map kinase kinase 2

Summary

Summary: A 44 kDa mitogen-activated protein kinase kinase with specificity for MITOGEN-ACTIVATED PROTEIN KINASE 1 and MITOGEN-ACTIVATED PROTEIN KINASE 3.

Top Publications

  1. Yeh T, Marsh V, Bernat B, Ballard J, Colwell H, Evans R, et al. Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor. Clin Cancer Res. 2007;13:1576-83 pubmed
    ..ARRY-142886 is a potent and selective MEK1/2 inhibitor that is highly active in both in vitro and in vivo tumor models. This compound is currently being investigated in clinical studies. ..
  2. Yang J, Chang C, Xia W, Wang Y, WONG K, Engelman J, et al. Activation of FOXO3a is sufficient to reverse mitogen-activated protein/extracellular signal-regulated kinase kinase inhibitor chemoresistance in human cancer. Cancer Res. 2010;70:4709-18 pubmed publisher
    ..Furthermore, they suggest a mechanism of resistance to MEK inhibitors that may arise in the clinic yet can be overcome by cotreatment with PI3K/AKT inhibitors. ..
  3. Wang X, Khaleque M, Zhao M, Zhong R, Gaestel M, Calderwood S. Phosphorylation of HSF1 by MAPK-activated protein kinase 2 on serine 121, inhibits transcriptional activity and promotes HSP90 binding. J Biol Chem. 2006;281:782-91 pubmed
    ..These experiments indicate a novel mechanism for the regulation of HSF1 by proinflammatory signaling and may permit HSF1 to respond rapidly to extracellular events, permitting optimal physiological regulation. ..
  4. Iverson C, Larson G, Lai C, Yeh L, Dadson C, Weingarten P, et al. RDEA119/BAY 869766: a potent, selective, allosteric inhibitor of MEK1/2 for the treatment of cancer. Cancer Res. 2009;69:6839-47 pubmed publisher
    ..RDEA119/BAY 869766, an exquisitely selective, orally available MEK inhibitor, has been selected for clinical development because of its potency and favorable pharmacokinetic profile...
  5. 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
    ..These data indicate that Mek1/2 are functionally redundant in the epidermis, where they act as a linear relay in the MAPK pathway to mediate development and homeostasis. ..
  6. Ji H, Wang Z, Perera S, Li D, Liang M, Zaghlul S, et al. Mutations in BRAF and KRAS converge on activation of the mitogen-activated protein kinase pathway in lung cancer mouse models. Cancer Res. 2007;67:4933-9 pubmed
    ..These results unveil a potential common vulnerability of BRAF and KRas mutant lung tumors that potentially affects rational deployment of MEK targeted therapies to non-small-cell lung cancer patients. ..
  7. Mittal R, Peak Chew S, McMahon H. Acetylation of MEK2 and I kappa B kinase (IKK) activation loop residues by YopJ inhibits signaling. Proc Natl Acad Sci U S A. 2006;103:18574-9 pubmed
  8. 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
  9. 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. ..

More Information

Publications62

  1. Daouti S, Wang H, Li W, Higgins B, Kolinsky K, Packman K, et al. Characterization of a novel mitogen-activated protein kinase kinase 1/2 inhibitor with a unique mechanism of action for cancer therapy. Cancer Res. 2009;69:1924-32 pubmed publisher
    ..The unique MAPK signaling blockade mediated by RO4927350 in cancer may reduce the risk of developing drug resistance. Thus, RO4927350 represents a novel therapeutic modality in cancers with aberrant MAPK pathway activation. ..
  2. 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
    ..Our findings highlight the involvement of the MAPK pathway in human development and will provide a molecular diagnosis of CFC syndrome. ..
  3. Yamaguchi T, Kakefuda R, Tajima N, Sowa Y, Sakai T. Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo. Int J Oncol. 2011;39:23-31 pubmed publisher
    ..These results suggest the usefulness of JTP-74057 in therapeutic applications for colorectal cancer patients. ..
  4. Yoon Y, Kim H, Han S, Hur H, Oh D, Im S, et al. Combination of EGFR and MEK1/2 inhibitor shows synergistic effects by suppressing EGFR/HER3-dependent AKT activation in human gastric cancer cells. Mol Cancer Ther. 2009;8:2526-36 pubmed publisher
    ..Our results provide the basis for a rational combination strategy against human EGFR WT gastric cancers, predicated on the understanding of cross-talk between the MEK and EGFR pathways. ..
  5. Pei X, Dai Y, Youssefian L, Chen S, Bodie W, Takabatake Y, et al. Cytokinetically quiescent (G0/G1) human multiple myeloma cells are susceptible to simultaneous inhibition of Chk1 and MEK1/2. Blood. 2011;118:5189-200 pubmed publisher
    ..These findings provide evidence that cytokinetically quiescent MM cells are highly susceptible to simultaneous Chk1 and MEK1/2 inhibition. ..
  6. Banerji U, Camidge D, Verheul H, Agarwal R, Sarker D, Kaye S, et al. The first-in-human study of the hydrogen sulfate (Hyd-sulfate) capsule of the MEK1/2 inhibitor AZD6244 (ARRY-142886): a phase I open-label multicenter trial in patients with advanced cancer. Clin Cancer Res. 2010;16:1613-23 pubmed publisher
    ..The AZD6244 Hyd-Sulfate capsule formulation has shown a favorable toxicity, pharmacokinetic, and pharmacodynamic profile, and is being taken forward in ongoing clinical trials. ..
  7. Flaherty K, Robert C, Hersey P, Nathan P, Garbe C, Milhem M, et al. Improved survival with MEK inhibition in BRAF-mutated melanoma. N Engl J Med. 2012;367:107-14 pubmed publisher
    ..Funded by GlaxoSmithKline; METRIC ClinicalTrials.gov number, NCT01245062.). ..
  8. 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
    ..Our results suggest that MEK2 plays a more important role than MEK1 in sustaining the proliferation of human colorectal cancer cells. ..
  9. Scholl F, Dumesic P, Barragan D, Charron J, Khavari P. Mek1/2 gene dosage determines tissue response to oncogenic Ras signaling in the skin. Oncogene. 2009;28:1485-95 pubmed publisher
    ..Thus, the effects of oncogenic Ras on proliferation and differentiation in skin show a gene dosage-dependent requirement for the Erk1/2 MAPK cascade at the level of Mek1/2 MAPKKs. ..
  10. Pei X, Dai Y, Tenorio S, Lu J, Harada H, Dent P, et al. MEK1/2 inhibitors potentiate UCN-01 lethality in human multiple myeloma cells through a Bim-dependent mechanism. Blood. 2007;110:2092-101 pubmed
  11. Xiong B, Sun S, Lin S, Li M, Xu B, Ouyang Y, et al. Involvement of Polo-like kinase 1 in MEK1/2-regulated spindle formation during mouse oocyte meiosis. Cell Cycle. 2008;7:1804-9 pubmed
    ..Taken together, these data indicate that Plk1 and MEK1/2 regulate the spindle formation in the same pathway and that Plk1 is involved in MEK1/2-regulated spindle assembly during mouse oocyte meiotic maturation. ..
  12. Daouti S, Higgins B, Kolinsky K, Packman K, Wang H, Rizzo C, et al. Preclinical in vivo evaluation of efficacy, pharmacokinetics, and pharmacodynamics of a novel MEK1/2 kinase inhibitor RO5068760 in multiple tumor models. Mol Cancer Ther. 2010;9:134-44 pubmed publisher
    ..This study may facilitate future clinical trial design in using biochemical markers for early proof of mechanism and in selecting the right patients and optimal dose regimen. ..
  13. Yu L, Xiong B, Gao W, Wang C, Zhong Z, Huo L, et al. MEK1/2 regulates microtubule organization, spindle pole tethering and asymmetric division during mouse oocyte meiotic maturation. Cell Cycle. 2007;6:330-8 pubmed
    ..Our results suggest that MEK1/2 may function as a centrosomal protein and may have roles in microtubule organization, spindle pole tethering and asymmetric division during mouse oocyte maturation. ..
  14. Burgermeister E, Chuderland D, Hanoch T, Meyer M, Liscovitch M, Seger R. Interaction with MEK causes nuclear export and downregulation of peroxisome proliferator-activated receptor gamma. Mol Cell Biol. 2007;27:803-17 pubmed
    ..This unanticipated role for the stimulation-induced nuclear shuttling of MEKs shows that MEKs can regulate additional signaling components besides the ERK cascade. ..
  15. 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
  16. Kirkwood J, Bastholt L, Robert C, Sosman J, Larkin J, Hersey P, et al. Phase II, open-label, randomized trial of the MEK1/2 inhibitor selumetinib as monotherapy versus temozolomide in patients with advanced melanoma. Clin Cancer Res. 2012;18:555-67 pubmed publisher
    ..Five of six patients with partial response to selumetinib had BRAF mutant tumors. ..
  17. LoRusso P, Adjei A, Varterasian M, Gadgeel S, Reid J, Mitchell D, et al. Phase I and pharmacodynamic study of the oral MEK inhibitor CI-1040 in patients with advanced malignancies. J Clin Oncol. 2005;23:5281-93 pubmed
    ..CI-1040 was well tolerated at 800 mg BID administered with food. Both target suppression and antitumor activity were demonstrated in this phase I study. ..
  18. Catalanotti F, Reyes G, Jesenberger V, Galabova Kovacs G, de Matos Simoes R, Carugo O, et al. A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal. Nat Struct Mol Biol. 2009;16:294-303 pubmed publisher
    ..Our data establish Mek1 as the crucial modulator of Mek and Erk signaling and have potential implications for the role of Mek1 and Mek2 in tumorigenesis. ..
  19. 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's inhibition of the expected target and clinical activity warrants its further development as a monotherapy and in combination. GlaxoSmithKline. ..
  20. Nadeau V, Guillemette S, Bélanger L, Jacob O, Roy S, Charron J. Map2k1 and Map2k2 genes contribute to the normal development of syncytiotrophoblasts during placentation. Development. 2009;136:1363-74 pubmed publisher
    ..Thus, even though Map2k1 plays a predominant role, these results enlighten the function of Map2k2 in placenta development. ..
  21. 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
  22. Scholl F, Dumesic P, Barragan D, Harada K, Charron J, Khavari P. Selective role for Mek1 but not Mek2 in the induction of epidermal neoplasia. Cancer Res. 2009;69:3772-8 pubmed publisher
    ..These data show that Mek1 is important for skin tumor development and that Mek2 cannot compensate for the loss of Mek1 function in this setting...
  23. Sturgill T. MAP kinase: it's been longer than fifteen minutes. Biochem Biophys Res Commun. 2008;371:1-4 pubmed publisher
    ..Functional differences may explain why instances of cell cycle arrest can be MEK1 or MEK2 dependent. ..
  24. 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
  25. Yao Z, Seger R. The ERK signaling cascade--views from different subcellular compartments. Biofactors. 2009;35:407-16 pubmed publisher
    ..In this review, we discuss the intracellular localizations of different components of the ERK cascade, and the impact of these localizations on their activation and specificity. ..
  26. Tsai J, Qiu W, Kohen Avramoglu R, Adeli K. MEK-ERK inhibition corrects the defect in VLDL assembly in HepG2 cells: potential role of ERK in VLDL-ApoB100 particle assembly. Arterioscler Thromb Vasc Biol. 2007;27:211-8 pubmed
    ..Modulation of this pathway in primary hepatocytes also regulates apoB secretion and appears to alter the formation of VLDL-1 sized particles. ..
  27. Bekaii Saab T, Phelps M, Li X, Saji M, Goff L, Kauh J, et al. Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancers. J Clin Oncol. 2011;29:2357-63 pubmed publisher
    ..Selumetinib is an inhibitor of MEK1/2, so this trial was designed to determine the safety and efficacy of selumetinib in BC...
  28. Jin H, Liu Y, Yang K, Kim C, Baker B, Zhang S. Function of a mitogen-activated protein kinase pathway in N gene-mediated resistance in tobacco. Plant J. 2003;33:719-31 pubmed
  29. Bélanger L, Roy S, Tremblay M, Brott B, Steff A, Mourad W, et al. Mek2 is dispensable for mouse growth and development. Mol Cell Biol. 2003;23:4778-87 pubmed
    ..Altogether, our findings demonstrate that MEK2 is not necessary for the normal development of the embryo and T-cell lineages, suggesting that the loss of MEK2 can be compensated for by MEK1. ..
  30. Bardwell A, Abdollahi M, Bardwell L. Anthrax lethal factor-cleavage products of MAPK (mitogen-activated protein kinase) kinases exhibit reduced binding to their cognate MAPKs. Biochem J. 2004;378:569-77 pubmed
    ..Here we show that the C-terminal LF-cleavage products of MEK1, MEK2, MKK3, MKK4, MKK6 and MKK7 are impaired in their ability to bind to their MAPK substrates, suggesting a common mechanism for the LF-induced inhibition of signalling. ..
  31. 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
    ..Thus, the structures reported here reveal a novel, noncompetitive mechanism for protein kinase inhibition. ..
  32. Fukuda R, Hirota K, Fan F, Jung Y, Ellis L, Semenza G. Insulin-like growth factor 1 induces hypoxia-inducible factor 1-mediated vascular endothelial growth factor expression, which is dependent on MAP kinase and phosphatidylinositol 3-kinase signaling in colon cancer cells. J Biol Chem. 2002;277:38205-11 pubmed
    ..Involvement of the MAP kinase pathway represents a novel mechanism for the induction of HIF-1 alpha protein expression in human cancer cells. ..
  33. Scholl F, Dumesic P, Khavari P. Mek1 alters epidermal growth and differentiation. Cancer Res. 2004;64:6035-40 pubmed
    ..Mek1 is thus sufficient to promote the proliferative epithelial phenotype in a manner independent of intact kinase function. ..
  34. Huang Y, Li R, Chen X, Zhuo Y, Jin R, Qian X, et al. Doxycycline up-regulates the expression of IL-6 and GM-CSF via MAPK/ERK and NF-?B pathways in mouse thymic epithelial cells. Int Immunopharmacol. 2011;11:1143-9 pubmed publisher
    ..These findings warrant further investigation into the potential application of Dox in T-cell reconstitution in such situations as chemotherapy, radiotherapy, bone marrow transplantation and HIV infection. ..
  35. Flamand N, Luo M, Peters Golden M, Brock T. Phosphorylation of serine 271 on 5-lipoxygenase and its role in nuclear export. J Biol Chem. 2009;284:306-13 pubmed publisher
    ..This action works in concert with nuclear import, which is regulated by phosphorylation on Ser-523, to determine the subcellular distribution of 5-LO, which in turn regulates leukotriene biosynthesis. ..
  36. 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
    ..In conclusion, our data emphasizes the importance of the translational regulation of p21 by the MEK1/2-ERK1/2-p70S6K pathway to negatively control the cell cycle progression. ..
  37. Na K, Kim Y, Park Y. Mitogen-activated protein kinase pathway in osteosarcoma. Pathology. 2012;44:540-6 pubmed
    ..Furthermore, there may be a decrease in EFS and OVS in OS patients who have tumours that stain positively for pMEK. ..
  38. Cai Y, Liu Y, Zhang X. Suppression of coronavirus replication by inhibition of the MEK signaling pathway. J Virol. 2007;81:446-56 pubmed
    ..These findings indicate that the Raf/MEK/ERK signaling pathway is involved in MHV RNA synthesis. ..
  39. Sbroggiò M, Carnevale D, Bertero A, Cifelli G, De Blasio E, Mascio G, et al. IQGAP1 regulates ERK1/2 and AKT signalling in the heart and sustains functional remodelling upon pressure overload. Cardiovasc Res. 2011;91:456-64 pubmed publisher
    ..These data demonstrate, for the first time, a key role for the scaffold protein IQGAP1 in integrating hypertrophy and survival signals in the heart and regulating long-term left ventricle remodelling upon pressure overload. ..
  40. Xu Z, Jiang Y, Steed H, Davidge S, Fu Y. TGF? and EGF synergistically induce a more invasive phenotype of epithelial ovarian cancer cells. Biochem Biophys Res Commun. 2010;401:376-81 pubmed publisher
    ..Taken together, our data demonstrate that TGF? and EGF signaling pathways synergistically induce EMT and render EOC cells a more invasive phenotype. ..
  41. Rabot M, El Costa H, Polgar B, Marie Cardine A, Aguerre Girr M, Barakonyi A, et al. CD160-activating NK cell effector functions depend on the phosphatidylinositol 3-kinase recruitment. Int Immunol. 2007;19:401-9 pubmed
    ..These data demonstrate that PI3K is a crucial signaling element for both effector functions of the CD160 NK cell-activating receptor. ..
  42. Villalpando I, Lira E, Medina G, Garcia Garcia E, Echeverria O. Insulin-like growth factor 1 is expressed in mouse developing testis and regulates somatic cell proliferation. Exp Biol Med (Maywood). 2008;233:419-26 pubmed publisher
  43. Fontes G, Semache M, Hagman D, Tremblay C, Shah R, Rhodes C, et al. Involvement of Per-Arnt-Sim Kinase and extracellular-regulated kinases-1/2 in palmitate inhibition of insulin gene expression in pancreatic beta-cells. Diabetes. 2009;58:2048-58 pubmed publisher
    ..Both the PASK and ERK1/2 signaling pathways mediate palmitate inhibition of insulin gene expression. These findings identify PASK as a novel mediator of glucolipotoxicity on the insulin gene in pancreatic beta-cells. ..
  44. Joo J, Jetten A. NF-kappaB-dependent transcriptional activation in lung carcinoma cells by farnesol involves p65/RelA(Ser276) phosphorylation via the MEK-MSK1 signaling pathway. J Biol Chem. 2008;283:16391-9 pubmed publisher
    ..The activation of the NF-kappaB pathway by farnesol might be part of a prosurvival response during farnesol-induced ER stress...
  45. Estes N, Thottassery J, Westbrook L, Kern F. MEK ablation in MCF-7 cells blocks DNA synthesis induced by serum, but not by estradiol or growth factors. Int J Oncol. 2006;29:1573-80 pubmed
    ..These results suggest that pathways regulating DNA synthesis induced by serum in MCF-7 cells are significantly more dependent on constitutive MEK levels than that induced by E(2) or growth factors. ..
  46. Xia Y, Wang J, Liu T, Yung W, Hunter T, Lu Z. c-Jun downregulation by HDAC3-dependent transcriptional repression promotes osmotic stress-induced cell apoptosis. Mol Cell. 2007;25:219-32 pubmed
  47. Hayes G, Carrigan P, Miller L. Serine-arginine protein kinase 1 overexpression is associated with tumorigenic imbalance in mitogen-activated protein kinase pathways in breast, colonic, and pancreatic carcinomas. Cancer Res. 2007;67:2072-80 pubmed
    ..The up-regulation of SRPK1 in multiple cancers and its ability to regulate multiple relevant signaling pathways provide support for developing agents to inhibit this kinase for possible broad application to treat epithelial cancers. ..
  48. Jung H, Yoon B, Jun J, Kim M, Kim Y, Kim C. Differential activation of mitogen activated protein kinases and nuclear factor-kappaB in lipopolysaccharide-treated term and preterm amnion cells. Virchows Arch. 2005;447:45-52 pubmed
  49. Yamamoto T, Nishida E. [Spatio-temporal regulation of ERK1/2 MAP kinase]. Tanpakushitsu Kakusan Koso. 2007;52:747-52 pubmed
  50. Gilbert S, Blain E, Duance V, Mason D. Sphingomyelinase decreases type II collagen expression in bovine articular cartilage chondrocytes via the ERK signaling pathway. Arthritis Rheum. 2008;58:209-20 pubmed publisher
    ..This new mechanism for cartilage degradation provides potential targets for future treatment of arthritic disease. ..
  51. Pisitkun T, Jacob V, Schleicher S, Chou C, Yu M, Knepper M. Akt and ERK1/2 pathways are components of the vasopressin signaling network in rat native IMCD. Am J Physiol Renal Physiol. 2008;295:F1030-43 pubmed publisher
    ..Based on the current findings integrated with previous findings in the IMCD, we now report a 33-node vasopressin signaling network involved in vasopressin regulation of IMCD function. ..
  52. Larsen C, Povlsen G, Rasmussen M, Edvinsson L. Improvement in neurological outcome and abolition of cerebrovascular endothelin B and 5-hydroxytryptamine 1B receptor upregulation through mitogen-activated protein kinase kinase 1/2 inhibition after subarachnoid hemorrhage in rats. J Neurosurg. 2011;114:1143-53 pubmed publisher
    ..The aim in the present study was to determine whether treatment with the MEK1/2 inhibitor U0126 can prevent cerebrovascular receptor upregulation and improve functional outcome after experimental SAH in rats...
  53. Fukushima K, Matsumura I, Ezoe S, Tokunaga M, Yasumi M, Satoh Y, et al. FIP1L1-PDGFRalpha imposes eosinophil lineage commitment on hematopoietic stem/progenitor cells. J Biol Chem. 2009;284:7719-32 pubmed publisher
    ..Together, these results indicate that FIP1L1-PDGFRalpha enhances eosinophil development by modifying the expression and activity of lineage-specific transcription factors through Ras/MEK and p38(MAPK) cascades...