Affinage

MAP2K2

Dual specificity mitogen-activated protein kinase kinase 2 · UniProt P36507

Length
400 aa
Mass
44.4 kDa
Annotated
2026-06-10
100 papers in source corpus 33 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MAP2K2 (MEK2) is a dual-specificity protein kinase that phosphorylates ERK1/2 on both threonine and tyrosine within their activation lip, switching them on more than 100-fold and thereby relaying RAS-RAF signaling to the ERK MAP kinase cascade (PMID:8388392, PMID:8393135, PMID:8297798, PMID:8626767). It is activated through phosphorylation of two activation-loop serines by Raf-family kinases (c-Raf, v-Raf) and by MEKK1, with c-Raf engaging MEK2 while A-Raf selectively favors MEK1 (PMID:8393135, PMID:8388392, PMID:7624324, PMID:8621729). Crystal structures of MEK2 reveal a unique allosteric pocket adjacent to the ATP site where inhibitors lock the unphosphorylated enzyme in a closed, catalytically inactive conformation, defining a noncompetitive inhibition mechanism (PMID:15543157). MEK2 activity is further tuned by post-translational modifications: O-GlcNAcylation at Thr13 by OGT enhances activation-loop phosphorylation and downstream ERK signaling (PMID:33226073), USP21 removes Lys48-linked polyubiquitin to stabilize MEK2 and sustain ERK output (PMID:29706623), and the bacterial effector YopJ acetylates the activation-loop serines to block phosphorylation and shut down signaling (PMID:17116858). MEK2 functions in dynamic balance with MEK1: the two form a heterodimer in which ERK feedback phosphorylation of the MEK1-specific Thr292 dampens MEK2 phosphorylation, and MEK2-activated ERK2 is biased toward cytoplasmic retention and survival rather than the nuclear, proliferative output driven by MEK1 (PMID:19219045, PMID:17928366). Beyond canonical ERK activation, MEK2 phosphorylates the tumor suppressor GCIP to drive its degradation (PMID:31907980), scaffolds Pin1–BPGAP1 complexes to restrain ERK activation and migration (PMID:20179103), regulates ribonucleotide reductase via p53R2 binding (PMID:22895183), and acts through ERK-independent routes on the MKK3/6–p38 axis and the PI3Kδ–IL-1Ra pathway (PMID:27181679, PMID:20837746). Genetically, MEK2 is dispensable for normal mouse development because MEK1 compensates, yet combined MEK dosage below a threshold causes placental defects and embryonic lethality, and isoform swapping shows MEK1 and MEK2 are functionally redundant at the protein level (PMID:12832465, PMID:19304888, PMID:26814233).

Mechanistic history

Synthesis pass · year-by-year structured walk · 13 steps
  1. 1993 High

    Established the core enzymatic identity of MEK2 as a dual-specificity kinase that activates ERK, answering what biochemical step MEK2 performs in the cascade.

    Evidence in vitro kinase assays with recombinant MEK2 phosphorylating ERK1 on Thr and Tyr

    PMID:8297798 PMID:8388392 PMID:8393135

    Open questions at the time
    • Did not define upstream activators in cells
    • Did not address MEK1 vs MEK2 functional divergence
  2. 1993 High

    Placed MEK2 downstream of Raf, defining the canonical RAS-RAF-MEK-ERK linkage for this isoform.

    Evidence in vitro phosphorylation by v-Raf and serum-induced in vivo activation in COS cells

    PMID:8388392 PMID:8393135

    Open questions at the time
    • Raf isoform selectivity not resolved
    • Activation-loop phosphosites not yet mapped
  3. 1995 High

    Identified MEKK1 as an additional activator and mapped activation-loop serines as the activating sites, clarifying how MEK2 is switched on.

    Evidence in vitro kinase assay, yeast two-hybrid, and mammalian cell activation

    PMID:7624324

    Open questions at the time
    • Physiological versus overexpression contribution of MEKK1 unclear
    • ERK activation by MEKK1 was modest
  4. 1996 High

    Revealed isoform-selective upstream coupling — c-Raf activates both MEK1/MEK2 while A-Raf and the RAS:RAF complex favor MEK1 — beginning the distinction between the two MEKs.

    Evidence yeast two-hybrid, in vitro kinase assays, RAS pulldowns, EGF-stimulated HeLa cells

    PMID:7565670 PMID:7969158 PMID:8621729

    Open questions at the time
    • Functional consequence of differential coupling in vivo not established
    • Mechanistic basis of selectivity incomplete
  5. 1996 High

    Defined the substrate-recognition determinants by showing the ERK phosphorylation lip dictates MEK1/MEK2 specificity, explaining the dual-specificity reaction at residue level.

    Evidence site-directed mutagenesis of ERK1 with in vitro phosphorylation

    PMID:8626767

    Open questions at the time
    • MEK2-side recognition residues not mapped
    • Did not address non-ERK substrates
  6. 2003 High

    Demonstrated MEK2 is dispensable for development due to MEK1 compensation, framing the redundancy question central to MEK biology.

    Evidence germline Mek2-null mouse with phenotypic analysis

    PMID:12832465

    Open questions at the time
    • Did not test combined MEK dosage
    • Non-redundant cell-type-specific roles not excluded
  7. 2004 High

    Provided the structural basis for noncompetitive allosteric inhibition by capturing MEK2 locked in an inactive conformation, defining a druggable pocket.

    Evidence X-ray crystallography of MEK2 ternary complex with MgATP and inhibitor

    PMID:15543157

    Open questions at the time
    • Active phosphorylated-state structure not determined
    • Conformational dynamics of activation not captured
  8. 2006 High

    Uncovered covalent regulation of MEK2 by pathogen-driven acetylation of activation-loop serines, revealing a competitive PTM that blocks activating phosphorylation.

    Evidence mass spectrometry mapping of YopJ acetylation sites and biochemical inhibition

    PMID:17116858

    Open questions at the time
    • Endogenous (non-pathogen) acetylation not addressed
    • Reversibility by host deacetylases unknown
  9. 2009 High

    Established the MEK1-MEK2 heterodimer and ERK feedback through MEK1-Thr292 as the mechanism by which MEK2 activity is negatively regulated.

    Evidence reciprocal Co-IP, phospho-specific blots, Thr292 mutagenesis, MEK1 knockout embryos

    PMID:19219045

    Open questions at the time
    • Stoichiometry and dynamics of heterodimer in vivo unclear
    • Whether all MEK2 signaling passes through heterodimer unknown
  10. 2007 High

    Showed MEK2-activated ERK2 is biased to cytoplasmic, pro-survival output versus MEK1-driven nuclear proliferative output, assigning functional divergence to subcellular ERK fate.

    Evidence siRNA, NES constructs, fractionation/immunofluorescence, phosphosite mutagenesis

    PMID:17928366

    Open questions at the time
    • Molecular basis for cytoplasmic retention by MEK2 incomplete
    • Generality across cell types not established
  11. 2008 High

    Localized a MEK2 pool to endosomes via clathrin-dependent endocytosis acting in negative feedback, linking MEK2 trafficking to signal attenuation.

    Evidence GFP-MEK2 live imaging, clathrin/RAF siRNA, ERK readout in HeLa

    PMID:18657070

    Open questions at the time
    • Endosomal substrates of MEK2 not identified
    • Signal contribution of endosomal pool not quantified
  12. 2009 High

    Defined a MEK dosage threshold for placental development and embryonic viability, showing combined MEK quantity rather than isoform identity is limiting.

    Evidence compound mutant allelic series with conditional Map2k1 deletion and histology

    PMID:19304888

    Open questions at the time
    • Molecular target requiring high MEK dose in placenta unknown
    • Tissue-specific thresholds not fully mapped
  13. 2016 High

    Proved MEK1 and MEK2 are biochemically interchangeable by rescuing Mek1-null lethality with Mek2 coding sequence, settling that phenotypes reflect protein quantity not isoform-specific chemistry.

    Evidence knock-in rescue mouse genetics with embryo viability assays

    PMID:26814233

    Open questions at the time
    • Cannot explain isoform-specific findings in cultured cells
    • Regulatory (non-coding) differences not addressed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Multiple ERK-independent and non-canonical MEK2 functions are reported but their integration with the canonical cascade and physiological weight remain unresolved.
  • Most non-canonical substrates rest on single Co-IP/activity studies without reciprocal validation
  • Whether kinase activity versus scaffolding drives each function is inconsistent
  • Reconciliation with strict MEK1/MEK2 redundancy in vivo is unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0016740 transferase activity 2 GO:0060089 molecular transducer activity 2 GO:0140657 ATP-dependent activity 1
Localization
GO:0005634 nucleus 2 GO:0005886 plasma membrane 2 GO:0005768 endosome 1 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-168256 Immune System 3 R-HSA-1266738 Developmental Biology 2 R-HSA-5653656 Vesicle-mediated transport 2
Partners
ARAFDLG1MAP2K1MAP3K1PIN1RAF1RMRPUSP21
Complex memberships
MEK1-MEK2 heterodimerRAS:RAF-1:MEK1 complex (MEK2 excluded)

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 Crystal structures of human MEK1 and MEK2 each determined as ternary complexes with MgATP and an inhibitor reveal a unique allosteric inhibitor-binding pocket adjacent to the ATP-binding site. The inhibitor induces conformational changes that lock unphosphorylated MEK1 and MEK2 into a closed but catalytically inactive species, establishing a noncompetitive mechanism for kinase inhibition. X-ray crystallography (2.4 Å for MEK1, 3.2 Å for MEK2) Nature structural & molecular biology High 15543157
1993 Human MEK2 was cloned and shown to be a dual-specificity kinase that phosphorylates ERK1 on both threonine and tyrosine residues, activating ERK1 kinase activity more than 100-fold in vitro. Recombinant MEK2 can be activated by serum-stimulated cell extract in vitro. In vitro kinase assay with recombinant proteins expressed in E. coli The Journal of biological chemistry High 8297798 8388392 8393135
1993 MEK2 (MKK2) can be phosphorylated and activated by v-Raf in vitro, and both MEK1 and MEK2 are activated in vivo in response to serum, establishing Raf as an upstream activator of MEK2. In vitro kinase assay; in vivo activation assay in COS cells Molecular and cellular biology High 8388392 8393135
1995 MEKK1 catalytic domain phosphorylates MEK1 and MEK2 activation-loop serines (S218/S222 equivalents) in vitro and interacts with MEK1 in the two-hybrid system. Expression of MEKK1 in mammalian cells causes constitutive activation of both MEK1 and MEK2, although downstream ERK2 activation is modest compared to EGF stimulation. In vitro kinase assay, yeast two-hybrid, transfection in mammalian cells with Western blot Proceedings of the National Academy of Sciences of the United States of America High 7624324
1995 A proline-rich (PR) sequence unique to MEK1 and MEK2 is required for Raf family binding and MEK activation. Deletion of the PR sequence from MEK1 blocked association with Raf and markedly attenuated growth factor-induced activation. A phosphorylation site within the PR sequence of MEK1 sustains activity, whereas MEK2 lacks this site and shows only transient activation after serum stimulation. Deletion mutagenesis, co-immunoprecipitation, in vivo kinase assays in fibroblasts Molecular and cellular biology High 7565670
1994 RAS and RAF-1 form a signaling complex with MEK1 but not MEK2. MEK-2 was not detected in the RAS:RAF-1:MEK-1 complex, and consistent with this, basal MEK2 activity in v-ras-transformed cells was elevated only twofold vs. sixfold for MEK1, indicating differential coupling of MEK1 and MEK2 to the RAS signaling complex. Immobilized RAS pulldown, co-immunoprecipitation from cell lysates, kinase activity assay Molecular and cellular biology High 7969158
1996 A-Raf selectively phosphorylates and activates MEK1 but not MEK2 upon EGF stimulation of HeLa cells, whereas c-Raf activates both MEK1 and MEK2. Using MEK1-S218/222A as bait in yeast two-hybrid screens, all three Raf isoforms were identified as MEK1 interactors. Yeast two-hybrid screening, in vitro kinase assay, EGF stimulation of HeLa cells The Journal of biological chemistry High 8621729
2006 The Yersinia effector YopJ acetylates two serine residues in the activation loop of MEK2, preventing their phosphorylation required for MEK2 activation. This covalent acetylation is the mechanism by which YopJ blocks MAPK signaling. Mass spectrometry-based identification of acetylation sites, biochemical inhibition assays Proceedings of the National Academy of Sciences of the United States of America High 17116858
2009 MEK1 and MEK2 form a heterodimer in which MEK1 downregulates MEK2-dependent ERK signaling. ERK phosphorylates MEK1 at Thr292 (a residue absent in MEK2), creating a negative feedback that also reduces MEK2 phosphorylation within the heterodimer. Loss of MEK1 stabilizes MEK2 phosphorylation and sustains ERK activation in cultured cells and in vivo. Co-immunoprecipitation, phospho-specific Western blot, MEK1 knockout mouse embryos, site-directed mutagenesis of Thr292 Nature structural & molecular biology High 19219045
2007 MEK1-activated ERK2 accumulates in the nucleus and promotes proliferation, whereas MEK2-activated ERK2 is retained in the cytoplasm and supports cell survival. MEK1-mediated nuclear translocation of ERK2 depends on phosphorylation of MEK1 residues S298 (by PAK) and T292 (by ERK2 feedback), sites present in MEK1 but not MEK2. siRNA knockdown, nuclear export sequence constructs, immunofluorescence/subcellular fractionation, phospho-site mutagenesis FASEB journal High 17928366
2008 Upon EGF receptor activation, a pool of MEK2 is recruited to the plasma membrane and then to early and late endosomes via clathrin-dependent endocytosis. RAF kinase activity and MEK catalytic activity are required for endosomal targeting of MEK2. Clathrin knockdown abolishes MEK2 endosomal recruitment and increases ERK activation, suggesting endosomal MEK2 participates in negative feedback regulation. GFP-tagged MEK2 live imaging, siRNA knockdown of clathrin and RAF, fluorescence microscopy in HeLa cells Traffic High 18657070
2018 The deubiquitinase USP21 stabilizes MEK2 by removing Lys48-linked polyubiquitin chains from MEK2, preventing its proteasomal degradation and thereby sustaining ERK signaling. Co-immunoprecipitation, ubiquitination assay, siRNA knockdown, ectopic expression in cell lines Cell death & disease Medium 29706623
2014 The small GTPase RBJ interacts with MEK1/MEK2 in the nucleus, prolongs MEK/ERK activation by nuclear entrapment, and promotes carcinogenesis. RBJ deficiency abrogates nuclear accumulation of MEK1/MEK2 and attenuates ERK1/ERK2 activation. Co-immunoprecipitation, subcellular fractionation, RBJ knockout mouse model, tumor model Cancer cell Medium 24746703
2010 Active MEK2 (but not kinase-dead MEK2) serves as a scaffold that bridges Pin1 and BPGAP1, promoting Pin1 binding to BPGAP1 to suppress acute ERK activation and cell migration. Only catalytically active MEK2 can bind Pin1, and this interaction requires release of an autoinhibited proline-rich motif in BPGAP1. Co-immunoprecipitation, kinase-dead and constitutively active MEK2 mutants, siRNA knockdown, cell migration assay Journal of cell science Medium 20179103
2011 The human Discs-large tumor suppressor hDlg interacts with the phosphorylated (active) form of MEK2 at the midbody ring during cytokinesis. The interaction depends on MEK2 phosphorylation and is mediated by the PDZ domains of hDlg binding the C-terminal portion of MEK2. E-cadherin expression is required for isoform-specific recruitment of hDlg (but not active MEK2) to the midbody. Co-immunoprecipitation, immunofluorescence, cell cycle synchronization, E-cadherin knockdown BMC cell biology Medium 22185284
2021 MEK2 directly interacts with and phosphorylates the tumor suppressor GCIP at Ser313 and Ser356, promoting ubiquitin-mediated proteasomal degradation of GCIP and enhancing cancer cell proliferation and migration. Co-immunoprecipitation, in vitro kinase assay, phospho-site mutagenesis, ubiquitination assay FASEB journal High 31907980
2012 MEK2 physically interacts with ribonucleotide reductase small subunit p53R2 and upregulates RNR enzymatic activity. The MEK2 segment comprising amino acids 65–171 is critical for p53R2-MEK2 interaction. Ionizing radiation augments MEK2 phosphorylation and concurrently increases RNR activity in a MEK2-dependent manner. Co-immunoprecipitation, deletion mapping, MEK inhibitor treatment, siRNA knockdown, RNR activity assay Cell cycle Medium 22895183
2021 MEK2 is O-GlcNAcylated at Thr13 by OGT. O-GlcNAcylation at Thr13 (located in the docking domain) enhances MEK2 Thr394 phosphorylation and downstream ERK1/2 activation. Ablation of Thr13 O-GlcNAcylation abolishes MEK2-driven proliferation and migration of breast cancer cells. Mass spectrometry identification of O-GlcNAc site, site-directed mutagenesis, Western blot, cell proliferation/migration assay Glycobiology High 33226073
2002 A-Raf interacts with MEK2 through its kinase domain (residues 255–606), as identified by yeast two-hybrid screening and confirmed by in vitro binding assay. Yeast two-hybrid, in vitro binding assay Biochimica et biophysica acta Medium 11909642
1996 MEK2 is the predominant MEK isoform activated in human neutrophils by chemotactic peptides, with activity at least 3-fold greater than MEK1. MEK2 activation is more sensitive to the PI3-kinase inhibitor wortmannin than MEK1, indicating differential upstream regulation, and both isoforms are activated by PKC agonists. Immunoprecipitation kinase assay, pharmacological inhibition, fMLP stimulation of primary neutrophils The Journal of biological chemistry Medium 8702863
2010 MEK2, but not MEK1, controls MKK3/MKK6-p38 MAPK axis phosphorylation in MDA-MB-231 breast cancer cells independent of ERK1/2 activation. MEK2 silencing decreases cyclin D1 expression and increases apoptosis, while MEK1 silencing has the opposite effect. siRNA knockdown of MEK1 and MEK2 individually, Western blot for p38, MKK3/6 phosphorylation, cell viability assay Cellular signalling Medium 27181679
2010 MEK2 acts upstream of PI3Kδ in IFN-β-stimulated human monocytes to regulate IL-1Ra production. Blockade of MEK2 (but not MEK1) prevented PI3Kδ membrane recruitment, Akt phosphorylation, and IL-1Ra production. ERK1/2 are dispensable for this pathway, suggesting a non-canonical MEK2 signaling function. MEK isoform-selective inhibitors, siRNA knockdown, subcellular fractionation, immunoprecipitation in primary human monocytes Journal of leukocyte biology Medium 20837746
2019 MEK2 inversely and independently regulates HIF-1α expression and IL-1β production in LPS-stimulated macrophages. MEK2-deficient bone marrow-derived macrophages show preserved ERK1/2 phosphorylation but higher HIF-1α, Glut1, and IL-1β levels. Overexpression of MEK2 in RAW264.7 cells decreases IL-1β production after LPS stimulation, establishing MEK2 as a negative regulator of HIF-1α/IL-1β independent of ERK. MEK2 knockout macrophages, siRNA knockdown of HIF-1α, MEK2 overexpression, Western blot, cytokine ELISA Journal of immunology Medium 30710049
2016 TRNA interacts with MEK2 in pancreatic cancer cells, and the MEK2 inhibitor U0126 significantly reduces the tRNA-MEK2 interaction. tRNA modulates MEK2 catalytic activity differently for wild-type and cancer-associated mutant forms (Q60P, P128Q, S154F, E207K). Co-immunoprecipitation, in vitro kinase activity assay, MEK2 mutant constructs Scientific reports Low 27301426
2003 Mek2-null mice are viable and fertile with no overt morphological defects, demonstrating that MEK2 is dispensable for normal mouse development and that its loss is compensated by MEK1. Gene targeting (knockout mouse), phenotypic analysis including thymocyte development and T-cell proliferation Molecular and cellular biology High 12832465
2009 Map2k2 haploinsufficiency in combination with one null Map2k1 allele causes placental defects restricted to extra-embryonic tissues and embryonic lethality. The severity correlates with total MEK protein levels regardless of isoform identity, indicating a dosage threshold effect for placental development. Compound mutant mouse genetics (allelic series), conditional Map2k1 deletion, histological analysis Development High 19304888
2016 MEK1 and MEK2 are functionally redundant at the protein level: knock-in of Mek2 coding sequences under Mek1 regulatory control rescues Mek1-null lethality, establishing that the embryonic phenotype reflects protein quantity rather than isoform-specific biochemistry. Knock-in mouse genetics, allelic series analysis, embryo viability assays Science signaling High 26814233
2022 MAP2K2 (MEK2) in myeloid/leukocyte cells delays resolution of acute lung injury. Mek2-/- mice show faster resolution of alveolar neutrophilia and vascular leak following Pseudomonas aeruginosa injury. Bone marrow chimera studies confirm leukocyte MAP2K2 as the key regulator of ALI duration. Mek2-null mouse model, bone marrow chimera, acute lung injury models, gene expression analysis American journal of respiratory cell and molecular biology Medium 35157553
1996 ERK1 residues flanking its regulatory phosphorylation sites determine specificity of recognition and phosphorylation by MEK1 and MEK2. Mutation of Arg-208 dramatically increases tyrosine phosphorylation while eliminating threonine phosphorylation; mutation of Gly-199 increases threonine vs. tyrosine phosphorylation, demonstrating that the phosphorylation lip of ERK is a determinant of MEK substrate recognition. Site-directed mutagenesis of ERK1, in vitro phosphorylation assay with MEK1 and MEK2 The Journal of biological chemistry High 8626767
2011 MEK2 is sufficient to sustain ERK activation, proliferation, and anchorage-independent growth of SK-MEL-28 melanoma cells when other MKKs are cleaved by anthrax lethal toxin. MEK1 and MEK2 drive non-overlapping downstream transcriptional programs in these cells. Anthrax lethal toxin MEK cleavage, protease-resistant MEK mutants (MEK1cr, MEK2cr), microarray transcriptomics, proliferation assay PloS one Medium 21365009
2020 In Pelizaeus-Merzbacher disease model mice, oligodendrocyte-specific expression of a kinase-deficient dominant-inhibitory MEK2 mutant (MEK2K101A) promotes CNS myelination and improves motor coordination, establishing that MEK2 signaling suppresses oligodendrocyte differentiation and myelination. Transgenic mouse expressing kinase-dead MEK2K101A in oligodendrocytes, histological myelination analysis, Rotarod behavioral testing Biochemical and biophysical research communications Medium 32800341
2024 MEK2, but not MEK1, mediates uptake of breast cancer cell-derived extracellular vesicles by lung fibroblasts through a macropinocytosis mechanism. Gene knockdown and overexpression studies established MEK2 as required for this process. siRNA knockdown, MEK2 overexpression, high-content microscopy, macropinocytosis assay Cancer research communications Medium 38259097

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nature structural & molecular biology 507 15543157
2015 MEK1 and MEK2 inhibitors and cancer therapy: the long and winding road. Nature reviews. Cancer 495 26399658
2012 Phase II study of the MEK1/MEK2 inhibitor Trametinib in patients with metastatic BRAF-mutant cutaneous melanoma previously treated with or without a BRAF inhibitor. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 403 23248257
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
2015 A randomized phase II study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small-cell lung cancer (NSCLC)†. Annals of oncology : official journal of the European Society for Medical Oncology 298 25722381
1993 Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2. The Journal of biological chemistry 293 8388392
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
1995 Three genes of the MAP kinase cascade, mek-2, mpk-1/sur-1 and let-60 ras, are required for meiotic cell cycle progression in Caenorhabditis elegans. Development (Cambridge, England) 257 7671816
2006 Acetylation of MEK2 and I kappa B kinase (IKK) activation loop residues by YopJ inhibits signaling. Proceedings of the National Academy of Sciences of the United States of America 233 17116858
1999 Lipopolysaccharide-induced tumor necrosis factor alpha production by human monocytes involves the raf-1/MEK1-MEK2/ERK1-ERK2 pathway. Infection and immunity 212 10417144
2014 IL-6 negatively regulates osteoblast differentiation through the SHP2/MEK2 and SHP2/Akt2 pathways in vitro. Journal of bone and mineral metabolism 179 24122251
1995 A proline-rich sequence unique to MEK1 and MEK2 is required for raf binding and regulates MEK function. Molecular and cellular biology 174 7565670
1995 MEKK1 phosphorylates MEK1 and MEK2 but does not cause activation of mitogen-activated protein kinase. Proceedings of the National Academy of Sciences of the United States of America 158 7624324
2013 Concurrent MEK2 mutation and BRAF amplification confer resistance to BRAF and MEK inhibitors in melanoma. Cell reports 153 24055054
2003 Mek2 is dispensable for mouse growth and development. Molecular and cellular biology 146 12832465
2009 A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal. Nature structural & molecular biology 139 19219045
1993 Identification and characterization of a new mammalian mitogen-activated protein kinase kinase, MKK2. Molecular and cellular biology 139 8393135
1994 RAS and RAF-1 form a signalling complex with MEK-1 but not MEK-2. Molecular and cellular biology 110 7969158
1996 Selective activation of MEK1 but not MEK2 by A-Raf from epidermal growth factor-stimulated Hela cells. The Journal of biological chemistry 107 8621729
2004 MEK1 and MEK2, different regulators of the G1/S transition. The Journal of biological chemistry 97 15284233
1995 MEK-2, a Caenorhabditis elegans MAP kinase kinase, functions in Ras-mediated vulval induction and other developmental events. Genes & development 88 7729690
1995 The Caenorhabditis elegans gene mek-2 is required for vulval induction and encodes a protein similar to the protein kinase MEK. Genes & development 82 7729691
2007 Mutation analysis of BRAF, MEK1 and MEK2 in 15 ovarian cancer cell lines: implications for therapy. PloS one 74 18060073
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
2018 The deubiquitinase USP21 stabilizes MEK2 to promote tumor growth. Cell death & disease 66 29706623
2019 βC1 protein encoded in geminivirus satellite concertedly targets MKK2 and MPK4 to counter host defense. PLoS pathogens 61 30998777
1996 Characterization of ERK1 activation site mutants and the effect on recognition by MEK1 and MEK2. The Journal of biological chemistry 61 8626767
2017 Phosphoproteome-based kinase activity profiling reveals the critical role of MAP2K2 and PLK1 in neuronal autophagy. Autophagy 55 28933595
2008 Activation of MEK1 or MEK2 isoform is sufficient to fully transform intestinal epithelial cells and induce the formation of metastatic tumors. BMC cancer 55 19014680
1993 MEK2 is a kinase related to MEK1 and is differentially expressed in murine tissues. Cell growth & differentiation : the molecular biology journal of the American Association for Cancer Research 55 8297798
2009 Map2k1 and Map2k2 genes contribute to the normal development of syncytiotrophoblasts during placentation. Development (Cambridge, England) 51 19304888
2002 Estradiol-induced phosphorylation of ERK1/2 in explants of the mouse cerebral cortex: the roles of heat shock protein 90 (Hsp90) and MEK2. Journal of neurobiology 50 11748628
2019 Disruption of the MAMP-Induced MEKK1-MKK1/MKK2-MPK4 Pathway Activates the TNL Immune Receptor SMN1/RPS6. Plant & cell physiology 45 30590768
2009 Selective role for Mek1 but not Mek2 in the induction of epidermal neoplasia. Cancer research 45 19383924
1997 Differential regulation of mitogen-activated protein/ERK kinase (MEK)1 and MEK2 and activation by a Ras-independent mechanism. Molecular endocrinology (Baltimore, Md.) 45 9328344
2004 Phosphorylation regulates nucleophosmin targeting to the centrosome during mitosis as detected by cross-reactive phosphorylation-specific MKK1/MKK2 antibodies. The Biochemical journal 43 14670079
2007 MEK1 and MEK2 regulate distinct functions by sorting ERK2 to different intracellular compartments. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 40 17928366
1996 Chemotactic peptide-induced activation of MEK-2, the predominant isoform in human neutrophils. Inhibition by wortmannin. The Journal of biological chemistry 40 8702863
2014 Small GTPase RBJ mediates nuclear entrapment of MEK1/MEK2 in tumor progression. Cancer cell 39 24746703
2008 Endosomal targeting of MEK2 requires RAF, MEK kinase activity and clathrin-dependent endocytosis. Traffic (Copenhagen, Denmark) 39 18657070
2021 Myc-associated zinc-finger protein promotes clear cell renal cell carcinoma progression through transcriptional activation of the MAP2K2-dependent ERK pathway. Cancer cell international 38 34183010
2022 YTHDF2 promotes multiple myeloma cell proliferation via STAT5A/MAP2K2/p-ERK axis. Oncogene 37 35075244
2021 Phase II study of selumetinib, an orally active inhibitor of MEK1 and MEK2 kinases, in KRASG12R-mutant pancreatic ductal adenocarcinoma. Investigational new drugs 36 33405090
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
2010 Molecular and functional analysis of a novel MEK2 mutation in cardio-facio-cutaneous syndrome: transmission through four generations. American journal of medical genetics. Part A 34 20358587
2016 Functional redundancy of the kinases MEK1 and MEK2: Rescue of the Mek1 mutant phenotype by Mek2 knock-in reveals a protein threshold effect. Science signaling 33 26814233
2011 Two mitogen-activated protein kinase kinases, MKK1 and MEK2, are involved in wounding- and specialist lepidopteran herbivore Manduca sexta-induced responses in Nicotiana attenuata. Journal of experimental botany 33 21610019
2017 Comparative Phosphoproteomics Reveals an Important Role of MKK2 in Banana (Musa spp.) Cold Signal Network. Scientific reports 30 28106078
2013 Deletion of MAP2K2/MEK2: a novel mechanism for a RASopathy? Clinical genetics 28 23379592
2010 Distinct effects of knocking down MEK1 and MEK2 on replication of herpes simplex virus type 2. Virus research 28 20172001
2016 MEK2 controls the activation of MKK3/MKK6-p38 axis involved in the MDA-MB-231 breast cancer cell survival: Correlation with cyclin D1 expression. Cellular signalling 26 27181679
2021 O-GlcNAcylation of MEK2 promotes the proliferation and migration of breast cancer cells. Glycobiology 24 33226073
2015 The Mkk2 MAPKK Regulates Cell Wall Biogenesis in Cooperation with the Cek1-Pathway in Candida albicans. PloS one 24 26197240
2010 Active Mek2 as a regulatory scaffold that promotes Pin1 binding to BPGAP1 to suppress BPGAP1-induced acute Erk activation and cell migration. Journal of cell science 22 20179103
2011 MEK2 is sufficient but not necessary for proliferation and anchorage-independent growth of SK-MEL-28 melanoma cells. PloS one 21 21365009
1997 Mutation analysis of the coding sequences of MEK-1 and MEK-2 genes in human lung cancer cell lines. Oncogene 21 9121773
2020 Lycorine Induces autophagy-associated apoptosis by targeting MEK2 and enhances vemurafenib activity in colorectal cancer. Aging 20 31901897
2019 Differential effects of MEK inhibitors on rat neural stem cell differentiation: Repressive roles of MEK2 in neurogenesis and induction of astrocytogenesis by PD98059. Pharmacological research 20 31562895
2010 MEK1 and MEK2 isoforms regulate distinct functions in pancreatic cancer cells. Oncology reports 20 20514469
2021 Genistein suppresses allergic contact dermatitis through regulating the MAP2K2/ERK pathway. Food & function 18 33908440
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
2023 Lnc_000048 Promotes Histone H3K4 Methylation of MAP2K2 to Reduce Plaque Stability by Recruiting KDM1A in Carotid Atherosclerosis. Molecular neurobiology 16 36689133
2013 MEK1 and MEK2 differentially control the duration and amplitude of the ERK cascade response. Physical biology 16 23735655
2016 The TAK1→IKKβ→TPL2→MKK1/MKK2 Signaling Cascade Regulates IL-33 Expression in Cystic Fibrosis Airway Epithelial Cells Following Infection by Pseudomonas aeruginosa. Frontiers in cell and developmental biology 15 26793709
2003 Basic fibroblast growth factor induces the expression of matrix metalloproteinase-3 in human periodontal ligament cells through the MEK2 mitogen-activated protein kinase pathway. Journal of periodontal research 15 12608905
2003 Inhibition of CCL11, CCL24, and CCL26-induced degranulation in HL-60 eosinophilic cells by specific inhibitors of MEK1/MEK2, p38 MAP kinase, and PI 3-kinase. Immunopharmacology and immunotoxicology 14 12784909
2012 Implication of MEK1 and MEK2 in the establishment of the blood-placenta barrier during placentogenesis in mouse. Reproductive biomedicine online 12 22561024
2010 A novel MEK2/PI3Kδ pathway controls the expression of IL-1 receptor antagonist in IFN-β-activated human monocytes. Journal of leukocyte biology 12 20837746
2021 The Raf-like kinase Raf36 negatively regulates plant resistance against the oomycete pathogen Phytophthora parasitica by targeting MKK2. Molecular plant pathology 11 34935273
2011 The MEK2-binding tumor suppressor hDlg is recruited by E-cadherin to the midbody ring. BMC cell biology 11 22185284
2024 Soybean MKK2 establishes intricate signalling pathways to regulate soybean response to cyst nematode infection. Molecular plant pathology 10 38695657
2023 PhyB-dependent phosphorylation of mitogen-activated protein kinase cascade MKK2-MPK2 positively regulates red light-induced stomatal opening. Plant, cell & environment 10 37493364
2019 MEK2 Negatively Regulates Lipopolysaccharide-Mediated IL-1β Production through HIF-1α Expression. Journal of immunology (Baltimore, Md. : 1950) 10 30710049
2016 Interaction of tRNA with MEK2 in pancreatic cancer cells. Scientific reports 10 27301426
2011 A full-length 3D structure for MAPK/ERK kinase 2 (MEK2). Science China. Life sciences 10 21509657
2019 MEK2 is a critical modulating mechanism to down-regulate GCIP stability and function in cancer cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 9 31907980
2018 MAP2K2 mutation as a cause of cardio-facio-cutaneous syndrome in an infant with a severe and fatal course of the disease. American journal of medical genetics. Part A 9 29799162
2012 MEK2 regulates ribonucleotide reductase activity through functional interaction with ribonucleotide reductase small subunit p53R2. Cell cycle (Georgetown, Tex.) 9 22895183
2023 Investigating a Library of Flavonoids as Potential Inhibitors of a Cancer Therapeutic Target MEK2 Using in Silico Methods. International journal of molecular sciences 8 36901876
2022 MAP2K2 Delays Recovery in Murine Models of Acute Lung Injury and Associates with Acute Respiratory Distress Syndrome Outcome. American journal of respiratory cell and molecular biology 7 35157553
2013 Multiple café au lait spots in familial patients with MAP2K2 mutation. American journal of medical genetics. Part A 7 24311457
2021 Mek1 and Mek2 Functional Redundancy in Erythropoiesis. Frontiers in cell and developmental biology 6 34386488
2014 Familial cardiofaciocutaneous syndrome in a father and a son with a novel MEK2 mutation. American journal of medical genetics. Part A 6 25487361
2025 The positive feedback loop between SP1 and MAP2K2 significantly drives resistance to VEGFR inhibitors in clear cell renal cell carcinoma. International journal of biological sciences 5 39781472
2023 The MAP2K2 Gene as Potential Diagnostic Marker in Monitoring Adalimumab Therapy of Psoriatic Arthritis. Current pharmaceutical biotechnology 5 35762548
2023 Circular RNA MAP2K2-modified immunosuppressive dendritic cells for preventing alloimmune rejection in organ transplantation. Bioengineering & translational medicine 5 38193111
2021 A Heterozygous Missense Variant in MAP2K2 in a Stillborn Romagnola Calf with Skeletal-Cardio-Enteric Dysplasia. Animals : an open access journal from MDPI 5 34209498
2016 Concurrent occurrence of an inherited 16p13.11 microduplication and a de novo 19p13.3 microdeletion involving MAP2K2 in a patient with developmental delay, distinctive facial features, and lambdoid synostosis. European journal of medical genetics 5 27751966
2015 Activation of MEK2 is sufficient to induce skin papilloma formation in transgenic zebrafish. Journal of biomedical science 5 26572230
2000 Chromosome mapping of the human genes encoding the MAP kinase kinase MEK1 (MAP2K1) to 15q21 and MEK2 (MAP2K2) to 7q32. Cytogenetics and cell genetics 5 10828601
2024 Lung Fibroblasts Take up Breast Cancer Cell-derived Extracellular Vesicles Partially Through MEK2-dependent Macropinocytosis. Cancer research communications 4 38259097
2012 MEK1 and MEK2 differentially regulate human insulin- and insulin glargine-induced human bladder cancer T24 cell proliferation. Chinese medical journal 4 23217386
1997 Cloning and characterization of cDNAs encoding chicken mitogen-activated protein kinase kinase type 2, MEK2: downregulation of MEK2 in response to inhibition of mitochondrial DNA expression. Biochemistry 4 9398267
2024 MicroRNA-2285f regulates milk fat metabolism by targeting MAP2K2 in bovine mammary epithelial cells. Reproduction in domestic animals = Zuchthygiene 3 38798178
2024 Low PD-L1 expression, MAP2K2 alterations, and enriched HPV gene signatures characterize brain metastases in head and neck squamous cell carcinoma. Journal of translational medicine 3 39438862
2018 Characterization and functional analysis of grouper (Epinephelus coioides) MEK1 and MEK2. Fish & shellfish immunology 3 30419398
2002 Identification of interaction between MEK2 and A-Raf-1. Biochimica et biophysica acta 3 11909642
2020 Expression of kinase-deficient MEK2 ameliorates Pelizaeus-Merzbacher disease phenotypes in mice. Biochemical and biophysical research communications 2 32800341

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