MEK2

Summary

Gene Symbol: MEK2
Description: mitogen-activated protein kinase kinase 2
Alias: CFC4, MAPKK2, MEK2, MKK2, PRKMK2, dual specificity mitogen-activated protein kinase kinase 2, ERK activator kinase 2, MAP kinase kinase 2, MAPK/ERK kinase 2, mitogen-activated protein kinase kinase 2, p45
Species: human
Products:     MEK2

Top Publications

  1. Rodriguez Viciana P, Tetsu O, Tidyman W, Estep A, Conger B, Cruz M, et al. Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome. Science. 2006;311:1287-90 pubmed
    ..Furthermore, three of five individuals without BRAF mutations had missense mutations in either MEK1 or MEK2, downstream effectors of B-Raf...
  2. Zheng C, Guan K. Cloning and characterization of two distinct human extracellular signal-regulated kinase activator kinases, MEK1 and MEK2. J Biol Chem. 1993;268:11435-9 pubmed
    ..MEK (MAP kinase or ERK kinase) is the immediate upstream activator kinase of ERK. Two cDNAs, MEK1 and MEK2, were cloned and sequenced. MEK1 and MEK2 encode 393 and 400 amino acid residues, respectively...
  3. Duesbery N, Webb C, Leppla S, Gordon V, Klimpel K, Copeland T, et al. Proteolytic inactivation of MAP-kinase-kinase by anthrax lethal factor. Science. 1998;280:734-7 pubmed
    ..LF is a protease that cleaves the amino terminus of mitogen-activated protein kinase kinases 1 and 2 (MAPKK1 and MAPKK2) and that this cleavage inactivates MAPKK1 and inhibits the MAPK signal transduction pathway...
  4. Vitale G, Bernardi L, Napolitani G, Mock M, Montecucco C. Susceptibility of mitogen-activated protein kinase kinase family members to proteolysis by anthrax lethal factor. Biochem J. 2000;352 Pt 3:739-45 pubmed
    ..anthracis is a Zn(2+)-endopeptidase that cleaves the mitogen-activated protein kinase kinases (MAPKKs) MEK1, MEK2 and MKK3...
  5. Ohren J, Chen H, Pavlovsky A, Whitehead C, Zhang E, Kuffa P, et al. Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition. Nat Struct Mol Biol. 2004;11:1192-7 pubmed
    MEK1 and MEK2 are closely related, dual-specificity tyrosine/threonine protein kinases found in the Ras/Raf/MEK/ERK mitogen-activated protein kinase (MAPK) signaling pathway...
  6. Narumi Y, Aoki Y, Niihori T, Neri G, Cave H, Verloes A, et al. Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome: overlapping clinical manifestations with Costello syndrome. Am J Med Genet A. 2007;143A:799-807 pubmed
  7. Scholl F, Dumesic P, Barragan D, Harada K, Bissonauth V, Charron J, et al. Mek1/2 MAPK kinases are essential for Mammalian development, homeostasis, and Raf-induced hyperplasia. Dev Cell. 2007;12:615-29 pubmed
    ..at a single level of this signaling pathway in mammals, and to investigate functional redundancy between Mek1 and Mek2, we disrupted these genes in murine and human epidermis...
  8. Adjei A, Cohen R, Franklin W, Morris C, Wilson D, Molina J, et al. Phase I pharmacokinetic and pharmacodynamic study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 2008;26:2139-46 pubmed publisher
    ..AZD6244 was well tolerated with target inhibition demonstrated at the recommended phase II dose. PK analyses supported twice-daily dosing. Prolonged SD was seen in a variety of advanced cancers. Phase II studies are ongoing. ..
  9. Voisin L, Julien C, Duhamel S, Gopalbhai K, Claveau I, Saba El Leil M, et al. Activation of MEK1 or MEK2 isoform is sufficient to fully transform intestinal epithelial cells and induce the formation of metastatic tumors. BMC Cancer. 2008;8:337 pubmed publisher
    ..Small-molecule inhibitors of MEK1/MEK2 are therefore viewed as attractive drug candidates for the targeted therapy of this malignancy...

More Information

Publications225 found, 100 shown here

  1. Infante J, Fecher L, Falchook G, Nallapareddy S, Gordon M, Becerra C, et al. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13:773-81 pubmed publisher
    ..Trametinib is a selective, orally administered MEK1/MEK2 inhibitor...
  2. Maïga O, Philippe M, Kotelevets L, Chastre E, Benadda S, Pidard D, et al. Identification of mitogen-activated protein/extracellular signal-responsive kinase kinase 2 as a novel partner of the scaffolding protein human homolog of disc-large. FEBS J. 2011;278:2655-65 pubmed publisher
    ..showed a major involvement of the PSD-95, disc-large, ZO-1 domain-2 of hDlg and the C-terminal sequence RTAV of MEK2 in this interaction...
  3. Yan H, Zhao Y, Shi H, Li J, Wang Y, Tang D. BRASSINOSTEROID-SIGNALING KINASE1 Phosphorylates MAPKKK5 to Regulate Immunity in Arabidopsis. Plant Physiol. 2018;176:2991-3002 pubmed publisher
    ..Furthermore, MAPKKK5 interacts with multiple MAPK kinases, including MKK1, MKK2, MKK4, MKK5, and MKK6...
  4. Duhamel S, Girondel C, Dorn J, Tanguay P, Voisin L, Smits R, et al. Deregulated ERK1/2 MAP kinase signaling promotes aneuploidy by a Fbxw7?-Aurora A pathway. Cell Cycle. 2016;15:1631-42 pubmed publisher
    ..In vivo, conditional activation of MEK2 in the mouse intestine lowers Fbxw7? expression, resulting in the accumulation of cells with enlarged nuclei...
  5. Drag M, Skinkyté Juskiené R, Do D, Kogelman L, Kadarmideen H. Differential expression and co-expression gene networks reveal candidate biomarkers of boar taint in non-castrated pigs. Sci Rep. 2017;7:12205 pubmed publisher
    ..Future work should evaluate the biomarkers in large populations to ensure their usefulness in genomic selection programs. ..
  6. Ouyang W, Guo P, Fang H, Frucht D. Anthrax lethal toxin rapidly reduces c-Jun levels by inhibiting c-Jun gene transcription and promoting c-Jun protein degradation. J Biol Chem. 2017;292:17919-17927 pubmed publisher
    ..Ectopic expression of LT-resistant MKK2 and MKK4 variants partially restored Erk1/2 and JNK1/2 signaling in LT-exposed cells, enabling the cells to ..
  7. Maher G, Ralph H, Ding Z, Koelling N, Mlcochova H, Giannoulatou E, et al. Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes. Genome Res. 2018;: pubmed publisher
    ..Our findings extend the link between mutations dysregulating the RAS-MAPK pathway and selfish selection, and show that the ageing male germline is a repository for such deleterious mutations. ..
  8. Fukumura K, Kawazu M, Kojima S, Ueno T, Sai E, Soda M, et al. Genomic characterization of primary central nervous system lymphoma. Acta Neuropathol. 2016;131:865-75 pubmed publisher
  9. Nevado J, Rosenfeld J, Mena R, Palomares Bralo M, Vallespín E, Ángeles Mori M, et al. PIAS4 is associated with macro/microcephaly in the novel interstitial 19p13.3 microdeletion/microduplication syndrome. Eur J Hum Genet. 2015;23:1615-26 pubmed publisher
  10. Wei H, Chakravarthy S, Mathieu J, Helmann T, Stodghill P, Swingle B, et al. Pseudomonas syringae pv. tomato DC3000 Type III Secretion Effector Polymutants Reveal an Interplay between HopAD1 and AvrPtoB. Cell Host Microbe. 2015;17:752-62 pubmed publisher
    ..AvrPtoBM3 also gained the ability to interact with the immunity-kinase MKK2, which is required for HopAD1-dependent cell death...
  11. Rosner A, Alfassi G, Moiseeva E, Paz G, Rabinowitz C, Lapidot Z, et al. The involvement of three signal transduction pathways in botryllid ascidian astogeny, as revealed by expression patterns of representative genes. Int J Dev Biol. 2014;58:677-92 pubmed publisher
    ..supported by administering Wnt agonist and anatagonist, TGF-β receptor antagonists and inhibitors of Mek1/Mek2. Independent of their expression during ontogeny, some of the spatiotemporal patterns of STPs developed within ..
  12. Orchel J, Witek L, Kimsa M, Strzalka Mrozik B, Kimsa M, Olejek A, et al. Expression patterns of kinin-dependent genes in endometrial cancer. Int J Gynecol Cancer. 2012;22:937-44 pubmed publisher
    ..This will eventually help to improve treatment strategies for patients with endometrial cancer in the future. ..
  13. Jang S, Kim C, Kim J, Choi K. Transcriptional regulatory network of SOX4 during myoblast differentiation. Biochem Biophys Res Commun. 2015;462:365-70 pubmed publisher
    ..These results will provide opportunities to better understand the SOX4-centered transcriptional regulation network and TF-based specific gene expression in various cellular environments. ..
  14. Yamagishi M, Hosoda Yabe R, Tamai H, Konishi M, Imamura A, Ishida H, et al. Structure-Activity Relationship Study of the Neuritogenic Potential of the Glycan of Starfish Ganglioside LLG-3 (‡). Mar Drugs. 2015;13:7250-74 pubmed publisher
    ..These effects were abolished by pretreatment with the MAPK inhibitor U0126, which inhibits enzymes MEK1 and MEK2. In addition, U0126 inhibited the phosphorylation of ERK 1/2 in response to the trisaccharide dose-dependently...
  15. Siqueira R, Barros M, Barbosa É, Onofre T, Gonçalves V, Pereira H, et al. Trifluoromethyl arylamides with antileukemia effect and intracellular inhibitory activity over serine/arginine-rich protein kinases (SRPKs). Eur J Med Chem. 2017;134:97-109 pubmed publisher
    ..Therefore, novel compounds with increased intracellular effects against SRPK activity were obtained, contributing to medicinal chemistry efforts towards the development of new anticancer agents. ..
  16. de Cássia Viu Carrara R, Fontes A, Abraham K, Orellana M, Haddad S, Palma P, et al. Expression differences of genes in the PI3K/AKT, WNT/b-catenin, SHH, NOTCH and MAPK signaling pathways in CD34+ hematopoietic cells obtained from chronic phase patients with chronic myeloid leukemia and from healthy controls. Clin Transl Oncol. 2018;20:542-549 pubmed publisher
    ..We also identified five transcripts upregulated in CD34-CML patients named OSBPL9, MEK2, p90RSK, TCF4 and FZD7 that can be potential biomarkers in CD34-CML-CP...
  17. Abbott D, Holt J. Mitogen-activated protein kinase kinase 2 activation is essential for progression through the G2/M checkpoint arrest in cells exposed to ionizing radiation. J Biol Chem. 1999;274:2732-42 pubmed
    ..We show that both mitogen-activated protein (MAP) kinase kinase 1 (MEK1) and MAP kinase kinase 2 (MEK2) are activated by ionizing radiation...
  18. Kim J, Yang Y, Park K, Oh H, Greenblatt M, Shim J. The ERK MAPK Pathway Is Essential for Skeletal Development and Homeostasis. Int J Mol Sci. 2019;20: pubmed publisher
    ..Deletion of Mek1 and Mek2, kinases upstream of ERK MAPK, in osteoprogenitors (Mek1OsxMek2-/-), resulted in ..
  19. Janku F, Diamond E, Goodman A, Kandadai Raghavan V, Barnes T, Kato S, et al. Molecular Profiling of Tumor Tissue and Plasma Cell-Free DNA from Patients with Non-Langerhans Cell Histiocytosis. Mol Cancer Ther. 2019;: pubmed publisher
    ..Therefore, our multi-modal comprehensive genomics reveals clinically relevant alterations and suggests that MAPK activation is a hallmark of non-LCH. ..
  20. Coxon P, Rane M, Uriarte S, Powell D, Singh S, Butt W, et al. MAPK-activated protein kinase-2 participates in p38 MAPK-dependent and ERK-dependent functions in human neutrophils. Cell Signal. 2003;15:993-1001 pubmed
    ..ERK phosphorylated MK2 in vitro and activated MK2 in f-methionyl-leucyl-phenylalanine (FMLP)-stimulated neutrophils. These data suggest that MK2 mediates both ERK- and p38 MAPK-dependent neutrophil responses. ..
  21. Pinilla Macua I, Watkins S, Sorkin A. Endocytosis separates EGF receptors from endogenous fluorescently labeled HRas and diminishes receptor signaling to MAP kinases in endosomes. Proc Natl Acad Sci U S A. 2016;113:2122-7 pubmed publisher
    ..However, sustained minimal activation of Ras by a small pool of active EGFRs in the plasma membrane is sufficient for extending MEK1/2 and ERK1/2 activities. ..
  22. Brandt K, Carpintero R, Gruaz L, Molnarfi N, Burger D. A novel MEK2/PI3K? pathway controls the expression of IL-1 receptor antagonist in IFN-?-activated human monocytes. J Leukoc Biol. 2010;88:1191-200 pubmed publisher
    ..In this study, we identified PI3K? and MEK2 as key elements that control sIL-1Ra production in isolated human monocytes activated by IFN-?...
  23. Tetsu O, McCormick F. ETS-targeted therapy: can it substitute for MEK inhibitors?. Clin Transl Med. 2017;6:16 pubmed publisher
    ..MEK1 and MEK2 are ideal targets because these enzymes are physiologically important and have narrow substrate specificities and ..
  24. Li J, Wang R, Hu X, Gao Y, Wang Z, Li J, et al. Activated MEK/ERK Pathway Drives Widespread and Coordinated Overexpression of UHRF1 and DNMT1 in Cancer cells. Sci Rep. 2019;9:907 pubmed publisher
    ..in pluripotent ground state mouse embryonic stem cells (mESCs) cultured in the presence of two kinase (MEK1/MEK2 and GSK3β) inhibitors (termed 2i), raising the question whether UHRF1 is similarly regulated in cancer cells...
  25. Powell C, Wright M, Jackson R. p38mapk and MEK1/2 inhibition contribute to cellular oxidant injury after hypoxia. Am J Physiol Lung Cell Mol Physiol. 2004;286:L826-33 pubmed
    ..Stress-related signaling pathways in epithelial cells are modulated by hypoxia and confer protection from reoxygenation, since hypoxia and chemical inhibition of p38mapk and MEK1/2 similarly increase cytolysis resulting from O2-. ..
  26. Stove V, Verhasselt B. Modelling thymic HIV-1 Nef effects. Curr HIV Res. 2006;4:57-64 pubmed
    ..These in vitro and in vivo studies have led to a better understanding of Nef's mechanism of action, although there still exists discord as to the contribution of Nef-mediated disturbance of thymopoiesis in the pathogenesis of AIDS. ..
  27. Halbrook C, Wen H, Ruggeri J, Takeuchi K, Zhang Y, di Magliano M, et al. Mitogen-activated Protein Kinase Kinase Activity Maintains Acinar-to-Ductal Metaplasia and Is Required for Organ Regeneration in Pancreatitis. Cell Mol Gastroenterol Hepatol. 2017;3:99-118 pubmed publisher
    ..MEK inhibition may be useful in the treatment of chronic pancreatitis to interrupt the vicious cycle of destruction and repair but at the expense of organ regeneration. ..
  28. Lv X, Zhang X, Deng L, Jiang L, Meng W, Lu Z, et al. MiR-92a mediates AZD6244 induced apoptosis and G1-phase arrest of lymphoma cells by targeting Bim. Cell Biol Int. 2014;38:435-43 pubmed publisher
    ..Thus, miR-92a mediates AZD6244-induced cytotoxicity of lymphoma cells by targeting Bim. Downregulation of miR-92a by AZD6244 is mediated by the ERK1/2-AP1 signalling pathway. ..
  29. Donlin M, Upadhya R, Gerik K, Lam W, VanArendonk L, Specht C, et al. Cross talk between the cell wall integrity and cyclic AMP/protein kinase A pathways in Cryptococcus neoformans. MBio. 2014;5: pubmed publisher
    ..has shown that deletion of genes encoding the four major kinases in the CWI signaling pathway, namely, PKC1, BCK1, MKK2, and MPK1 results in severe cell wall phenotypes, sensitivity to a variety of cell wall stressors, and for Mpk1, ..
  30. Aoidi R, Maltais A, Charron J. Functional redundancy of the kinases MEK1 and MEK2: Rescue of the Mek1 mutant phenotype by Mek2 knock-in reveals a protein threshold effect. Sci Signal. 2016;9:ra9 pubmed publisher
    The mammalian genome contains two mitogen-activated protein kinase (MAPK) kinase (MEK)-encoding genes, Mek1 and Mek2. MEKs phosphorylate and activate the two extracellular signal-regulated kinase (ERK) isoforms ERK1 and ERK2...
  31. Liang H, Liu T, Chen F, Liu Z, Liu S. A full-length 3D structure for MAPK/ERK kinase 2 (MEK2). Sci China Life Sci. 2011;54:336-41 pubmed publisher
    ..to be elucidated how so many different signals can be variously transferred by only two MEK molecules (MEK1 and MEK2). Because of technological limitations the complete structures of the MEKs are still unavailable...
  32. Nenasheva V, Kovaleva G, Uryvaev L, Ionova K, Dedova A, Vorkunova G, et al. Enhanced expression of trim14 gene suppressed Sindbis virus reproduction and modulated the transcription of a large number of genes of innate immunity. Immunol Res. 2015;62:255-62 pubmed publisher
    ..1, akt1, tyk2, erk2, mek2) and lowered transcription of 3 genes (ifnγ, gata1, il-17a)...
  33. Bhat S, Mallya S, Varghese V, Jayaram P, Chakrabarty S, Joshi K, et al. DNA methylation detection at single base resolution using targeted next generation bisulfite sequencing and cross validation using capillary sequencing. Gene. 2016;594:259-267 pubmed publisher
    ..Use of targeted next generation bisulfite sequencing may provide an opportunity to explore genes in the discovery panel for biomarker identification and facilitate functional validation. ..
  34. Senger K, Pham V, Varfolomeev E, Hackney J, Corzo C, Collier J, et al. The kinase TPL2 activates ERK and p38 signaling to promote neutrophilic inflammation. Sci Signal. 2017;10: pubmed publisher
    ..is a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) that phosphorylates the MAPK kinases MEK1 and MEK2 (MEK1/2), which, in turn, activate the MAPKs extracellular signal-regulated kinase 1 (ERK1) and ERK2 (ERK1/2) in ..
  35. Aoidi R, Houde N, Landry Truchon K, Holter M, Jacquet K, Charron L, et al. Mek1Y130C mice recapitulate aspects of human cardio-facio-cutaneous syndrome. Dis Model Mech. 2018;11: pubmed publisher
    ..CFC) is a rare RASopathy associated with mutations in BRAF, KRAS, MEK1 (MAP2K1) and MEK2 (MAP2K2)...
  36. Legius E, Schollen E, Matthijs G, Fryns J. Fine mapping of Noonan/cardio-facio cutaneous syndrome in a large family. Eur J Hum Genet. 1998;6:32-7 pubmed
    ..We report a maximum lod score of 4.43 at zero recombination for marker D12S84 in 12q24. A crossover in this pedigree narrows the candidate gene region for NS to a 5 cM interval between markers D12S84 and D12S1341. ..
  37. Matheny S, Chen C, Kortum R, Razidlo G, Lewis R, White M. Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP. Nature. 2004;427:256-60 pubmed
  38. Vomastek T, Schaeffer H, Tarcsafalvi A, Smolkin M, Bissonette E, Weber M. Modular construction of a signaling scaffold: MORG1 interacts with components of the ERK cascade and links ERK signaling to specific agonists. Proc Natl Acad Sci U S A. 2004;101:6981-6 pubmed
    ..We propose that MORG1 is a component of a modular scaffold system that participates in the regulation of agonist-specific ERK signaling. ..
  39. Estep A, Palmer C, McCormick F, Rauen K. Mutation analysis of BRAF, MEK1 and MEK2 in 15 ovarian cancer cell lines: implications for therapy. PLoS ONE. 2007;2:e1279 pubmed
    ..were screened for mutations using bidirectional direct sequencing in all coding regions of BRAF, MEK1 and MEK2. BRAF mutations were identified in four of the fifteen ovarian cancer cell lines studied...
  40. Patel S, Singh S, Singh S. Standardized extract of Bacopa monnieri (CDRI-08): Effect on germ cell dynamics and possible mechanisms of its beneficial action on spermatogenesis and sperm quality in male mice. Biochem Biophys Res Commun. 2017;494:34-41 pubmed publisher
    ..A total of 26 phytocomponents were identified in CDRI-08 by GC-MS. The results suggest that CDRI-08 also may prove useful in improving reproductive health in males...
  41. Yoshizuka N, Yoshizuka Chadani Y, Krishnan V, Zeichner S. Human immunodeficiency virus type 1 Vpr-dependent cell cycle arrest through a mitogen-activated protein kinase signal transduction pathway. J Virol. 2005;79:11366-81 pubmed
    ..We found that Vpr expression is associated with the down-regulation of genes in the MEK2-ERK pathway and with decreased phosphorylation of the MEK2 effector protein ERK...
  42. Ellens H, Johnson M, Lawrence S, Watson C, Chen L, Richards Peterson L. Prediction of the Transporter-Mediated Drug-Drug Interaction Potential of Dabrafenib and Its Major Circulating Metabolites. Drug Metab Dispos. 2017;45:646-656 pubmed publisher
    ..alone or in combination therapy with the mitogen-activated extracellular signal regulated kinase 1 (MEK1) and MEK2 inhibitor, trametinib...
  43. Meloche S, Gopalbhai K, Beatty B, Scherer S, Pellerin J. Chromosome mapping of the human genes encoding the MAP kinase kinase MEK1 (MAP2K1) to 15q21 and MEK2 (MAP2K2) to 7q32. Cytogenet Cell Genet. 2000;88:249-52 pubmed
    ..this pathway, the MAP kinases ERK1/ERK2 are phosphorylated and activated by the dual-specificity kinases MEK1 and MEK2, which in turn are activated by serine phosphorylation by a number of MAP kinase kinase kinases...
  44. Johnson S, Winner D, Wang X. Ran binding protein 9 interacts with Raf kinase but does not contribute to downstream ERK1/2 activation in skeletal myoblasts. Biochem Biophys Res Commun. 2006;340:409-16 pubmed
    ..Knockdown of RanBP9 expression did not restore the differentiation program to Raf-expressing myoblasts. Thus, RanBP9 physically associates with Raf but does not substantially contribute to the inhibitory actions of the kinase...
  45. Ho D, Bardwell A, Grewal S, Iverson C, Bardwell L. Interacting JNK-docking sites in MKK7 promote binding and activation of JNK mitogen-activated protein kinases. J Biol Chem. 2006;281:13169-79 pubmed
    ..high affinity D-site has been identified near the N terminus of each of the MAPK kinases (MKKs or MEKs) MEK1, MEK2, MKK3, MKK4, and MKK6...
  46. Gailhouste L, Ezan F, Bessard A, Frémin C, Rageul J, Langouet S, et al. RNAi-mediated MEK1 knock-down prevents ERK1/2 activation and abolishes human hepatocarcinoma growth in vitro and in vivo. Int J Cancer. 2010;126:1367-77 pubmed publisher
    ..and ERK2 after growth factors stimulation, whereas oncogenic level of ERK1/2 phosphorylation appears to be MEK1 and MEK2 dependent in basal condition...
  47. Zeiser R, Andrlova H, Meiss F. Trametinib (GSK1120212). Recent Results Cancer Res. 2018;211:91-100 pubmed publisher
    ..Trametinib (GSK1120212), an oral MEK inhibitor which is selective for MEK1 and MEK2, has been approved by the FDA for the treatment of metastatic melanoma in a combination with a BRAF inhibitor...
  48. Redwan I, Dyrager C, Solano C, Fernández de Trocóniz G, Voisin L, Bliman D, et al. Towards the development of chromone-based MEK1/2 modulators. Eur J Med Chem. 2014;85:127-38 pubmed publisher
    Inhibition or allosteric modulation of mitogen-activated protein kinase kinases MEK1 and MEK2 (MEK1/2) represent a promising strategy for the discovery of new specific anticancer agents...
  49. NicoÅ› M, Krawczyk P, Jarosz B, Sawicki M, Michnar M, Trojanowski T, et al. Sensitive methods for screening of the MEK1 gene mutations in patients with central nervous system metastases of non-small cell lung cancer. Clin Transl Oncol. 2016;18:1039-43 pubmed publisher
    The mitogen-activated protein kinases 1 and 2 (MEK1, MEK2) are fundamental partners in the RAS-RAF-MEK-ERK pathway that is involved in regulation of cell proliferation, differentiation and survival...
  50. Shimojima K, Ondo Y, Matsufuji M, Sano N, Tsuru H, Oyoshi T, et al. 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. Eur J Med Genet. 2016;59:559-563 pubmed publisher
    ..11 microduplications. Genetic contributions of both chromosomal aberrations were discussed. ..
  51. Loviglio M, Beck C, White J, Leleu M, Harel T, Guex N, et al. Identification of a RAI1-associated disease network through integration of exome sequencing, transcriptomics, and 3D genomics. Genome Med. 2016;8:105 pubmed
    ..Our findings support a pan-genomic approach to the molecular diagnosis of a distinctive disorder. ..
  52. Linden H, Price S. Cardiofaciocutaneous syndrome in a mother and two sons with a MEK2 mutation. Clin Dysmorphol. 2011;20:86-8 pubmed publisher
  53. Anton L, Brown A, Parry S, Elovitz M. Lipopolysaccharide induces cytokine production and decreases extravillous trophoblast invasion through a mitogen-activated protein kinase-mediated pathway: possible mechanisms of first trimester placental dysfunction. Hum Reprod. 2012;27:61-72 pubmed publisher
    ..LPS increased IL-8 and IL-6 and decreased EVT invasion through activation of MAPK signaling. MEK1/2 activation may contribute to placental dysfunction, in the setting of inflammation-associated adverse obstetrical outcomes. ..
  54. Wood K, Hensing T, Malik R, Salgia R. Prognostic and Predictive Value in KRAS in Non-Small-Cell Lung Cancer: A Review. JAMA Oncol. 2016;2:805-12 pubmed publisher
    ..and phase 3 clinical trials have demonstrated success in inhibiting downstream effectors, specifically MEK1 and/or MEK2 with selumetinib and trametinib (albeit with poor tolerability)...
  55. Gomez Millan J, Pajares B, Perez Villa L, Carnero A, Alvarez M, de Luque V, et al. Subcellular localisation of pMEK has a different prognosis in locally advanced head and neck cancer treated with concomitant radiochemotherapy. BMC Cancer. 2016;16:829 pubmed
    MEK1 (MAP2K1) and MEK2 (MAP2K2) are closely related dual-specificity protein kinases which function by phosphorylating both serine/threonine and tyrosine residues of their substrates ERK1 and ERK2, controlling fundamental cellular ..
  56. Ikeda M, Ioka T, Fukutomi A, Morizane C, Kasuga A, Takahashi H, et al. Efficacy and safety of trametinib in Japanese patients with advanced biliary tract cancers refractory to gemcitabine. Cancer Sci. 2017;: pubmed publisher
    ..Trametinib is a potent, highly selective, allosteric non-competitive inhibitor of MEK1/MEK2. In this Phase IIa open-label, single-arm study, we investigated efficacy and safety of trametinib in Japanese ..
  57. Todd J, Tanner K, Denu J. Extracellular regulated kinases (ERK) 1 and ERK2 are authentic substrates for the dual-specificity protein-tyrosine phosphatase VHR. A novel role in down-regulating the ERK pathway. J Biol Chem. 1999;274:13271-80 pubmed
    ..The data strongly suggest that VHR is responsible for the rapid inactivation of ERK following stimulation and for its repression in quiescent cells. ..
  58. Li W, Cui K, Prochownik E, Li Y. The deubiquitinase USP21 stabilizes MEK2 to promote tumor growth. Cell Death Dis. 2018;9:482 pubmed publisher
    ..Mechanistically, USP21 stabilized MEK2 by decreasing its polyubiquitination at Lys48, thereby activating the ERK signaling pathway...
  59. Leach N, Wilson Mathews D, Rosenblum L, Zhou Z, Zhu H, Heim R. Comparative assessment of gene-specific variant distribution in prenatal and postnatal cohorts tested for Noonan syndrome and related conditions. Genet Med. 2019;21:417-425 pubmed publisher
    ..3% for postnatal. Comparison of prenatal versus postnatal specimens demonstrates that the pattern of specific gene involvement is similar, whereas the classification spectrum of observed variants differs considerably. ..
  60. Derijard B, Raingeaud J, Barrett T, Wu I, Han J, Ulevitch R, et al. Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms. Science. 1995;267:682-5 pubmed
    ..These data demonstrate that the activators of p38 (MKK3 and MKK4), JNK (MKK4), and ERK (MEK1 and MEK2) define independent MAP kinase signal transduction pathways.
  61. Wang J, Chen S, Liao Y, Zhang E, Feng S, Yu S, et al. Mitogen-Activated Protein Kinase Kinase 2, a Novel E2-Interacting Protein, Promotes the Growth of Classical Swine Fever Virus via Attenuation of the JAK-STAT Signaling Pathway. J Virol. 2016;90:10271-10283 pubmed publisher
    ..In this study, MEK2 was identified as a novel binding partner of the E2 protein of CSFV using yeast two-hybrid screening...
  62. Ganju R, Munshi N, Nair B, Liu Z, Gill P, Groopman J. Human immunodeficiency virus tat modulates the Flk-1/KDR receptor, mitogen-activated protein kinases, and components of focal adhesion in Kaposi's sarcoma cells. J Virol. 1998;72:6131-7 pubmed
    ..These studies reveal that Tat stimulation activates a number of signal transduction pathways that are associated with cell growth and migration. ..
  63. McKay M, Ritt D, Morrison D. Signaling dynamics of the KSR1 scaffold complex. Proc Natl Acad Sci U S A. 2009;106:11022-7 pubmed publisher
    ..Here, we identify a hydrophobic motif within the proline-rich sequence (PRS) of MEK1 and MEK2 that is required for constitutive binding to KSR1 and find that MEK binding and residues in the KSR1 CA1 region ..
  64. Huth H, Albarnaz J, Torres A, Bonjardim C, Ropert C. MEK2 controls the activation of MKK3/MKK6-p38 axis involved in the MDA-MB-231 breast cancer cell survival: Correlation with cyclin D1 expression. Cell Signal. 2016;28:1283-91 pubmed publisher
    ..However, the exact contributions of MEK1 and MEK2 to the development of cancer remain to be established...
  65. Schaeffer H, Catling A, Eblen S, Collier L, Krauss A, Weber M. MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. Science. 1998;281:1668-71 pubmed
    ..Expression of MP1 in cells increased binding of ERK1 to MEK1. MP1 apparently functions as an adapter to enhance the efficiency of the MAP kinase cascade. ..
  66. Meng J, Fang B, Liao Y, Chresta C, Smith P, Roth J. Apoptosis induction by MEK inhibition in human lung cancer cells is mediated by Bim. PLoS ONE. 2010;5:e13026 pubmed publisher
    ..These results have implications in the development of strategies to overcome resistance to MEK inhibitors. ..
  67. Nava C, Hanna N, Michot C, Pereira S, Pouvreau N, Niihori T, et al. Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome. J Med Genet. 2007;44:763-71 pubmed
    ..This study was a mutation analysis of the KRAS, BRAF, MEK1 and MEK2 genes in a total of 130 patients (40 patients with a clinical diagnosis of CFC, 20 patients without HRAS mutations ..
  68. Schweppe R, Kerege A, Sharma V, Poczobutt J, Gutierrez Hartmann A, Grzywa R, et al. Distinct genetic alterations in the mitogen-activated protein kinase pathway dictate sensitivity of thyroid cancer cells to mitogen-activated protein kinase kinase 1/2 inhibition. Thyroid. 2009;19:825-35 pubmed publisher
    ..These results indicate that MKK1/2 inhibitors have the potential to inhibit thyroid cancer growth and invasion, but that responses differ based on mutation status and growth conditions. ..
  69. Ciara E, Pelc M, Jurkiewicz D, Kugaudo M, Gieruszczak Białek D, Skórka A, et al. Is diagnosing cardio-facio-cutaneous (CFC) syndrome still a challenge? Delineation of the phenotype in 15 Polish patients with proven mutations, including novel mutations in the BRAF1 gene. Eur J Med Genet. 2015;58:14-20 pubmed publisher
    ..We documented three novel mutations in the BRAF gene and correlated clinical findings with causative mutations in the BRAF or MEK1/MEK2 genes.
  70. Xia Y, Wu Z, Su B, Murray B, Karin M. JNKK1 organizes a MAP kinase module through specific and sequential interactions with upstream and downstream components mediated by its amino-terminal extension. Genes Dev. 1998;12:3369-81 pubmed
    ..These results underscore a role for the amino-terminal extension of MAPKKs in determination of response specificity. ..
  71. Schrager J, Der Minassian V, Marsh J. HIV Nef increases T cell ERK MAP kinase activity. J Biol Chem. 2002;277:6137-42 pubmed
    ..By increasing ERK MAP kinase activity, Nef is functionally associated with a kinase known to affect T cell activity, viral replication, and viral infectivity. ..
  72. Guenther M, Graab U, Fulda S. Synthetic lethal interaction between PI3K/Akt/mTOR and Ras/MEK/ERK pathway inhibition in rhabdomyosarcoma. Cancer Lett. 2013;337:200-9 pubmed publisher
    ..This identification of a synthetic lethal interaction between PI3K/mTOR and MEK inhibitors has important implications for the development of novel treatment strategies in RMS. ..
  73. Guegan J, Ezan F, Gailhouste L, Langouet S, Baffet G. MEK1/2 overactivation can promote growth arrest by mediating ERK1/2-dependent phosphorylation of p70S6K. J Cell Physiol. 2014;229:903-15 pubmed publisher
    ..Indeed, whereas MEK1 silencing inhibits cell cycle progression, we demonstrate that active mutant form of MEK1 or MEK2 triggers a G1 phase arrest by stimulating an activation of p70S6K by ERK1/2 kinases...
  74. Queralt B, Cuyàs E, Bosch Barrera J, Massaguer A, de Llorens R, Martin Castillo B, et al. Synthetic lethal interaction of cetuximab with MEK1/2 inhibition in NRAS-mutant metastatic colorectal cancer. Oncotarget. 2016;7:82185-82199 pubmed publisher
  75. Khoo S, Cobb M. Activation of mitogen-activating protein kinase by glucose is not required for insulin secretion. Proc Natl Acad Sci U S A. 1997;94:5599-604 pubmed
    ..These findings suggest that some of the glucose-dependent actions of ERKs will be exerted in the nucleus. ..
  76. Manna S, Aggarwal B. Differential requirement for p56lck in HIV-tat versus TNF-induced cellular responses: effects on NF-kappa B, activator protein-1, c-Jun N-terminal kinase, and apoptosis. J Immunol. 2000;164:5156-66 pubmed
    ..Overall, our results demonstrate that p56lck plays a critical role in the activation of NF-kappa B, AP-1, JNK, and apoptosis by HIV-tat protein but has minimal or no role in activation of these responses by TNF. ..
  77. Kutsch O, Oh J, Nath A, Benveniste E. Induction of the chemokines interleukin-8 and IP-10 by human immunodeficiency virus type 1 tat in astrocytes. J Virol. 2000;74:9214-21 pubmed
    ..In contrast, Tat-mediated IP-10 mRNA induction was suppressed by SB202190 but not by the MEK1/2 inhibitor UO126. These findings indicate that MAPKs play a major role in Tat(72aa)-mediated chemokine induction in astrocytes. ..
  78. Ma S, Musa T, Bag J. Reduced stability of mitogen-activated protein kinase kinase-2 mRNA and phosphorylation of poly(A)-binding protein (PABP) in cells overexpressing PABP. J Biol Chem. 2006;281:3145-56 pubmed
    ..Thus, a novel signaling pathway involving MKK-2 and ERK1/2 may down-regulate the activity of PABP and eIF4E by controlling their phosphorylation and compensates for the effect of excess cellular PABP. ..
  79. Ong Q, Guo S, Zhang K, Cui B. U0126 protects cells against oxidative stress independent of its function as a MEK inhibitor. ACS Chem Neurosci. 2015;6:130-7 pubmed publisher
    U0126 is a potent and selective inhibitor of MEK1 and MEK2 kinases. It has been widely used as an inhibitor for the Ras/Raf/MEK/ERK signaling pathway with over 5000 references on the NCBI PubMed database...
  80. Ozkaya N, Rosenblum M, Durham B, Pichardo J, Abdel Wahab O, Hameed M, et al. The histopathology of Erdheim-Chester disease: a comprehensive review of a molecularly characterized cohort. Mod Pathol. 2017;: pubmed publisher
    ..Modern Pathology advance online publication, 1 December 2017; doi:10.1038/modpathol.2017.160...
  81. Jameson K, Mazur P, Zehnder A, Zhang J, Zarnegar B, Sage J, et al. IQGAP1 scaffold-kinase interaction blockade selectively targets RAS-MAP kinase-driven tumors. Nat Med. 2013;19:626-630 pubmed publisher
    ..Furthermore, recently identified ERK1/2-inducing mutations in MEK1 and MEK2 (MEK1/2) MAPK genes in melanoma confer resistance to emerging therapeutic MEK inhibitors, underscoring the ..
  82. Román E, Alonso Monge R, Miranda A, Pla J. The Mkk2 MAPKK Regulates Cell Wall Biogenesis in Cooperation with the Cek1-Pathway in Candida albicans. PLoS ONE. 2015;10:e0133476 pubmed publisher
    ..In the present work, the C. albicans MKK2 gene that encodes the putative MAPKK of this pathway was deleted in different backgrounds and the phenotypes of the ..
  83. Shangguan X, Zhang J, Liu B, Zhao Y, Wang H, Wang Z, et al. A Mucin-Like Protein of Planthopper Is Required for Feeding and Induces Immunity Response in Plants. Plant Physiol. 2018;176:552-565 pubmed publisher
    ..These defense responses are related to Ca2+ mobilization and the MEK2 MAP kinase and jasmonic acid signaling pathways...
  84. Won M, Park K, Byun H, Kim Y, Choi B, Hong J, et al. Protein kinase SGK1 enhances MEK/ERK complex formation through the phosphorylation of ERK2: implication for the positive regulatory role of SGK1 on the ERK function during liver regeneration. J Hepatol. 2009;51:67-76 pubmed publisher
    ..SGK1 expression during liver regeneration is a part of a signaling pathway that is necessary for enhancing ERK signaling activation through modulating the MEK/ERK complex formation. ..
  85. Yokota S, Okabayashi T, Rehli M, Fujii N, Amano K. Helicobacter pylori lipopolysaccharides upregulate toll-like receptor 4 expression and proliferation of gastric epithelial cells via the MEK1/2-ERK1/2 mitogen-activated protein kinase pathway. Infect Immun. 2010;78:468-76 pubmed publisher
    ..H. pylori LPS may be a pathogenic factor causing gastric tumors by enhancing cell proliferation and inflammation via the MEK1/2-ERK1/2 mitogen-activated protein kinase cascade in gastric epithelial cells. ..
  86. Chen H, Feener E. MEK1,2 response element mediates angiotensin II-stimulated plasminogen activator inhibitor-1 promoter activation. Blood. 2004;103:2636-44 pubmed
    ..This report identifies the MEK1,2 response element that mediates angiotensin II-stimulated PAI-1 promoter activation and shows that activation of this element requires Sp1 and AP-1 co-activation. ..
  87. Lemeer S, Gholami A, Wu Z, Kuster B. Quantitative proteome profiling of human myoma and myometrium tissue reveals kinase expression signatures with potential for therapeutic intervention. Proteomics. 2015;15:356-64 pubmed publisher
    ..Of note, the receptor tyrosine kinase DDR1 holds future potential as a drug target owing to its strong links to collagen signaling and the excessive formation of extracellular matrix typical for leiomyomas in humans. ..
  88. van Trier D, van Nierop J, Draaisma J, van der Burgt I, Kunst H, Croonen E, et al. External ear anomalies and hearing impairment in Noonan Syndrome. Int J Pediatr Otorhinolaryngol. 2015;79:874-8 pubmed publisher
    ..NS is characterized by dysmorphic external ear anomalies and both sensorineural and conductive hearing impairment. Audiological examinations are recommended in all patients with Noonan Syndrome. ..
  89. Wang C, Wang P, Chen X, Wang W, Jin Y. Saururus chinensis (Lour.) Baill blocks enterovirus 71 infection by hijacking MEK1-ERK signaling pathway. Antiviral Res. 2015;119:47-56 pubmed publisher
    ..Knockdown of MEK1 but not MEK2 blocked EV71 replication. And SCB treatment inhibited the activation of MEK1-ERK signal during EV71 infection...
  90. Siqueira R, Barbosa Ã, Polêto M, Righetto G, Seraphim T, Salgado R, et al. Potential Antileukemia Effect and Structural Analyses of SRPK Inhibition by N-(2-(Piperidin-1-yl)-5-(Trifluoromethyl)Phenyl)Isonicotinamide (SRPIN340). PLoS ONE. 2015;10:e0134882 pubmed publisher
    ..Moreover, the obtained SRPK-ligand interaction data provide useful structural information to guide further medicinal chemistry efforts towards the development of novel drug candidates. ..
  91. Deng X, Zhu T, Peng X, Xi D, Guo H, Yin Y, et al. Role of brassinosteroid signaling in modulating Tobacco mosaic virus resistance in Nicotiana benthamiana. Sci Rep. 2016;6:20579 pubmed publisher
    ..Furthermore, we found MEK2-SIPK cascade activated while BES1/BZR1 inhibited RBOHB-dependent ROS production, defense gene expression and virus ..
  92. Roskoski R. Targeting oncogenic Raf protein-serine/threonine kinases in human cancers. Pharmacol Res. 2018;135:239-258 pubmed publisher
    ..These enzymes are protein-serine/threonine kinases that catalyze the phosphorylation and activation of MEK1 and MEK2 which, in turn, catalyze the phosphorylation and activation of ERK1 and ERK2...