MEK1

Summary

Gene Symbol: MEK1
Description: mitogen-activated protein kinase kinase 1
Alias: CFC3, MAPKK1, MEK1, MKK1, PRKMK1, ERK activator kinase 1, MAPK/ERK kinase 1, MAPKK 1, MEK 1, protein kinase, mitogen-activated, kinase 1 (MAP kinase kinase 1)
Species: human

Top Publications

  1. pmc Preexisting MEK1 exon 3 mutations in V600E/KBRAF melanomas do not confer resistance to BRAF inhibitors
    Hubing Shi
    Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095 1750, USA
    Cancer Discov 2:414-24. 2012
  2. doi In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models
    Klaus P Hoeflich
    Translational Oncology, Genentech, Inc, South San Francisco, California 94080, USA
    Clin Cancer Res 15:4649-64. 2009
  3. doi Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial
    Jeffrey R Infante
    Sarah Cannon Research Institute Tennessee Oncology, PLLC, Nashville, TN, USA
    Lancet Oncol 13:773-81. 2012
  4. pmc Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma
    Jenifer L Marks
    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Cancer Res 68:5524-8. 2008
  5. ncbi Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome
    Pablo Rodriguez-Viciana
    Comprehensive Cancer Center and Cancer Research Institute, University of California, San Francisco, CA 94115, USA
    Science 311:1287-90. 2006
  6. pmc Activation of MEK family kinases requires phosphorylation of two conserved Ser/Thr residues
    C F Zheng
    Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor 48109
    EMBO J 13:1123-31. 1994
  7. ncbi Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome: overlapping clinical manifestations with Costello syndrome
    Yoko Narumi
    Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan
    Am J Med Genet A 143:799-807. 2007
  8. ncbi Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK
    Lindsey A Allan
    Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK
    Nat Cell Biol 5:647-54. 2003
  9. ncbi Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo
    J S Sebolt-Leopold
    Department of Cell Biology, Parke Davis Pharmaceutical Research, Division of Warner Lambert, Ann Arbor, Michigan 48105, USA
    Nat Med 5:810-6. 1999
  10. ncbi Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition
    Jeffrey F Ohren
    Department of Discovery Technologies, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA
    Nat Struct Mol Biol 11:1192-7. 2004

Detail Information

Publications232 found, 100 shown here

  1. pmc Preexisting MEK1 exon 3 mutations in V600E/KBRAF melanomas do not confer resistance to BRAF inhibitors
    Hubing Shi
    Division of Dermatology, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095 1750, USA
    Cancer Discov 2:414-24. 2012
    ..Somatic activating MEK1 mutations are thought to be rare in melanomas, but their potential concurrence with V600E/KBRAF may be selected for ..
  2. doi In vivo antitumor activity of MEK and phosphatidylinositol 3-kinase inhibitors in basal-like breast cancer models
    Klaus P Hoeflich
    Translational Oncology, Genentech, Inc, South San Francisco, California 94080, USA
    Clin Cancer Res 15:4649-64. 2009
    ..We investigated the role of mitogen-activated protein kinase kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) inhibitors as targeted therapies for basal-like breast cancer...
  3. doi Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial
    Jeffrey R Infante
    Sarah Cannon Research Institute Tennessee Oncology, PLLC, Nashville, TN, USA
    Lancet Oncol 13:773-81. 2012
    ..Trametinib is a selective, orally administered MEK1/MEK2 inhibitor...
  4. pmc Novel MEK1 mutation identified by mutational analysis of epidermal growth factor receptor signaling pathway genes in lung adenocarcinoma
    Jenifer L Marks
    Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
    Cancer Res 68:5524-8. 2008
    ..We have identified in 2 of 207 primary lung tumors a somatic activating mutation in exon 2 of MEK1 (i.e...
  5. ncbi Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome
    Pablo Rodriguez-Viciana
    Comprehensive Cancer Center and Cancer Research Institute, University of California, San Francisco, CA 94115, USA
    Science 311:1287-90. 2006
    ..Furthermore, three of five individuals without BRAF mutations had missense mutations in either MEK1 or MEK2, downstream effectors of B-Raf...
  6. pmc Activation of MEK family kinases requires phosphorylation of two conserved Ser/Thr residues
    C F Zheng
    Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor 48109
    EMBO J 13:1123-31. 1994
    ..Here, we report the activation phosphorylation sites of human MEK1 and yeast STE7 kinase as determined by a combination of biochemical and genetic approaches...
  7. ncbi Molecular and clinical characterization of cardio-facio-cutaneous (CFC) syndrome: overlapping clinical manifestations with Costello syndrome
    Yoko Narumi
    Department of Medical Genetics, Tohoku University School of Medicine, Sendai, Japan
    Am J Med Genet A 143:799-807. 2007
    ..We analyzed KRAS, BRAF, and MAP2K1/2 (MEK1/2) in 13 new CFC patients and identified five BRAF and one MAP2K1 mutations in nine patients...
  8. ncbi Inhibition of caspase-9 through phosphorylation at Thr 125 by ERK MAPK
    Lindsey A Allan
    Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee DD1 9SY, Scotland, UK
    Nat Cell Biol 5:647-54. 2003
    ..activity is overcome by treatment with the broad-specificity kinase inhibitor staurosporine or with inhibitors of MEK1/2...
  9. ncbi Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo
    J S Sebolt-Leopold
    Department of Cell Biology, Parke Davis Pharmaceutical Research, Division of Warner Lambert, Ann Arbor, Michigan 48105, USA
    Nat Med 5:810-6. 1999
    ..These data indicate that MEK inhibitors represent a promising, noncytotoxic approach to the clinical management of colon cancer...
  10. ncbi Structures of human MAP kinase kinase 1 (MEK1) and MEK2 describe novel noncompetitive kinase inhibition
    Jeffrey F Ohren
    Department of Discovery Technologies, Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA
    Nat Struct Mol Biol 11:1192-7. 2004
    b>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...
  11. ncbi Critical role of the phosphatidylinositol 3-kinase/Akt/glycogen synthase kinase-3 signaling pathway in recovery from anthrax lethal toxin-induced cell cycle arrest and MEK cleavage in macrophages
    Soon Duck Ha
    Department of Microbiology and Immunology, Siebens Drake Research Institute, University of Western Ontario, London, Ontario, Canada N6G 2V4
    J Biol Chem 282:36230-9. 2007
    ..This study showed that a brief exposure of LeTx caused a continual MEK1 cleavage and prevented tumor necrosis factor-alpha (TNF) production in response to lipopolysaccharide (LPS) in non-..
  12. ncbi The CXC chemokine stromal cell-derived factor activates a Gi-coupled phosphoinositide 3-kinase in T lymphocytes
    Y Sotsios
    Department of Pharmacy and Pharmacology, Bath University, Claverton Down, Bath, Avon, United Kingdom
    J Immunol 163:5954-63. 1999
    ..Hence, it appears that ERK1/2 activation is dependent on PI 3-kinase activation, and both biochemical events are involved in the regulation of SDF-1-stimulated chemotaxis...
  13. ncbi Laminin-10/11 and fibronectin differentially prevent apoptosis induced by serum removal via phosphatidylinositol 3-kinase/Akt- and MEK1/ERK-dependent pathways
    Jianguo Gu
    Division of Protein Chemistry, Institute for Protein Research, Osaka University, 3 2 Yamadaoka, Suita, Osaka 565 0871, Japan
    J Biol Chem 277:19922-8. 2002
    ..by treatment with PD98059, a specific inhibitor of mitogen- or extracellular signal-regulated kinase kinase-1 (MEK1) and by expression of a dominant-negative mutant of MEK1...
  14. pmc 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
    Alex A Adjei
    Roswell Park Cancer Institute, Elm and Carlton Streets, Buffalo, NY 14263, USA
    J Clin Oncol 26:2139-46. 2008
    ..To assess the tolerability, pharmacokinetics (PKs), and pharmacodynamics (PDs) of the mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancer...
  15. ncbi MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade
    H J Schaeffer
    Department of Microbiology and Cancer Center, University of Virginia Health Sciences Center, Charlottesville, VA 22908, USA
    Science 281:1668-71. 1998
    ..A protein called MP1 (MEK Partner 1) was identified that bound specifically to MEK1 and ERK1 and facilitated their activation...
  16. pmc Identification of a novel mitogen-activated protein kinase kinase activation domain recognized by the inhibitor PD 184352
    Amy M Delaney
    Cell Biology, Discovery Technologies, Pfizer Global Research and Development, Ann Arbor Laboratories, Ann Arbor, Michigan 48105, USA
    Mol Cell Biol 22:7593-602. 2002
    ..a genetic screen in the yeast Saccharomyces cerevisiae, we identified a novel autoactivation region in mammalian MEK1 that is involved in binding the specific MEK inhibitor, PD 184352...
  17. ncbi The roles of phosphatidylinositol 3-kinase and protein kinase Czeta for thrombopoietin-induced mitogen-activated protein kinase activation in primary murine megakaryocytes
    P Rojnuckarin
    Division of Hematology, University of Washington School of Medicine, Seattle, Washington 98195, USA
    J Biol Chem 276:41014-22. 2001
    ..These data demonstrate a novel role of PI3K and PKCzeta in steady-state megakaryopoiesis...
  18. ncbi MEK1-induced Golgi dynamics during cell cycle progression is partly mediated by Polo-like kinase-3
    Suqing Xie
    Department of Medicine, New York Medical College, Valhalla, NY 10595, USA
    Oncogene 23:3822-9. 2004
    b>MEK1, a gene product that regulates cell growth and differentiation, also plays an important role in Golgi breakdown during the cell cycle...
  19. pmc Hepatitis C virus core protein interacts with 14-3-3 protein and activates the kinase Raf-1
    H Aoki
    Department of Experimental Pathology, Cancer Institute, Japanese Foundation for Cancer Research, 1 37 1 Kami Ikebukuro, Toshima ku, Tokyo 170 8455, Japan
    J Virol 74:1736-41. 2000
    ..These results suggest that HCV core protein may represent a novel type of Raf-1 kinase-activating protein through its interaction with 14-3-3 protein and may contribute to hepatocyte growth regulation...
  20. doi Activation of mitogen activated protein kinase-Erk kinase (MEK) increases T cell immunoglobulin mucin domain-3 (TIM-3) transcription in human T lymphocytes and a human mast cell line
    Soo Jin Yoon
    Department of Microbiology, Ajou University School of Medicine, Youngtongku Wonchondong San 5, Suwon 442 749, Republic of Korea
    Mol Immunol 48:1778-83. 2011
    ..5kb TIM-3 promoter activity was reduced by MEK inhibitors, but was not responsive to TGF-β stimulation in HMC-1 cells. These results suggest the regulatory role of MEK in TIM-3 transcription by human CD4+ T cells and mast cells...
  21. ncbi Selective activation of MEK1 but not MEK2 by A-Raf from epidermal growth factor-stimulated Hela cells
    X Wu
    Department of Biological Chemistry and the Institute of Gerontology, The University of Michigan Medical School, Ann Arbor, Michigan 48109, USA
    J Biol Chem 271:3265-71. 1996
    ..were substituted by alanines, was used as a bait, whereas no positive clones were isolated when the wild type MEK1 was used as a bait in a similar screening...
  22. ncbi Thermodynamics of nucleotide and non-ATP-competitive inhibitor binding to MEK1 by circular dichroism and isothermal titration calorimetry
    Catherine K Smith
    Schering Plough Research Institute, 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, USA
    Biochemistry 46:1358-67. 2007
    b>MEK1 is a member of the MAPK signal transduction pathway that responds to growth factors and cytokines...
  23. pmc Nuclear factor-kappa B activation by the CXC chemokine melanoma growth-stimulatory activity/growth-regulated protein involves the MEKK1/p38 mitogen-activated protein kinase pathway
    D Wang
    Department of Veterans Affairs, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA
    J Biol Chem 276:3650-9. 2001
    ..Moreover, MGSA/GROalpha induction of NF-kappaB is independent of the MEK1/ERK cascade, because MGSA/GROalpha failed to increase ERK and ELK activation, and specific chemical inhibitors for ..
  24. ncbi Constitutive activation of the Saccharomyces cerevisiae mating response pathway by a MAP kinase kinase from Candida albicans
    K L Clark
    Eukaryotic Genetics Group, Biotechnology Research Institute, National Research Council Canada, Montreal, Quebec, Canada
    Mol Gen Genet 249:609-21. 1995
    ..loss of either the Pbs2 (Hog4) MAP kinase kinase required for response to high osmolarity, or loss of the Mkk1 and Mkk2 MAP kinase kinases required for proper cell wall biosynthesis...
  25. pmc Coordination of the mating and cell integrity mitogen-activated protein kinase pathways in Saccharomyces cerevisiae
    B M Buehrer
    Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, 27599 7260, USA
    Mol Cell Biol 17:6517-25. 1997
    ..through the cell integrity phosphorylation cascade and depends on Pkc1 and the redundant MAP/Erk kinases (MEKs), Mkk1 and Mkk2...
  26. doi 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
    Carl Christian Larsen
    Departments of Neurosurgery, Glostrup University Hospital, Glostrup, Denmark
    J Neurosurg 114:1143-53. 2011
    ..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 ..
  27. ncbi Atypical protein kinase C-zeta stimulates thyrotropin-independent proliferation in rat thyroid cells
    N Fernandez
    Center for Experimental Therapeutics, University of Pennsylvania School of Medicine, Philadelphia 19104-6160, USA
    Endocrinology 141:146-52. 2000
    ..Interestingly, stimulation of Elk-1 transcriptional activity by MEK1, a p42/p44 MAPK kinase, was significantly enhanced in cells overexpressing PKCzeta...
  28. ncbi [Parathyroid hormone 1-34 induce cardiac myocytes hypertrophy via extracellular regulated protein kinase 1/2 pathway]
    Xiao gang Liu
    Department of Nephrology, Second Hospital, Harbin Medical University, Harbin 150086, China
    Zhonghua Xin Xue Guan Bing Za Zhi 36:439-43. 2008
    To investigate the role of mitogen activated protein kinase kinase 1 (MAPKK, MEK1) and regulated kinase1/2 (ERK1/2) on cardiac hypertrophy induced by rat parathyroid hormone1-34 (rPTH1-34).
  29. ncbi Galectin-3 expression in macrophages is signaled by Ras/MAP kinase pathway and up-regulated by modified lipoproteins
    Koanhoi Kim
    Department of Pathology and Microbiology, University of South Carolina School of Medicine, Columbia, SC 29208, USA
    Biochim Biophys Acta 1641:13-23. 2003
    ..genistein and tyrphostin A25; PD 98059, a selective inhibitor of mitogen-activated protein kinase (MAPK) kinase 1 (MEK1 or MKK1); and SB 203580, a specific inhibitor of p38 MAPK...
  30. pmc Porins from Salmonella enterica serovar Typhimurium activate the transcription factors activating protein 1 and NF-kappaB through the Raf-1-mitogen-activated protein kinase cascade
    Massimiliano Galdiero
    Istituto di Microbiologia, Facolta di Medicina e Chirurgia, Seconda Universita degli Studi di Napoli, 80138 Naples, Italy
    Infect Immun 70:558-68. 2002
    ..the porin-mediated increase in Raf-1 phosphorylation is accompanied by the phosphorylation of MAPK kinase 1/2 (MEK1/2), p38, extracellular-signal-regulated kinase 1/2, and c-Jun N-terminal kinase...
  31. pmc Hypoxia enhances FGF2- and VEGF-stimulated human placental artery endothelial cell proliferation: roles of MEK1/2/ERK1/2 and PI3K/AKT1 pathways
    K Wang
    Department of Obstetrics and Gynecology, Perinatal Research Laboratories, University of Wisconsin, Madison, WI 53715, USA
    Placenta 30:1045-51. 2009
    ..endothelial growth factor (VEGF)-stimulated cell proliferation via the mitogen-activated protein kinase kinase 1/2 (MEK1/2)/extracellular signal-regulated kinases 1/2 (ERK1/2) and phosphatidylinositol-3 kinase (PI3K)/v-akt murine ..
  32. ncbi Calcium-sensing receptor induces proliferation through p38 mitogen-activated protein kinase and phosphatidylinositol 3-kinase but not extracellularly regulated kinase in a model of humoral hypercalcemia of malignancy
    J Tfelt-Hansen
    Division of Endocrinology, Diabetes and Hypertension, Department of Medicine and Membrane Biology Program, Brigham and Women s Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA
    Endocrinology 145:1211-7. 2004
    ..g. MAPK kinase 1 (MEK1), p38 MAPK, and stress-activated protein kinase 1/c-Jun N-terminal kinase...
  33. ncbi Epicatechin and a cocoa polyphenolic extract modulate gene expression in human Caco-2 cells
    Veronique Noe
    Department of Biochemistry and Molecular Biology, School of Pharmacy, University of Barcelona, E 08028 Barcelona, Spain
    J Nutr 134:2509-16. 2004
    ..The changes in expression for ferritin heavy polypeptide 1 (FTH1), mitogen-activated protein kinase kinase 1 (MAPKK1), signal transducer and activator of transcription 1 (STAT1), and topoisomerase 1 upon incubation with epicatechin,..
  34. doi Activation of MEK1/ERK1/2/iNOS/sGC/PKG pathway associated with peroxynitrite formation contributes to hypotension and vascular hyporeactivity in endotoxemic rats
    Belma Korkmaz
    Department of Pharmacology, Faculty of Pharmacy, Mersin University, Mersin, Turkey
    Nitric Oxide 24:160-72. 2011
    ..increase in protein expression and activity of the enzymes involved in mitogen-activated protein kinase kinase 1 (MEK1)/extracellular signal-regulated kinase 1/2 (ERK1/2)/iNOS/soluble guanylyl cyclase (sGC)/protein kinase G (PKG) ..
  35. ncbi Constitutively active mitogen-activated protein kinase kinase 1 (MAPKK1) and MAPKK2 mediate similar transcriptional and morphological responses
    S J Mansour
    Department of Molecular, Cellular, and Developmental Biology, University of Colorado, Boulder 80309, USA
    Cell Growth Differ 7:243-50. 1996
    Both mitogen-activated protein kinase kinase 1 (MAPKK1) and MAPKK2 function downstream of the proto-oncogene product Raf in signaling pathways that affect cell proliferation and differentiation...
  36. pmc The novel adipocytokine visfatin exerts direct cardioprotective effects
    Shiang Y Lim
    The Hatter Cardiovascular Institute, University College London Hospital and Medical School, London, United Kingdom
    J Cell Mol Med 12:1395-403. 2008
    ..phosphatidylinositol-3-OH kinase (PI3K)-protein kinase B (Akt) and mitogen-activated protein kinase kinase 1 and 2 (MEK1/2)-extracellular signal-regulated kinase 1 and 2 (Erk 1/2)...
  37. ncbi Diurnal variation in p42/44 mitogen-activated protein kinase in the rat pineal gland
    A K Ho
    Department of Physiology, Faculty of Medicine, 7 26 Medical Sciences Building, University of Alberta, Edmonton, Alta, Canada T6G 2H7
    Mol Cell Endocrinol 208:23-30. 2003
    ..regimen with 12h of darkness, there was a two- to four-fold increase in phosphorylated levels of MAPK kinase 1/2 (MEK1/2) and p42/44(MAPK) 2h after onset of darkness, an increase that was sustained for 8h...
  38. pmc Mitogen-activated protein kinase kinase 1 (MEK1) stabilizes MyoD through direct phosphorylation at tyrosine 156 during myogenic differentiation
    Chulman Jo
    Division of Brain Disease, Center for Biomedical Science, National Institutes of Health, Korea Center for Disease Control and Prevention, 187 Osongsaengmyeong2 ro, Gangoe myeon, Cheongwon Gun, Chungcheongbuk do 363 951, South Korea
    J Biol Chem 286:18903-13. 2011
    Previously, we reported that mitogen-activated protein kinase kinase 1 (MEK1) activated in the mid-stage of skeletal muscle differentiation promotes myogenic differentiation...
  39. pmc Mitogen-activated protein kinase kinase 1/2 inhibitors and 17-allylamino-17-demethoxygeldanamycin synergize to kill human gastrointestinal tumor cells in vitro via suppression of c-FLIP-s levels and activation of CD95
    Margaret A Park
    Department of Biochemistry and Molecular Biology, Virginia Commonwealth University, 401 College Street, Massey Cancer Center, Box 980035, Richmond, VA 23298 0035, USA
    Mol Cancer Ther 7:2633-48. 2008
    Prior studies have noted that inhibitors of mitogen-activated protein kinase (MAPK) kinase 1/2 (MEK1/2) enhanced geldanamycin lethality in malignant hematopoietic cells by promoting mitochondrial dysfunction...
  40. doi MEK1 plays contrary stage-specific roles in skeletal myogenic differentiation
    Chulman Jo
    Center for Biomedical Sciences, National Institute of Health, Korea Center for Disease Control and Prevention, 194 Tongillo, Eunpyeong gu, Seoul, Republic of Korea
    Cell Signal 21:1910-7. 2009
    ..this discrepancy may arise from the stage-specific, different roles of mitogen-activated protein kinase kinase 1 (MEK1)...
  41. ncbi Development of cataractous macrophthalmia in mice expressing an active MEK1 in the lens
    X Gong
    Department of Cell Biology, The Scripps Research Institute, 10550 N Torrey Pines Road, La Jolla, CA 92037, USA
    Invest Ophthalmol Vis Sci 42:539-48. 2001
    ..To characterize the extracellular signal-regulated kinase (ERK) pathway in the lens and to try to understand how this pathway contributes to lens function and cataractogenesis...
  42. ncbi BRAF and MEK mutations make a late entrance
    Nick Duesbery
    Van Andel Institute, 333 Bostwick Avenue NE, Grand Rapids, MI 49503, USA
    Sci STKE 2006:pe15. 2006
    ..is a mitogen-activated protein kinase kinase kinase (MAPKKK), and mitogen-activated protein kinase kinase 1 and 2 (MAPKK1/2, also known as MKK1/2 or MEK1/2) are signaling partners in the MAPK signal transduction pathway...
  43. ncbi MEK1 and MEK2 isoforms regulate distinct functions in pancreatic cancer cells
    Lei Zhou
    Department of Hepato pancreato biliary Tumour Surgery, China Medical University Shengjing Hospital, Shenyang, PR China
    Oncol Rep 24:251-5. 2010
    The mitogen-activated protein kinase kinase 1/2 (MEK1/2) signalling pathway plays a central role in tumour progression. Small molecules that inhibit MEK1/2 are therefore considered attractive candidates for anti-cancer drugs...
  44. ncbi A new cellular signaling mechanism for angiotensin II activation of NF-kappaB: An IkappaB-independent, RSK-mediated phosphorylation of p65
    Liping Zhang
    Department of Internal Medicine, The University of Texas Medical Branch, Galveston 77555 1064, USA
    Arterioscler Thromb Vasc Biol 25:1148-53. 2005
    ..We examined the signaling mechanism whereby Ang II activates NF-kappaB in vascular smooth muscle cells (VSMCs)...
  45. ncbi Significant neuroprotection against ischemic brain injury by inhibition of the MEK1 protein kinase in mice: exploration of potential mechanism associated with apoptosis
    Xinkang Wang
    Department of Cardiovascular Sciences, Bristol Myers Squibb Company, Wilmington, Delaware 19880 0400, USA
    J Pharmacol Exp Ther 304:172-8. 2003
    b>MEK1/2 is a serine/threonine protein kinase that phosphorylates and activates extracellular signal-responsive kinase (ERK)1/2...
  46. ncbi ERK1/2 achieves sustained activation by stimulating MAPK phosphatase-1 degradation via the ubiquitin-proteasome pathway
    Yun Wei Lin
    Molecular Carcinogenesis Laboratory, Institute of Biotechnology, Department of Life Sciences, National Tsing Hua University, Hsinchu 300, Taiwan, Republic of China
    J Biol Chem 278:21534-41. 2003
    ..activation does not always correlate with its upstream Ras-Raf-mitogen-activated protein kinase kinase 1/2 (MKK1/2) signal cascade in cancer cells, and the mechanism remains elusive...
  47. doi Characterization of a novel mitogen-activated protein kinase kinase 1/2 inhibitor with a unique mechanism of action for cancer therapy
    Sherif Daouti
    Discovery Oncology, Discovery Chemistry, and Roche Discovery Technologies, Hoffmann La Roche, Inc, Nutley, New Jersey
    Cancer Res 69:1924-32. 2009
    ..Targeting this pathway represents a promising anticancer strategy. Small molecule inhibitors targeting MEK1/2 have shown promise in the clinic; however, ultimate clinical proof-of-concept remains elusive...
  48. pmc MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia
    A Alessandrini
    Medical Services, Massachusetts General Hospital, Charlestown, MA 02129, USA
    Proc Natl Acad Sci U S A 96:12866-9. 1999
    The MEK1 (MAP kinase/ERK kinase)/ERK (extracellular-signal-responsive kinase) pathway has been implicated in cell growth and differentiation [Seger, R. & Krebs, E. G. (1995) FASEB J. 9, 726-735]...
  49. ncbi Biological characterization of ARRY-142886 (AZD6244), a potent, highly selective mitogen-activated protein kinase kinase 1/2 inhibitor
    Tammie C Yeh
    Array BioPharma, Inc, Boulder, Colorado 80301, USA
    Clin Cancer Res 13:1576-83. 2007
    ..We have developed a highly potent and selective inhibitor of MEK1/2...
  50. pmc PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation
    Jill K Slack-Davis
    Department of Microbiology, University of Virginia Health System, Charlottesville, VA 22908, USA
    J Cell Biol 162:281-91. 2003
    ..Here, we provide evidence that phosphorylation of S298 of MAPK kinase 1 (MEK1) by p21-activated kinase (PAK) is a site of convergence for integrin and growth factor signaling...
  51. pmc Colorectal cancer cells with the BRAF(V600E) mutation are addicted to the ERK1/2 pathway for growth factor-independent survival and repression of BIM
    J A Wickenden
    Laboratory of Molecular Signalling, The Babraham Institute, Babraham Research Campus, Babraham, Cambridge, UK
    Oncogene 27:7150-61. 2008
    The RAF-mitogen-activated protein kinase kinase 1/2-extracellular signal-regulated kinase 1/2 (RAF-MEK1/2-ERK1/2) pathway is activated in many human tumours and can protect cells against growth factor deprivation; however, most such ..
  52. doi Molecular characterisation of MEK1/2- and MKK3/6-like mitogen-activated protein kinase kinases (MAPKK) from the fox tapeworm Echinococcus multilocularis
    Verena Gelmedin
    University of Wurzburg, Institute of Hygiene and Microbiology, Wurzburg, Germany
    Int J Parasitol 40:555-67. 2010
    ..Structurally, EmMKK1 and EmMKK2 closely resemble members of the MKK3/6- and the MEK1/2-MAPKK sub-families, respectively, from a variety of vertebrate and invertebrate organisms, and contain all ..
  53. ncbi Gonadotropin regulation of testosterone production by primary cultured theca and granulosa cells of Atlantic croaker: II. Involvement of a mitogen-activated protein kinase pathway
    Abby D Benninghoff
    Department of Marine Science, University of Texas at Austin, 750 Channel View Drive, Port Aransas, TX 78373, USA
    Gen Comp Endocrinol 147:288-96. 2006
    ..testosterone synthesis was markedly attenuated by two antagonists of mitogen-activated protein kinase kinases 1/2 (MEK1/2, also known as Map2k1/Map2k2)...
  54. ncbi Constitutively active mutant of the mitogen-activated protein kinase kinase MEK1 induces epithelial dedifferentiation and growth inhibition in madin-darby canine kidney-C7 cells
    H Schramek
    Department of Physiology, University of Innsbruck, A 6010 Innsbruck, Austria
    J Biol Chem 272:11426-33. 1997
    ..In the present study, we used a constitutively active MAPK/extracellular signal-regulated kinase (ERK) kinase 1 (MEK1) mutant to investigate the function of the highly conserved MEK1-ERK2 signaling module in renal epithelial cell ..
  55. pmc Arabidopsis mitogen-activated protein kinase kinases MKK1 and MKK2 have overlapping functions in defense signaling mediated by MEKK1, MPK4, and MKS1
    Jin Long Qiu
    Department of Biology, University of Copenhagen, 2200 Copenhagen N, Denmark
    Plant Physiol 148:212-22. 2008
    The Arabidopsis (Arabidopsis thaliana) MKK1 and MKK2 mitogen-activated protein kinase kinases have been implicated in biotic and abiotic stress responses as part of a signaling cascade including MEKK1 and MPK4...
  56. ncbi Differential expression of MEK1 and MEK2 during mouse development
    A Alessandrini
    Department of Molecular and Cellular Biology, Harvard University, Cambridge, Massachusetts 02138, USA
    Cell Growth Differ 8:505-11. 1997
    Map/Erk kinase 1 (MEK1) and MEK2 activate the Erk/ MAP kinases and have been implicated in cell growth and differentiation...
  57. ncbi Protein kinase C-zeta and phosphoinositide-dependent protein kinase-1 are required for insulin-induced activation of ERK in rat adipocytes
    M P Sajan
    J. A. Haley Veterans Hospital Research Service, Department of Internal Medicine, University of South Florida College of Medicine, Tampa, Florida 33612, USA
    J Biol Chem 274:30495-500. 1999
    ..we found that a tyrosine kinase (presumably the insulin receptor), the SH2 domain of GRB2, SOS, RAS, RAF, and MEK1 were required for insulin effects on ERK in the rat adipocyte...
  58. ncbi Arrangement of expression and distribution of tight junction protein claudin-1 in cell dissociation of pancreatic cancer cells
    Xiaodong Tan
    Department of Surgery II, Kumamoto University Medical School, Kumamoto, Japan
    Int J Oncol 25:1567-74. 2004
    ..and Western blot analysis were performed in pancreatic cancer cells using anti-claudin-1, MEK2 and phosphorylated MEK1/2 (p-MEK1/2) antibodies to reveal the correlation between TJ and cancer cell dissociation, as well as the ..
  59. ncbi Relationship between activation of epidermal growth factor receptor and cell dissociation in pancreatic cancer
    Xiaodong Tan
    Department of Surgery II, Kumamoto University Medical School, Honjo 1 1 1, Kumamoto 860 8556, Japan
    Int J Oncol 25:1303-9. 2004
    ..expressions of epidermal growth factor receptor (EGFR), phosphorylated EGFR (p-EGFR), and its downstream kinases MEK1/2 and ERK1/2, were analyzed to clarify the regulatory mechanism of cell dissociation in pancreatic cancer cells...
  60. ncbi Analysis of invasion-metastasis mechanism in pancreatic cancer: involvement of tight junction transmembrane protein occludin and MEK/ERK signal transduction pathway in cancer cell dissociation
    Xiaodong Tan
    Department of Surgery II, Kumamoto University Medical School, Kumamoto, Japan
    Oncol Rep 11:993-8. 2004
    ..and CAPAN-2) pancreatic cancer cell lines were analyzed immunocytochemically with anti-occludin, phosphorylated MEK1/2 (p-MEK1/2), phosphorylated ERK1/2 (p-ERK1/2) antibodies...
  61. pmc Identification and characterization of a new mammalian mitogen-activated protein kinase kinase, MKK2
    J Wu
    Department of Internal Medicine, University of Virginia Health Sciences Center, Charlottesville 22908
    Mol Cell Biol 13:4539-48. 1993
    ..A MAP kinase kinase (MKK1 or MEK1) has been identified as a dual-specificity protein kinase that is sufficient to phosphorylate MAP kinases p42mapk ..
  62. pmc Role of ERK/MAPK in endothelin receptor signaling in human aortic smooth muscle cells
    Qing wen Chen
    Division of Experimental Vascular Research, Institute of Clinical Science in Lund, Lund University, Lund, Sweden
    BMC Cell Biol 10:52. 2009
    ..This study was designed to investigate the ETA and ETB receptor intracellular signaling in human VSMCs and used phosphorylation (activation) of ERK1/2 as a functional signal molecule for endothelin receptor activity...
  63. pmc Activation of Erk and JNK MAPK pathways by acute swim stress in rat brain regions
    Chang peng Shen
    Department of Psychiatry, New York University School of Medicine, 550 First Ave, MHL HN511, New York, NY 10016, USA
    BMC Neurosci 5:36. 2004
    ..on the phosphorylation state of the upstream activators of the MAPKs, their respective MAPK kinases (MAPKKs; P-MEK1/2, P-MKK4 and P-MKK3/6), were determined...
  64. ncbi Preferential involvement of MEK1 in the tumor necrosis factor-alpha-induced activation of p42mapk/erk2 in mouse macrophages
    B W Winston
    Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206, USA
    J Biol Chem 270:27391-4. 1995
    ..In this study, we investigated the preferential involvement of the MEK isoforms MEK1 and MEK2 in the activation of p42mapk/erk2 in mouse macrophages stimulated with TNF alpha...
  65. ncbi Functional role of alpha-actinin, PI 3-kinase and MEK1/2 in insulin-like growth factor I receptor kinase regulated motility of human breast carcinoma cells
    Marina A Guvakova
    Department of Microbiology, University of Pennsylvania, 3610 Hamilton Walk, 211 Johnson Pavilion, Philadelphia PA 19104, USA
    J Cell Sci 115:4149-65. 2002
    ..The activity of MEK1/2 kinases was needed for consecutive cell migration. This work also defined a new function for alpha-actinin...
  66. ncbi [The role of mitogen-activated protein kinase cascades in inhibition of proliferation in human prostate carcinoma cells by raloxifene: an in vitro experiment]
    Yu xi Zhang
    Department of Urology, First Affiliated Hospital, China Medical University, Shenyang 110001, China
    Zhonghua Yi Xue Za Zhi 88:271-5. 2008
    ..To investigate the role of mitogen-activated protein kinase (MAPK) in the apoptosis and cell cycle arrest of human prostate carcinoma cells induced by raloxifene (RAL)...
  67. ncbi Regulation of intracellular MEK1/2 translocation in mouse oocytes: cytoplasmic dynein/dynactin-mediated poleward transport and cyclin B degradation-dependent release from spindle poles
    Bo Xiong
    State Key Laboratory of Reproductive Biology, Institute of Zoology and Graduate School, Chinese Academy of Sciences, Beijing, PR China
    Cell Cycle 6:1521-7. 2007
    We recently reported that MEK1/2 plays an important role in microtubule organization and spindle pole tethering in mouse oocytes, but how the intracellular transport of this protein is regulated remains unknown...
  68. pmc Inactivation of dual-specificity phosphatases is involved in the regulation of extracellular signal-regulated kinases by heat shock and hsp72
    Julia Yaglom
    Department of Biochemistry, Boston University School of Medicine, Boston, Massachusetts 02118, USA
    Mol Cell Biol 23:3813-24. 2003
    ..demonstrated that heat shock activates ERKs via two distinct mechanisms: stimulation of the ERK-activating kinases, MEK1/2, and inhibition of ERK dephosphorylation...
  69. pmc Novel changes in NF-{kappa}B activity during progression and regression phases of hyperplasia: role of MEK, ERK, and p38
    Parthasarathy Chandrakesan
    Department of Internal Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73104, USA
    J Biol Chem 285:33485-98. 2010
    ..Phosphorylation of MEK1/2 (Ser(217/221)), ERK1/2 (Thr(202)/Tyr(204)), and p38 (Thr(180)/Tyr(182)) paralleled IKKα/β kinetics at days 6 ..
  70. ncbi Regulation of meiotic progression by the meiosis-specific checkpoint kinase Mek1 in fission yeast
    Livia Perez-Hidalgo
    Centro de Investigacion del Cancer, CSIC University of Salamanca, Campus Unamuno, 37007 Salamanca, Spain
    J Cell Sci 116:259-71. 2003
    ..Here, we describe a role for a meiosis-specific kinase, Mek1, in the meiotic recombination checkpoint in fission yeast...
  71. pmc Constitutive activation of MEK1 in chondrocytes causes Stat1-independent achondroplasia-like dwarfism and rescues the Fgfr3-deficient mouse phenotype
    Shunichi Murakami
    Department of Molecular Genetics, The University of Texas, MD Anderson Cancer Center, Houston, Texas 77030, USA
    Genes Dev 18:290-305. 2004
    We generated transgenic mice that express a constitutively active mutant of MEK1 in chondrocytes. These mice showed a dwarf phenotype similar to achondroplasia, the most common human dwarfism, caused by activating mutations in FGFR3...
  72. ncbi Receptor-mediated tobacco toxicity: cooperation of the Ras/Raf-1/MEK1/ERK and JAK-2/STAT-3 pathways downstream of alpha7 nicotinic receptor in oral keratinocytes
    Juan Arredondo
    Department of Dermatology, University of California Davis, Sacramento, CA, USA
    FASEB J 20:2093-101. 2006
    ..The use of pathway inhibitors revealed that signaling through the Ras/Raf-1/MEK1/ERK steps mediated alpha7-dependent up-regulation of STAT-3...
  73. ncbi AG-041R stimulates cartilage matrix synthesis without promoting terminal differentiation in rat articular chondrocytes
    M Okazaki
    Fuji Gotemba Research Laboratories, Chugai Pharmaceutical Co, Ltd, 1 135 Komakado, Gotemba, Shizuoka 412 8513, Japan
    Osteoarthritis Cartilage 11:122-32. 2003
    ..AG-041R, a novel indolin-2-one derivative, has recently been demonstrated to induce systemic hyaline cartilage hyperplasia in rats. The aim of this study was to characterize its anabolic actions on chondrocytes...
  74. ncbi Myricetin is a novel natural inhibitor of neoplastic cell transformation and MEK1
    Ki Won Lee
    Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA
    Carcinogenesis 28:1918-27. 2007
    ..that 3,3',4',5,5',7-hexahydroxyflavone (myricetin), one of the major flavonols in red wine, is a novel inhibitor of MEK1 activity and transformation of JB6 P+ mouse epidermal cells...
  75. pmc Bypass of a meiotic checkpoint by overproduction of meiotic chromosomal proteins
    J M Bailis
    Department of Molecular, Cellular, and Developmental Biology, Yale University, New Haven, CT 06520 8103, USA
    Mol Cell Biol 20:4838-48. 2000
    ..Overproduction of either the meiotic chromosomal protein Red1 or the meiotic kinase Mek1 bypasses this checkpoint, allowing zip1 cells to sporulate...
  76. ncbi Further delineation of the phenotype resulting from BRAF or MEK1 germline mutations helps differentiate cardio-facio-cutaneous syndrome from Costello syndrome
    Karen W Gripp
    Division of Medical Genetics, A I duPont Hospital for Children Nemours Childrens Clinic, Wilmington, DE 19899, USA
    Am J Med Genet A 143:1472-80. 2007
    ..The recent discoveries of germline HRAS mutations in patients with Costello syndrome and mutations in BRAF, MEK1, and MEK2 in CFC syndrome uncovered the biologic mechanism for the shared phenotypic findings based on the close ..
  77. ncbi Epidermal growth factor induces c-fos and c-jun mRNA via Raf-1/MEK1/ERK-dependent and -independent pathways in bovine luteal cells
    Dong Bao Chen
    The Women s Research Institute, Department of Obstetrics and Gynecology, University of Kansas School of Medicine Wichita, 1010 North Kansas, Wichita 67214, USA
    Mol Cell Endocrinol 200:141-54. 2003
    ..Activation of Raf resulted in the phosphorylation and activation of MAPK kinase (MEK1) which subsequently activated ERKs...
  78. pmc Mek1 kinase is regulated to suppress double-strand break repair between sister chromatids during budding yeast meiosis
    Hengyao Niu
    Department of Biochemistry and Cell Biology, Stony Brook University, Stony Brook, NY 11794 5215, USA
    Mol Cell Biol 27:5456-67. 2007
    b>Mek1 is a meiosis-specific kinase in budding yeast which promotes recombination between homologous chromosomes by suppressing double-strand break (DSB) repair between sister chromatids...
  79. doi Dose-dependent effect of intracerebroventricular injection of ouabain on the phosphorylation of the MEK1/2-ERK1/2-p90RSK pathway in the rat brain related to locomotor activity
    Se Hyun Kim
    Department of Psychiatry and Behavioral Science, Seoul National University College of Medicine, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
    Prog Neuropsychopharmacol Biol Psychiatry 32:1637-42. 2008
    ..of ouabain in rats, we investigated changes in the phosphorylation of mitogen-activated protein kinase kinase1/2 (MEK1/2), ERK1/2, and p90 ribosomal s6 kinase (p90RSK) in rat striatum, frontal cortex, and hippocampus along with ..
  80. ncbi Clozapine and the mitogen-activated protein kinase signal transduction pathway: implications for antipsychotic actions
    Jeff L Browning
    Department of Psychiatry, Scott and White Memorial Hospital, Central Texas Veterans Health Care System, and Texas A and M University System Health Science Center College of Medicine, Temple, Texas, USA
    Biol Psychiatry 57:617-23. 2005
    ....
  81. doi Selective adenosine A2a receptor antagonism reduces JNK activation in oligodendrocytes after cerebral ischaemia
    Alessia Melani
    Department of Preclinical and Clinical Pharmacology, University of Florence, Viale Pieraccini, 6, Florence, Italy
    Brain 132:1480-95. 2009
    ..objective of the present study was to investigate whether the adenosine A(2A) antagonist SCH58261 affects JNK and MEK1/ERK MAPK activation...
  82. ncbi Role of osteoclast extracellular signal-regulated kinase (ERK) in cell survival and maintenance of cell polarity
    Hiroaki Nakamura
    Department of Oral Morphology, Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan
    J Bone Miner Res 18:1198-205. 2003
    Morphological changes of osteoclasts by a MEK1 inhibitor, PD98059, were investigated to clarify a role of ERK. PD98059 promoted apoptosis of osteoclasts and the loss of ruffled borders...
  83. doi Oxytocin reduces anxiety via ERK1/2 activation: local effect within the rat hypothalamic paraventricular nucleus
    Annegret Blume
    Department of Behavioural and Molecular Neuroendocrinology, Institute of Zoology, University of Regensburg, Germany
    Eur J Neurosci 27:1947-56. 2008
    ..Specifically, OT induced the phosphorylation of Raf-1, MEK1/2 and ERK1/2 in the hypothalamus in vivo and in hypothalamic H32 neurons via EGF receptors...
  84. doi Acetylsalicylic acid inhibits hepatitis C virus RNA and protein expression through cyclooxygenase 2 signaling pathways
    Karina Trujillo-Murillo
    Department of Biochemistry, School of Medicine and University Hospital, Autonomous University of Nuevo Leon, Monterrey, Nuevo Leon, Mexico
    Hepatology 47:1462-72. 2008
    ..COX-2 and activation of p38 and mitogen-activated protein kinase/extracellular signal-regulated kinase kinase 1/2 (MEK1/2) mitogen-activated protein kinases (MAPKs)...
  85. doi 1-Nitropyrene stabilizes the mRNA of cytochrome P450 1a1, a carcinogen-metabolizing enzyme, via the Akt pathway
    Wen Cheng Chu
    Department of Biochemical Science and Technology, National Chiayi University, Chiayi 600, Taiwan, ROC
    Chem Res Toxicol 22:1938-47. 2009
    ..1-NP-induced Cyp1a1 mRNA stabilization was mediated by Akt, but not by p38 MAPK, MEK1/2, or JNK...
  86. doi Roles of MKK1/2-ERK1/2 and phosphoinositide 3-kinase-AKT signaling pathways in erlotinib-induced Rad51 suppression and cytotoxicity in human non-small cell lung cancer cells
    Jen Chung Ko
    Department of Internal Medicine, Hsinchu Hospital, Department of Health, Executive Yuan, Taiwan
    Mol Cancer Res 7:1378-89. 2009
    ..Enforced expression of constitutively active MKK1 or AKT vectors could restore Rad51 protein levels, which were inhibited by erlotinib, and decrease erlotinib-..
  87. pmc PV1 is a key structural component for the formation of the stomatal and fenestral diaphragms
    Radu V Stan
    Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093 0651, USA
    Mol Biol Cell 15:3615-30. 2004
    ..Taken together, these data show that PV1 is a key structural component, necessary for the biogenesis of the stomatal and fenestral diaphragms...
  88. ncbi Short-term interleukin-1(beta) increases the release of secreted APP(alpha) via MEK1/2-dependent and JNK-dependent alpha-secretase cleavage in neuroglioma U251 cells
    Guozhao Ma
    Department of Neurology, Ruijin Hospital, Shanghai Second Medical University, Shanghai, China
    J Neurosci Res 80:683-92. 2005
    ..inhibitors and found that sAPP(alpha) release is significantly blocked by the mitogen-activated protein kinase (MEK1/2) inhibitor PD98059 and the c-Jun N-terminal kinase inhibitor SP600125...
  89. pmc Anti-myeloma activity of Akt inhibition is linked to the activation status of PI3K/Akt and MEK/ERK pathway
    Vijay Ramakrishnan
    The Divisions of Hematology, Mayo Clinic, Rochester, Minnesota, United States of America
    PLoS ONE 7:e50005. 2012
    ..Using MK-2206 in combination with rapamycin (mTORC1 inhibitor), LY294002 (PI3K inhibitor), or U0126 (MEK1/2 inhibitor), we show that Erk- mediated downstream activation of PI3K/Akt pathway results in resistance to Akt ..
  90. doi Ganglioside GD1a suppression of NOS2 expression via ERK1 pathway in mouse osteosarcoma FBJ cells
    Ting Cao
    Laboratory of Tumor Biology and Glycobiology, Department of Life Sciences, Shenyang Pharmaceutical University, Shenyang 110016, People s Republic of China
    J Cell Biochem 110:1165-74. 2010
    ..b>MEK1/2 inhibitor (U0126) increased NOS2 expression, whereas GD1a treatment decreased it...
  91. doi The mechanism of fucoidan-induced apoptosis in leukemic cells: involvement of ERK1/2, JNK, glutathione, and nitric oxide
    Jun O Jin
    Department of Biochemistry, School of Medicine and Medical Research Center for Cancer Molecular Therapy, Dong A University, Busan 602 714, Korea
    Mol Carcinog 49:771-82. 2010
    ..by depletion of mitogen-activated protein kinase (MAPK) kinase kinase 1 (MEKK1), and inhibitors of MAPK kinase 1 (MEK1) and c Jun NH2-terminal kinase (JNK)...
  92. doi Hmgb1 promotes wound healing of 3T3 mouse fibroblasts via RAGE-dependent ERK1/2 activation
    Elia Ranzato
    Department of Environment and Life Sciences, DISAV, University of Piemonte Orientale, Viale T Michel 11, 15121, Alessandria, Italy
    Cell Biochem Biophys 57:9-17. 2010
    ..showed that HMGb1 activates ERK1/2, while the use of an anti-RAGE receptor-blocking antibody and of the selective MEK1/2 inhibitor PD98059 blocked ERK1/2 activation and wound healing responses to HMGb1...
  93. ncbi Ras/MEK pathway is required for NGF-induced expression of tyrosine hydroxylase gene
    Takahiro Suzuki
    Department of Life Science, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan
    Biochem Biophys Res Commun 315:389-96. 2004
    ..Induction of TH mRNA by NGF was abolished by pretreatment of the cells with U0126, an inhibitor for MEK1/2, but not with inhibitors for p38 MAPK, PI3K, and PKA...
  94. doi Interleukin-22 promotes epithelial cell transformation and breast tumorigenesis via MAP3K8 activation
    Karam Kim
    College of Pharmacy, Chosun University and Department of Pathology, School of Medicine, Chosun University, Gwangju 501 759, South Korea
    Carcinogenesis 35:1352-61. 2014
    ..Pin1(-/-) mouse embryonic fibroblasts (MEF) exhibited significantly a decrease in IL-22-induced MEK1/2, c-Jun, and STAT3 phosphorylation compared with Pin1(+/+) MEF...
  95. pmc Raf kinase inhibitor protein interacts with NF-kappaB-inducing kinase and TAK1 and inhibits NF-kappaB activation
    K C Yeung
    Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02912, USA
    Mol Cell Biol 21:7207-17. 2001
    ..RKIP inhibits the phosphorylation of MAP/extracellular signal-regulated kinase 1 (MEK1) by Raf-1 by disrupting the interaction between these two kinases...
  96. ncbi HIV-1 Nef mediates Pak phosphorylation of Mek1 serine298 and elicits an active phospho-state of Pak2
    Arlette Kouwenhoven
    Section on Directed Gene Transfer, Laboratory of Cellular and Molecular Regulation, NIMH, Bethesda, MD 20892 4483, USA
    Curr HIV Res 11:198-209. 2013
    ..Here we demonstrate that Nef expression mediates phosphorylation of Mek1 serine298 in T cell lines as well as primary human T cells, thus directly affecting the Erk cascade...
  97. ncbi Epidermal growth factor treatment enhances the kinase activity of kinase suppressor of Ras
    H R Xing
    Laboratory of Signal Transduction, The Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10021, USA
    J Biol Chem 275:17276-80. 2000
    ..protein kinase activation was detected in KSR immunoprecipitates depleted of all contaminating kinases (c-Raf-1, MEK1, ERK2) by multiple high salt washes...
  98. doi Endothelin-1 stimulates suppressor of cytokine signaling-3 gene expression in adipocytes
    Hsin Huei Chang
    Department of Life Sciences, National Central University, Jhongli, Taoyuan, Taiwan
    Gen Comp Endocrinol 178:450-8. 2012
    ..The specific inhibitors of either MEK1 (U-0126 and PD-98059), JAK (AG-490), JNK (SP-600125), or PI3K (LY-294002 and wortmannin) reduced ET-1-increased ..
  99. ncbi Regulation of mesangial cell hexokinase activity by PKC and the classic MAPK pathway
    R B Robey
    Department of Medicine, Section of Nephrology, University of Illinois at Chicago College of Medicine, Chicago, Illinois 60612, USA
    Am J Physiol 277:F742-9. 1999
    ..accompanied by parallel increases in both Glc utilization and lactate production and was blocked by the specific MEK1/2 inhibitor PD-98059 (IC(50) approximately 3 microM)...
  100. doi The LRRK2 G2019S mutant exacerbates basal autophagy through activation of the MEK/ERK pathway
    José M Bravo-San Pedro
    Departamento de Bioquimica y Biologia Molecular y Genetica, E Enfermería y T O, Centro de Investigacion Biomedica en Red sobre Enfermedades Neurodegenerativas CIBERNED, Universidad de Extremadura, Avda Universidad, S N, 10003, Caceres, Spain
    Cell Mol Life Sci 70:121-36. 2013
    ..The use of 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio]butadiene (U0126), a highly selective inhibitor of MEK1/2, reduced the enhanced autophagy and sensibility observed in G2019S LRRK2 mutation cells...
  101. pmc Peroxisome proliferator-activated receptor α positively regulates complement C3 expression but inhibits tumor necrosis factor α-mediated activation of C3 gene in mammalian hepatic-derived cells
    Denis A Mogilenko
    Department of Biochemistry, Institute of Experimental Medicine, Russian Academy of Medical Sciences, St Petersburg 197376, Russia
    J Biol Chem 288:1726-38. 2013
    ..TNFα increases C3 gene via NF-κB and, to a lesser extent, MEK1/2 signaling pathways, whereas TNFα-mediated stimulation of C3 protein secretion depends on activation of MEK1/2, ..

Research Grants62

  1. ANGIOTENSIN II SIGNAL TRANSDUCTION
    Bradford C Berk; Fiscal Year: 2012
    ..Then we showed that GIT1 is a scaffold for several key pathways including PLC3-CamKII , MEK1-ERK1/2, and PIX-PAK...
  2. ANALYSIS OF MEIOTIC CHROMOSOME SYNAPSIS IN YEAST
    Nancy M Hollingsworth; Fiscal Year: 2013
    ..In meiosis, programmed DSBs instead activate the meiosis-specific Mek1 kinase...
  3. Linkage of Lung Inflammation to 8-oxoguanine and OGG1
    ISTVAN STEVEN BOLDOGH; Fiscal Year: 2013
    ..that EG8-oxoG increased the levels of 1) activated small GTPases;2) Ras to Raf-1 binding;and phosphorylation of 3) MEK1,2;4) ERK1,2;and 5) RelA-Ser276. EG8-oxoG induced luciferase expression driven from the CXCL-8 promoter...
  4. Mechanism of Action of Prohibitin in Ovarian Cell Function
    Winston E Thompson; Fiscal Year: 2013
    ..PHB1 is phosphorylated on Y249 in a MEK1-dependent fashion while PHB1 is required for ERK1/2 activation defining a new regulatory paradigm in response to ..
  5. Interaction of cationic lipids with dendritic cells
    Leaf Huang; Fiscal Year: 2012
    ..P38 activation leads to the production of IL-12. Inhibition of pERK activation by specific inhibitors of Mek1/2, the upstream kinase which phosphorylates ERK, inhibited CCL2 production and, more importantly, the antitumor ..
  6. Copper reduction as a novel therapy in BRAF-mutant positive cancers
    Donita C Brady; Fiscal Year: 2013
    ..To that end, my proposed research project evolved from our previous observations that copper (Cu) influx enhances MEK1 phosphorylation of its substrates ERK1/2 through a Cu-MEK1 interaction...
  7. Defining mechanisms of MEK1/2 inhibitor response in triple negative breast cancer
    Martin Whittle; Fiscal Year: 2013
    ..The observation of high RAF/MEK/ERK activity in many TNBC patient samples has prompted the investigation of using MEK1/2 inhibitors as a potential therapeutic strategy...
  8. Apoptosis Induced by Glucocorticoids and MEK1/2 Inhibitors in Leukemia
    Hisashi Harada; Fiscal Year: 2012
    ..abstract_text> ..
  9. Translational Control in Long-Term Synaptic Plasticity
    RAYMOND KELLEHER; Fiscal Year: 2009
    ..In the present application, conditional expression of a dominant-negative form of MEK1 in the post-natal murine forebrain is shown to inhibit ERK activation and cause selective deficits in hippocampal ..
  10. The IKK/Tpl2 axis of TLR signaling
    Shao Cong Sun; Fiscal Year: 2013
    ..inhibitor I(B, whereas Tpl2 is a MAP3K that activates the MAP kinase ERK through phosphorylating the ERK kinase, MEK1. Interestingly, Tpl2 is sequestered by an I(B-like molecule, p105, and the activation of Tpl2 requires IKK-mediated ..
  11. Dose-dependent Activation of the MEK/ERK Pathway in Hematopoiesis
    Jing Zhang; Fiscal Year: 2013
    ..To further test our hypothesis in vivo, we have generated a novel conditional MEK1 knockin allele carrying point mutations that mimic phosphorylation at serine 218 and serine 222 (LSL MEK1 S218;222E)..
  12. A Proteomics-based Approach to Identifying Mechanisms of Drug Resistance to Targe
    Scott Stuart; Fiscal Year: 2010
    ..method to profile MEK-dependent phosphorylation events in a number of metastatic melanoma cell lines using the MEK1/2 inhibitor AZD6244...
  13. COMBINATORIAL SIGNALING THROUGH MEK1
    Andrew Catling; Fiscal Year: 2009
    ..We will focus on MEK1 phosphorylation and assembly of MEKl-specific signaling complexes as points of integration for adhesion and growth ..
  14. INSULIN-REGULATED MAP KINASE PATHWAYS
    Melanie Cobb; Fiscal Year: 2006
    ..The ERK2 activator MEK1 binds to molecules other than ERK1/2 and Raf that are essential for signal transmission through the cascade...
  15. Oklahoma Autoimmunity Center of Excellence
    Judith A James; Fiscal Year: 2013
    ..The second tests the efficacy and early MRI changes of a novel MEK1/MEK2 inhibitor in RA with additional mechanistic studies...
  16. PSYCHOPHYSIOLOGY OF IRRITABLE BOWEL SYNDROME
    William E Whitehead; Fiscal Year: 2012
    ..Identifying these different phenotypes of IBS and the genetic markers associated with them may help to identify new targets for drug development and may help us to individualize treatment and thereby make it more successful. ..
  17. Pancreatic Cancer Management by Novel Gene Therapy &Dietary Agents
    Paul B Fisher; Fiscal Year: 2012
    ..When K-ras expression or its downstream MEK1/MEK2 pathway is inhibited or a reactive oxygen species (ROS) inducer is applied, mda-7/IL-24 mRNA is converted into ..
  18. Peri-arteriolar Myofibroblast Differentiation in the Pathobiology of IPAH
    ARTHUR ROGER STRAUCH; Fiscal Year: 2012
    ..to over-active PI3K/Akt feed-forward signaling kinases and/or impaired feed-back inhibition mediated by sub-optimal MEK1/Erk1,2/Egr-1 signaling...
  19. The role of Raf-MEK signaling in the pathogenesis of hypertrophic cardiomyopathy
    JASON BECKER; Fiscal Year: 2013
    ..We discovered that mitogen-activated protein kinase kinase (MEK1/2) was important in the pathological induction of this signaling pathway...
  20. Studying the initiation, progression and therapy of lung cancer in mouse models
    Martin McMahon; Fiscal Year: 2013
    ..the anti-tumor effects of potent, specific and selective pharmacological inhibitors of either RAF (SB590885) or MEK1/2 (PD0325901) using the KRasLSL mouse model of lung tumorigenesis...
  21. Manipulation of inflammasomes and NF-kB signaling in human myeloid cells by Myxom
    Grant McFadden; Fiscal Year: 2013
    ..response to MYXV infection;study the co-ordinating upstream role of virus-induced MAPK, in particular the role of MEK1/2-ERK1/2 kinases, in co-inducing both the type I IFN and pro-inflammatory cytokine signaling pathways in response ..
  22. Novel pathways modulating Raf-mediated cardiac hypertrophy
    Matthew J Wolf; Fiscal Year: 2013
    ..Moreover, the activation of EGFR and subsequent signals to the small GTPase, Ras, and the kinases, Raf and MEK1, cause cardiac hypertrophy in flies and mammals...
  23. Role of MEK1 in T cell function in asthma
    Rafeul Alam; Fiscal Year: 2013
    ..refractoriness we observed that T cells from asthmatic patients express increased levels of the signaling kinase MEK1, which stimulates IL-2 production. Interestingly, IL-2 directly induces MEK1...
  24. Role of PAR-1 and PAR-2 in Cardiac Remodeling
    Nigel Mackman; Fiscal Year: 2010
    ..Specific Aim 2 will evaluate the role of the MEK5-ERK5, MEK1-ERK1/2 and calcineurin signaling pathways in PAR-1- and PAR-2-dependent hypertrophy of cultured cardiomyocytes by ..
  25. The Molecular Basis of OX40 on CD4 T Cells
    Michael Croft; Fiscal Year: 2012
    ..Specifically, we will determine whether OX40 utilizes PKC0, PDK1, and MEK1/ERK to target Akt and NF-KB, and how these signaling cascades impact the expression and function of survivin and ..
  26. The Ras/Mapk pathway in cardiovascular disease.
    Forest M White; Fiscal Year: 2013
    ..Costello Syndrome (CS), caused by HRAS mutations, and Cardio-Facial- Cutaneous-Syndrome (CFCS) (caused by BRAF, MEK1 or MEK2 mutations)...
  27. TSC1-mTOR signaling and T cell tolerance
    XIAOPING ZHONG; Fiscal Year: 2013
    ..Using genetically manipulated mice and cell line models, we have recently revealed that the RasGRP1-Ras- Mek1/2-Erk1/2 pathway is critical for both mTORC1 and mTORC2 activation in T cells following T cell receptor (TCR) ..
  28. In-cell NMR technology to study protein interactions
    Alexander Shekhtman; Fiscal Year: 2013
    ..plasmid constructs capable of overexpressing viral HIV p6 domain, endocytic proteins TSG101 and Hrs, protein kinase MEK1 and ERK2, and monoubiquitination machinery in bacteria...
  29. Preclinical Development of Novel MEK1/2 Inhibitors to Treat Inherited Cardiomyopa
    Uday R Khire; Fiscal Year: 2013
    ..The research at Columbia has further shown that inhibitors of MAPK/ERK kinase1/2 (MEK1/2), the enzyme that activates ERK1/2, prevent ventricular dilatation, improve cardiac contractility and delay the ..
  30. SIGNALING PATHWAYS REGULATING EPITHELIAL CELL SURVIVAL
    Paul Dent; Fiscal Year: 2013
    ..We also have published data demonstrating that geldanamycins (17AAG, 17DMAG) + MEK1/2 inhibitors synergize to kill liver and pancreatic tumor cells via CD95 activation...
  31. ERK signaling and a hybrid surgical/molecular approach for chronic heart failure
    Michael J Mann; Fiscal Year: 2013
    ..studies, we will test this translational hypothesis utilizing a new and unique genetic model of regulatable MEK1-ERK1/2 signaling...
  32. Kinome Reprogramming in Response to Targeted Kinase Inhibitors
    Gary L Johnson; Fiscal Year: 2013
    ..MIB/MS identified a kinome response signature to a select MEK1/2 inhibitor AZD6244 that is currently in clinical testing for triple negative breast cancer...
  33. Checkpoint Abrogation and MEK 1/2 Inhibition in Myeloma
    Steven Grant; Fiscal Year: 2013
    ..period, important new insights emerged, including the observations that a) disruption of Chk1 by UCN-01 activates MEK1/2/ERK1/2 through a Ras- dependent mechanism that limits lethality;b) these findings may represent a generalized ..
  34. VALIDATING AND TARGETING LYSOPHOSPHATIDIC ACID ACYLTRANSFERASE-BETA IN CANCER
    Gregory Springett; Fiscal Year: 2013
    ..Aim 2, we will determine whether LPAAT-[unreadable] is required for, and/or cooperates with, RalGDS/RalA/B, Raf-1/Mek1/2 or PI3K/Akt pathways to transform immortalized human primary epithelial cells...
  35. The Impact of TLR on Intestinal Tumorigenesis
    Eyal Raz; Fiscal Year: 2010
    ..We will treat these animals with UO126 (a MEK1/2 inhibitor) and assess the impact of this intervention on survival and IEC tumor growth...
  36. Targeting BRAF and MEK in tumors with BRAF and RAS mutations.
    David B Solit; Fiscal Year: 2012
    ..tumor cells with activating BRAF(V600E) mutations are selectively sensitive to PD0325901, a selective inhibitor of MEK1/2...
  37. Targeting the Estrogen Pathway for the Prevention and Treatment of LAM
    Jane Yu; Fiscal Year: 2013
    ..Aim 3. To determine whether inhibition of MEK1/2 and ER( leads to a regression of established lung metastasis of ELT3 cells...
  38. CHARACTERIZING THE ROLE OF IQGAP1 IN ERK MAPK-DRIVEN EPIDERMAL NEOPLASIA
    KAVITA YANG SARIN; Fiscal Year: 2011
    ..recent work from our laboratory revealed that ablation of Erk MAPK cascade signaling at the level of both Mek1/2 and Erk1/2 not only blocked Ras/Raf driven neoplastic changes but also resulted in growth inhibition and ..
  39. Physiologic Function of RAS Effectors MEK 1/2 on Epidermal Differentiation
    Todd W Ridky; Fiscal Year: 2011
    ..b>MEK1 null mice are embryonic lethal, precluding establishment of epidermal phenotypes;however, MEK2 null mice are normal...
  40. Reducing dietary copper for the treatment of BRaf mutation-positive melanoma
    CHRISTOPHER COUNTER; Fiscal Year: 2013
    ..food components, we note that half of melanomas encode an oncogenic mutant BRafV600E kinase, which phosphorylates Mek1/2 kinases and in turn Erk1/2, thereby activating the MAPK pathway to promote melanoma...
  41. Overcoming Drug-Induced Resistance in BRaf mutated melanoma cells
    Ramin Samadani; Fiscal Year: 2013
    ..New treatments inhibiting BRaf or its direct target MEK1/2 proteins have recently been developed and have shown promising results in clinical trials...
  42. Mechanism of T Cell Resistance against Treg-mediated suppression in asthma
    Rafeul Alam; Fiscal Year: 2010
    ..will examine whether the ERK1/2 signaling module establishes a self-sustaining mechanism through the induction of a MEK1-dependent positive feedback loop and inhibition of a MKP3-dependent negative feedback loop...
  43. Molecular mechanisms of signaling co-ordination in innate lymphocytes
    Subramaniam Malarkannan; Fiscal Year: 2013
    ..forms a novel signalosome around the perinuclear region to regulate ERK1/2 activation via Rac1->Pak->Raf->MEK1/2 pathway...
  44. Mechanisms of MEK/ERK growth arrest signaling
    Jong In Park; Fiscal Year: 2013
    ..tissue specimens;(ii) determine whether mortalin regulates the Raf/MEK/ERK pathway by differentially sequestering MEK1 or MEK2;and (iii) determine molecular mechanisms underlying the non-catalytic ERK functions...
  45. Signaling Mechanisms Regulation Muscle Protein Turnover
    S Price; Fiscal Year: 2005
    ..Next, we will determine if regulating SGK or MEK1 (the upstream activator of ERK1/2) will change protein degradation and expression of ubiquitin-proteasome pathway ..
  46. MDA-7/IL-24 and free radicals in renal cancer therapy
    Paul Dent; Fiscal Year: 2009
    ..Specific aim 2 will determine the mechanisms by which combined treatment of RCCs with PI3 kinase and MEK1/2 inhibitors enhance cell killing by purified MDA-7 protein...
  47. ANTHRAX TOXIN, DENDRITIC CELLS AND ADAPTIVE IMMUNITY
    Bali Pulendran; Fiscal Year: 2006
    ..At low concentrations, it cleaves components of the MAP-kinase pathway (MKK1,2 & 3), thereby rendering macrophages anergic to further stimulation by LPS...
  48. Gene Structure and Transciptional Regulation
    RICHARD FIRTEL; Fiscal Year: 2007
    ..SMEK1, an evolutionarily-conserved, second-site suppressor of MEK1 that was identified in my lab in regulating the MEK 1/ERK1 pathway and chemotaxis...
  49. Developmental Retinal Neovascularization
    Lois Smith; Fiscal Year: 2007
    ..We will define in EC and in the new mouse model the selectivity of MEK1 inhibition for blocking vessel proliferation over survival...
  50. 17 alpha-Hydroxylase Expression in Human Ovarian Cells
    Jan M McAllister; Fiscal Year: 2010
    ..CYP17) gene expression in PCOS theca cells results from a combined reduction in the activation state of the MEK1/ERK pathway and a stimulation in the activation state of the MKK3 pathway...
  51. Caveolin-1, Caveolae and Placental Angiogenesis
    DongBao Chen; Fiscal Year: 2007
    ..e., Ras-Raf-MEK1-ERK2/1 and PI3K/Akt signaling modules, in the caveolae of endothelial cells (EC), thereby modulating VEGF ..
  52. Regulation of type IV collagenase expression
    Douglas Boyd; Fiscal Year: 2007
    ..Similarly, the MEK1 inhibitor PD098059 represses MMP-9 expression and in Specific Aim # 3 we will determine if the transcriptional ..
  53. Fibronectin Polymerization: Effects on Cell Signaling
    PAULA MC KEOWN LONGO; Fiscal Year: 2009
    ..inhibitors, and dominant/negative adenoviral constructs will be used to define the role of the Ras/Raf1 MEK1 pathway in the activation of ERK by LPA...
  54. REGULATION OF APOPTOSIS BY CELLULAR RAS ISOFORMS
    Alan Wolfman; Fiscal Year: 2003
    ..Raf-1, MEK1 and c-N-Ras are all found in a purified mitochondrial preparation, supporting our hypothesis that c-N-Ras plays a ..
  55. TOLL-LIKE RECEPTOR REGULATION IN THE MYOCARDIUM
    Marita Thompson; Fiscal Year: 2004
    ..Response to LPS will be determined by evaluating the LPS signal transduction pathway via MEK1, ERK2 and NF-kappaB...
  56. MECHANISMS OF GOLGI VESICULATION DURING MITOSIS
    Vivek Malhotra; Fiscal Year: 2007
    ..We have proposed the existence of a Golgi membrane specific cell-cycle checkpoint. We have found that kinases MEK1 and Polo like kinase (Plk); and Golgi associated proteins GRASP55 and GRASP65 are required for Golgi fragmentation...
  57. BIOLOGICAL ANALYSIS OF THE CD4 SILENCER
    Gerald Siu; Fiscal Year: 2002
    ..has determined that the translocation of SAF to the nucleus in DP T cells is mediated by signaling from the Mek1 branch of the MAPK pathway, which has been previously shown to convey positive selection signals in developing ..
  58. ARTERIAL INJURY AND SMOOTH MUSCLE CELL SIGNALING
    Michael Reidy; Fiscal Year: 2001
    ..Activation of this pathway will be inhibited in vivo with a topically applied MEK1 inhibitor and the effect on SMC replication quantitated...
  59. POTENTIATION OF ARA-C BY INHIBITION OF MAPK CASCADE
    WILLIAM JARVIS; Fiscal Year: 2005
    ..sustained generation of the cytoprotective lipid messenger diglyceride, and consequent activation of the Raf-1->MEK1->ERK1->ERK2 sequence...
  60. Regulation of angiotensin-induced PAI-1 expression
    EDWARD FEENER; Fiscal Year: 2006
    ..These results demonstrate a novel mechanism for MEKK-1/MEK1,2 activation of the PAI-1 promoter that is dependent on the cooperative effects of adjacent Sp1 and AP-1 elements...
  61. Non-Peptides Inhibitors of Anthrax Lethal Factor
    DARRYL RIDEOUT; Fiscal Year: 2003
    ..extracted 3D-pharmacophore information from the computationally modeled LF substrate MAPKK1 during Phase I...
  62. Mechanisms of Eosinophil Adhesion
    Xiangdong Zhu; Fiscal Year: 2006
    ..on eosinophil adhesion using selective MAPK pathway inhibitors and dominant negative and active mutants of MEK1. Using dominant negative Ras and ERK pathway inhibitors, the causal relationship between Ras, ERK and cPLA 2 ..