, prolonging GLI2 half-life and promoting nuclear translocation; RSK2 mimics MEK1 effects, and MEK1/RSK2 fail to stabilize a GLI2 mutant lacking GSK-3β phosphorylation sites. Constitutively active MEK1 expression; RSK2 overexpression; GLI2 half-life assay; ubiquitination assay; GLI2 GSK-3β site mutant; nuclear translocation imaging Oncogene High 23208494
2014 Constitutively active MEK1 expression in regulatory T cells destabilizes Foxp3 expression and Treg function in vivo, acting through a COT/Tpl2-MEK-ERK-dependent pathway that inhibits Foxp3 DNA-binding activity. Luciferase-based kinase screen for Foxp3 function; Treg-specific activated MEK1 transgenic mice; co-immunoprecipitation; Foxp3 DNA-binding assays The Journal of biological chemistry Medium 25361764
2015 MEK1 is phosphorylated by Cdk5 at Thr-292, and by ERK and Cdk1 at both Thr-292 and Thr-286 in brain tissue; these inhibitory phosphorylations suppress MEK1's ability to activate ERK. Thr-292 phosphorylation in striatum is regulated by cAMP-dependent signaling and represents a negative feedback mechanism. PP1 and PP2A maintain basal dephosphorylation of these sites. In vitro kinase assays with Cdk5, ERK, Cdk1; phospho-specific antibodies; brain tissue fractionation; pharmacologic cAMP manipulation; PP1/PP2A inhibitors; animal behavioral paradigm The Journal of biological chemistry High 25971971
2017 Pathogenic variants at MEK1 Phe-53 (in the negative regulatory helix A region) are phosphorylated by Raf faster than wild-type and exhibit constitutive kinase activity; the activating substitutions destabilize the inactive MEK1 conformation. In zebrafish, effects on embryonic development reflect joint control of the negative regulatory region and activating phosphorylation. In vitro kinase assays measuring Raf phosphorylation kinetics; activity assays of mutant vs. wild-type MEK1; structural modeling; zebrafish developmental phenotype assays The Journal of biological chemistry High 29018093
2021 circNFIB (cNFIB) competitively interacts with MEK1 and disrupts the MEK1-ERK2 interaction, thereby suppressing ERK signaling and inhibiting ICC cell proliferation and metastasis. RNA pulldown; RNA immunoprecipitation; co-IP; Duolink proximity ligation assay; in vitro and in vivo tumor growth assays Molecular cancer Medium 35039066
2021 Monensin enhances MEK1 SUMOylation in vitro and in vivo, which inhibits MEK-ERK pathway activity and suppresses ovarian cancer cell growth and invasion. SUMOylation assays in cell lines and xenografts; immunoblot for p-ERK; cell proliferation and invasion assays; xenograft tumor studies Experimental and therapeutic medicine Low 34650638
2015 Polo-like kinase 1 (Plk1) activation upon PDGF stimulation is required upstream of MEK1/2 phosphorylation and ERK1/2 activation in airway smooth muscle cells; Plk1 knockdown or T210A Plk1 expression inhibits MEK1/2 phosphorylation without affecting Raf-1 or AKT phosphorylation. Plk1 stable knockdown cells; T210A non-phosphorylatable Plk1 mutant; immunoblot for phospho-MEK1/2, phospho-ERK1/2, phospho-Raf-1, phospho-AKT; cell proliferation assays Respiratory research Medium 26242183

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2000 The MEK1-ERK1/2 signaling pathway promotes compensated cardiac hypertrophy in transgenic mice. The EMBO journal 645 11101507
2009 MEK1 mutations confer resistance to MEK and B-RAF inhibition. Proceedings of the National Academy of Sciences of the United States of America 526 19915144
2019 Architecture of autoinhibited and active BRAF-MEK1-14-3-3 complexes. Nature 234 31581174
2003 PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation. The Journal of cell biology 225 12876277
2011 MEK1/2 dual-specificity protein kinases: structure and regulation. Biochemical and biophysical research communications 209 22177953
2013 High prevalence of MAP2K1 mutations in variant and IGHV4-34-expressing hairy-cell leukemias. Nature genetics 206 24241536
2004 MEK1-ERK2 signaling pathway protects myocardium from ischemic injury in vivo. Circulation 201 15096454
2010 From basic research to clinical development of MEK1/2 inhibitors for cancer therapy. Journal of hematology & oncology 198 20149254
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 196 28664935
2009 A major role of the MEKK1-MKK1/2-MPK4 pathway in ROS signalling. Molecular plant 189 19529823
2015 MAP2K1 and MAP3K1 mutations in Langerhans cell histiocytosis. Genes, chromosomes & cancer 162 25899310
1994 Constitutive activation of Mek1 by mutation of serine phosphorylation sites. Proceedings of the National Academy of Sciences of the United States of America 146 8090753
2009 A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal. Nature structural & molecular biology 137 19219045
2006 The Arabidopsis MAP kinase kinase MKK1 participates in defence responses to the bacterial elicitor flagellin. The Plant journal : for cell and molecular biology 129 17059410
2014 S-sulfhydration of MEK1 leads to PARP-1 activation and DNA damage repair. EMBO reports 127 24778456
2017 Copper Chelation Inhibits BRAFV600E-Driven Melanomagenesis and Counters Resistance to BRAFV600E and MEK1/2 Inhibitors. Cancer research 122 28986383
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 105 26615130
2010 Trib1 links the MEK1/ERK pathway in myeloid leukemogenesis. Blood 97 20610816
2016 Allosteric MEK1/2 inhibitors including cobimetanib and trametinib in the treatment of cutaneous melanomas. Pharmacological research 93 27956260
2015 A Phosphoproteomic Comparison of B-RAFV600E and MKK1/2 Inhibitors in Melanoma Cells. Molecular & cellular proteomics : MCP 88 25850435
2007 Myricetin is a novel natural inhibitor of neoplastic cell transformation and MEK1. Carcinogenesis 85 17693661
2021 Dual Inhibition of DKC1 and MEK1/2 Synergistically Restrains the Growth of Colorectal Cancer Cells. Advanced science (Weinheim, Baden-Wurttemberg, Germany) 82 34026451
1997 MEK1 is required for PDGF-induced ERK activation and DNA synthesis in tracheal myocytes. The American journal of physiology 78 9124614
2020 Phytophthora infestans RXLR effector PITG20303 targets a potato MKK1 protein to suppress plant immunity. The New phytologist 75 32772378
2016 Chromosome Synapsis Alleviates Mek1-Dependent Suppression of Meiotic DNA Repair. PLoS biology 74 26870961
2006 Requirement for Map2k1 (Mek1) in extra-embryonic ectoderm during placentogenesis. Development (Cambridge, England) 73 16887817
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
2021 The copper chaperone CCS facilitates copper binding to MEK1/2 to promote kinase activation. The Journal of biological chemistry 70 34715128
2023 Erianin suppresses constitutive activation of MAPK signaling pathway by inhibition of CRAF and MEK1/2. Signal transduction and targeted therapy 69 36872366
2011 MicroRNA-1826 targets VEGFC, beta-catenin (CTNNB1) and MEK1 (MAP2K1) in human bladder cancer. Carcinogenesis 69 22049531
2004 Mek1 alters epidermal growth and differentiation. Cancer research 69 15342384
2016 Preclinical Therapeutic Synergy of MEK1/2 and CDK4/6 Inhibition in Neuroblastoma. Clinical cancer research : an official journal of the American Association for Cancer Research 67 27729458
2007 Roles of the MEK1/2 and AKT pathways in CXCL12/CXCR4 induced cholangiocarcinoma cell invasion. World journal of gastroenterology 66 17461449
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
2018 Somatic activating mutations in MAP2K1 cause melorheostosis. Nature communications 63 29643386
2014 The mitogen-activated protein kinase cascade MKK1-MPK4 mediates salt signaling in rice. Plant science : an international journal of experimental plant biology 63 25219319
2022 CircNFIB inhibits tumor growth and metastasis through suppressing MEK1/ERK signaling in intrahepatic cholangiocarcinoma. Molecular cancer 59 35039066
2019 YAP1 Mediates Resistance to MEK1/2 Inhibition in Neuroblastomas with Hyperactivated RAS Signaling. Cancer research 57 31672841
2021 SIRT2 regulates mitochondrial dynamics and reprogramming via MEK1-ERK-DRP1 and AKT1-DRP1 axes. Cell reports 56 34965411
2011 MicroRNA-1826 directly targets beta-catenin (CTNNB1) and MEK1 (MAP2K1) in VHL-inactivated renal cancer. Carcinogenesis 54 22180573
2003 Distribution, levels, and activation of MEK1 in Alzheimer's disease. Journal of neurochemistry 54 12807433
2022 Computational targeting of allosteric site of MEK1 by quinoline-based molecules. Cell biochemistry and function 53 35604288
2022 Costunolide is a dual inhibitor of MEK1 and AKT1/2 that overcomes osimertinib resistance in lung cancer. Molecular cancer 46 36203195
2018 Activating mutations in MEK1 enhance homodimerization and promote tumorigenesis. Science signaling 45 30377225
2013 Deletion of a tandem gene family in Arabidopsis: increased MEKK2 abundance triggers autoimmunity when the MEKK1-MKK1/2-MPK4 signaling cascade is disrupted. The Plant cell 45 23695980
2005 Effects of active MEK1 expression in vivo. Cancer letters 44 16253755
2022 The MEKK1-MKK1/2-MPK4 cascade phosphorylates and stabilizes STOP1 to confer aluminum resistance in Arabidopsis. Molecular plant 43 36419357
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 Disruption of the MAMP-Induced MEKK1-MKK1/MKK2-MPK4 Pathway Activates the TNL Immune Receptor SMN1/RPS6. Plant & cell physiology 43 30590768
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
2019 Trametinib in the treatment of multiple malignancies harboring MEK1 mutations. Cancer treatment reviews 42 31715422
2021 Research progress of MEK1/2 inhibitors and degraders in the treatment of cancer. European journal of medicinal chemistry 40 33774345
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 40 34507982
2019 Intramuscular fast-flow vascular anomaly contains somatic MAP2K1 and KRAS mutations. Angiogenesis 40 31486960
2021 Ethylene-induced stomatal closure is mediated via MKK1/3-MPK3/6 cascade to EIN2 and EIN3. Journal of integrative plant biology 39 33605510
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
2004 MEK1-induced Golgi dynamics during cell cycle progression is partly mediated by Polo-like kinase-3. Oncogene 38 15021912
2019 V211D Mutation in MEK1 Causes Resistance to MEK Inhibitors in Colon Cancer. Cancer discovery 37 31227518
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
2012 MEK1-RSK2 contributes to Hedgehog signaling by stabilizing GLI2 transcription factor and inhibiting ubiquitination. Oncogene 30 23208494
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
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 27 34129028
2019 MEK1 regulates pulmonary macrophage inflammatory responses and resolution of acute lung injury. JCI insight 26 31801908
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
2023 High-Throughput Functional Evaluation of MAP2K1 Variants in Cancer. Molecular cancer therapeutics 24 36442478
2022 The mechanism of activation of MEK1 by B-Raf and KSR1. Cellular and molecular life sciences : CMLS 24 35508574
2022 Cellular and Molecular Mechanisms of MEK1 Inhibitor-Induced Cardiotoxicity. JACC. CardioOncology 24 36444237
2020 Melanocytic Neoplasms With MAP2K1 in Frame Deletions and Spitz Morphology. The American Journal of dermatopathology 24 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
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 Epigenetic silencing of miR-1271 enhances MEK1 and TEAD4 expression in gastric cancer. Cancer medicine 20 29862663
2014 MEK1 transduces the prion protein N2 fragment antioxidant effects. Cellular and molecular life sciences : CMLS 20 25391659
2024 Activation of endogenous retroviruses and induction of viral mimicry by MEK1/2 inhibition in pancreatic cancer. Science advances 19 38536927
2015 Regulation of ERK Kinase by MEK1 Kinase Inhibition in the Brain. The Journal of biological chemistry 19 25971971
2020 MAP2K1 Mutations in Advanced Colorectal Cancer Predict Poor Response to Anti-EGFR Therapy and to Vertical Targeting of MAPK Pathway. Clinical colorectal cancer 18 33436306
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
1997 Differential expression of MEK1 and MEK2 during mouse development. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 18 9149902
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
2014 Constitutive activation of MEK1 promotes Treg cell instability in vivo. The Journal of biological chemistry 17 25361764
2023 Tumor Cell Resistance to the Inhibition of BRAF and MEK1/2. International journal of molecular sciences 16 37834284
2021 Fragment-Based Discovery of Novel Allosteric MEK1 Binders. ACS medicinal chemistry letters 16 33603979
2014 A novel heterozygous MAP2K1 mutation in a patient with Noonan syndrome with multiple lentigines. American journal of medical genetics. Part A 16 25423878
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