Map Kinases in Airway Disease: Standing at the Confluence of Basic and Clinical Science

  • Paul Vichi
  • James Posada
Part of the NATO ASI Series book series (NSSA, volume 297)


Mitogen activated protein (MAP) kinases are a family of serineJthreonine protein kinases that currently include three major subgroups; the extracellular regulated kinase 2 (ERK2), the c-Jun NH2 terminal kinase (JNK), and the p38 kinase. Each of the three major subgroups of MAP kinase has additional isozymes (reviewed in 1). For example, there are three ERK isozymes, and up to 10 JNK isozymes, including differentially processed transcripts2. The nomenclature of the JNK MAP kinases is somewhat disjoined owing primarily to the contemporaneous cloning of these kinases. Kyriakis et al. cloned what they termed stress activated protein kinases (SAPK) α, β, γ, which are identical to the JNK MAP kinases cloned by Derijard et al.3.


Mitogen Activate Protein Kinase Airway Smooth Muscle Adult Respiratory Distress Syndrome Airway Smooth Muscle Cell Mitogen Activate Protein Kinase Pathway 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Ferrell, J.E. Jr. Tripping the switch fantastic: how a protein kinase cascade can convert graded inputs into switch-like outputs. Trends in Biochemical Sciences 21: 460 (1996).PubMedCrossRefGoogle Scholar
  2. 2.
    Derijard B, Hibi M, Wu I-H, Barrett T, Su B, Deng T, Karin M, and Davis RJ. JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 76: 1025 (1994).PubMedCrossRefGoogle Scholar
  3. 3.
    Kyriakis, J.M., Banerjee, P., Nikolakaki, E., Dai, T., Rubie, E.A., Ahmad, M.F., Avruch, J., Woodgett, J.R. The stress-activated protein kinase subfamily of c-Jun kinases. Nature 369: 156 (1994).PubMedCrossRefGoogle Scholar
  4. 4.
    Boulton TG, Yancopoulos C, Slaughter C, Moomaw J, Hsu Gregory JS, and Cobb M. An insulin-stimulated protein kinase similar to yeast kinases involved in cell cycle control. Science 249: 64 (1990PubMedCrossRefGoogle Scholar
  5. 5.
    Pages, G., Lenormand, P., L’Allemain, G., Chambard, J.C., Meloche, S., and Pouyssegur, J. Mitogen-activated protein kinases p42mapk p44mapk are required for fibroblast proliferation. Proc. Natl. Acad. Sci. USA 90: 8319 (1993).PubMedCrossRefGoogle Scholar
  6. 6.
    Cowley, S., Paterson, H., Kemp, P., and Marshall, C. J. Activation of MAP Kinase Kinase is Necessary and Sufficient for PC 12 Differentiation and for Transformation of NIH 3T3 cells. Cel l 77: 841 (1994).CrossRefGoogle Scholar
  7. 7.
    Mansour, S. J., Matten, W. T., Hermann, A. S., Candia, J. M., Rong, S., Fukasawa, K., Vande Woude, G. F., and Ahn, N. G. 1994. Transformation of mammalian cells by constitutively active MAP kinase kinase. Science 265: 966 (1994).PubMedCrossRefGoogle Scholar
  8. 8.
    Fänger, G.R., Gerwins, P., Widman, C, Jarpe, M.B., Johnson, G.L. MEKKs, GCKs, MLKs, PAKs, TAKs, and tpls: upstream regulators of the c-jun amino terminal kinases? Curr. Opin. Gen. & Develop. 7: 67 (1997).CrossRefGoogle Scholar
  9. 9.
    Han, J., Lee, J.D., Bibbs, L., Ulevitch, R.J. 1994. A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265: 808 (1994).PubMedCrossRefGoogle Scholar
  10. 10.
    Raingeaud, J., Gupta, S., Roger, J.S., Dickens, M., Han, J., Ulevitch, R.J., and Davis, R.J. Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J. Biol. Chem. 270:7420 (1995).PubMedCrossRefGoogle Scholar
  11. 11.
    Xia, Z., Dickens, M., Raingeaud, J., Davis, R. J., and Greenberg, M. E. Opposing Effects of ERK and JNK-p38 MAP Kinases on Apoptosis. Science 270, 1326 (1995).PubMedCrossRefGoogle Scholar
  12. 12.
    Liu Z., Hsu, H., Goeddel, D. V., Karin, M. 1996. Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF kappa B activation prevents cell death. Cell 87: 565 (1996).PubMedCrossRefGoogle Scholar
  13. 13.
    Ray, L.B., and Sturgill, T.W. Rapid stimulation by insulin of a serineJthreonine kinase in 3T3-L1 adipocytes that phosphorylates microtubule-associated protein 2 in vitro. Proc. Natl. Acad. Sci USA. 84: 1502 (1987).PubMedCrossRefGoogle Scholar
  14. 14.
    Posada, J. A. and Cooper, J. A. Requirements for phosphorylation of MAP kinase during meiosis in Xenopus oocytes. Science, 255: 212 (1992).PubMedCrossRefGoogle Scholar
  15. 15.
    Crews, C. M., Alessandrini, A., and Erikson, R. L. The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. Science 258: 478 (1992).PubMedCrossRefGoogle Scholar
  16. 16.
    Zheng, C.-F., and Guan, K.-L. Activation of MEK family kinases requires phosphorylation of two conserved SerJThr residues. EMBO J. 13: 1123 (1994).PubMedGoogle Scholar
  17. 17.
    Dent, P., Haser, W., Haystead, T.A., Vincent, L.A., Roberts, T.M., and Sturgill, T.W. Activation of mitogen-activated protein kinase kinase by v-Raf in NIH 3T3 cells and in vitro. Nature 257: 1404 (1992).Google Scholar
  18. 18.
    Derijard, B., Raingeaud, J., Barrett, T., Wu, I-H, Han, J., Ulevitch, J., and Davis, R.J. Independent human MAP kinase signal transduction pathways defined by MEK and MKK isoforms. Science, 267: 682 (1995).PubMedCrossRefGoogle Scholar
  19. 19.
    Raingeaud, J., Whitmarsh, A.J., Barrett, T., Derijard, B., and Davis, R.J. MKK3-and MKK6-regulated gene expression is mediated by the p38 mitogen-activated protein kinase signal transduction pathway. Mol Cell. Biol. 16: 1247 (1996).PubMedGoogle Scholar
  20. 20.
    Han, J., Lee, J.-D., Jiang, Y., Li, Z., Feng, L., and Ulevitch, R.J. Characterization of the structure and function of a novel MAP kinase kinase (MKK6). J. Biol Chem. 271: 2886 (1996).PubMedCrossRefGoogle Scholar
  21. 21.
    Minden A, Lin A, McMahon M, Lange-Carter C, Derijard B, Davis RJ, Johnson GL, and Karin M. Differential activation of ERK and JNK mitogen-activated protein kinases by Raf-1 andMEKK. Science 266: 1719 (1994).PubMedCrossRefGoogle Scholar
  22. 22.
    Ichijo, H., Nishida, E., Irie, K., ten Dijke, P., Saitoh, M., Moriguchi, T., Takagi, M., Matsumoto, K., Miyazono, K., Gotoh, Y. Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science. 275: 90 (1997).PubMedCrossRefGoogle Scholar
  23. 23.
    Lin, L.-L., Wartmann, M., Lin, A. Y., Knopf, J. L., Seth, A., and Davis, R.J. cPLA2 is phosphorylated and activated by MAP kinase. Cell 72: 269 (1993).PubMedCrossRefGoogle Scholar
  24. 24.
    Gille, H., Kortenjann, M., Thomae, O., Moomaw, C, Slaughter, C, Cobb, M.H., and Shaw, P. E. ERK phosphorylation potentiates Elk-1-mediated ternary complex formation and transactivation. EMBOJ. 14: 951 (1995).Google Scholar
  25. 25.
    Whitmarsh, A.J., Shore, P., Sharrocks, A. D., and Davis, R.J. Integration of MAP kinase signal transduction pathways at the serum response element. Science 269: 403 (1995).PubMedCrossRefGoogle Scholar
  26. 26.
    Hibi, M., Lin, A., Smeal, T., Minden, A., and Karin, M. Identification of an oncoprotein-and UV-responsive protein kinase that binds and potentiates the c-jun activation domain. Genes and Development, 7: 2135 (1993).PubMedCrossRefGoogle Scholar
  27. 27.
    Gupta, S., Cambell, D., Derijard, B., Davis, R.J. Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science, 267: 389 (1996).CrossRefGoogle Scholar
  28. 28.
    Whitmarsh, A.J., Yang, S.H., Su, M.S., Sharrocks, A.D., and Davis, R.J. Role of p38 and JNK mitogen-activated protein kinases in the activation of ternary complex formation. Mol Cell Biol. 17: 2360 (1997).PubMedGoogle Scholar
  29. 29.
    Panettieri R.A., Jr. Airways smooth muscle cell growth and proliferation. In Airway Smooth Muscle: Development and Regulation of Contractility. D. Raeburn and M. A. Giambycz, editors. Birchauser Verlag, Basel, Switzerland, (1994).Google Scholar
  30. 30.
    Kellerher, M.D., Abe, M.K, Chao, T-S. O., Soloway, J., Rosner, M.R., and Hershenson, M.B. Role of MAP kinase in bovine airway smooth muscle proliferation. Am. J. Physiolo. 268: L894 (1995).Google Scholar
  31. 31.
    Shapiro, P.S., Evans, J.N., Davis, R.J., and Posada, J.A. The seven-transmembranespanning receptors for endothelin and thrombin cause proliferation of airway smooth muscle cells and activation of the extracellular regulated kinase and c-Jun NH2-terminal kinase groups of mitogen activated protein kinases. J. Biol Chem. 271: 5750 (1996).PubMedCrossRefGoogle Scholar
  32. 32.
    Panettieri, R.A., Hall, LP., Maki, C, and Murray, R.K. α-thrombin increases cytosolic calcium and induces human airway smooth muscle cell proliferation. Am. J. Resp. Cell Mo. Biol. 13: 205 (1995).Google Scholar
  33. 33.
    Whelchel, A., Evans, J., and Posada, J., Inhibition of ERK activation attenuates endothelin-stimulated airway smooth muscle cell proliferation. Am. J. Respir. Cell Mol. Biol. 16: 589 (1997).PubMedGoogle Scholar
  34. 34.
    Shapiro, P., Absher, M.P., Posada, J. A., and Evans, J.N. Activation of ERK and JNK1 MAP kinases in cultured lung tissue. Am. J. Physiol. In press (1997)Google Scholar
  35. 35.
    Matalon, S., DeMarco, V., Haddad, I.Y., Myles, C, Skimming, J.W. Schurch, S., Cheng, S., Cassin, S. Inhaled nitric oxide injures the pulmonary surfactant of lambs in vivo. Am. J. Physiol. 270: L273 (1996).PubMedGoogle Scholar
  36. 36.
    Haddad, I.Y., Pataki, G., Hu, P., Galliani, C, Beckman, J.S., Matalon, S. Quantitation of nitrotyrosine levels in lung sections of patients and animals with acute lung injury. J. Clin. Inves. 94: 2407 (1994).CrossRefGoogle Scholar
  37. 37.
    Ischiropoulos, H., al-Mehdi, Fisher, A.B. Reactive oxygen species in ischemic rat lung injury: contribution of peroxynitrite. Am. J. Physiol. 269: L158 (1995).PubMedGoogle Scholar
  38. 38.
    Abe, M.K., Chao, T.O., Solway, J., Rosner, M.R., Hershenson, M.B. 1994. Hydrogen Peroxide Stimulates Mitogen-activated Protein Kinase in Bovine Tracheal Myocytes: Implications for Human Airway Disease. Am. J. Respir. Cell and Mol. Biol. 11: 577 (1994).Google Scholar
  39. 39.
    Lo, Y.Y.C., Wong, J.M.S., Cruz, T.F. Reactive oxygen species mediate cytokine activation of c-JunNH2—terminal kinases. J. Biol.Chem. 271: 15703 (1996).PubMedCrossRefGoogle Scholar
  40. 40.
    Shieh, J.C., Wilkinson, M.G., Buck, V., Morgan, B.A., Makino, K, Millar, J.B. The Mcs4 response regulator coordinately controls the stress-activated Wakl-Wis-Styl MAP kinase pathway and fission yeast cell cycle. Genes & Development 11: 1008 (1997).CrossRefGoogle Scholar
  41. 41.
    Abe, J.-L, Kusuhara, M., Ulevitch, R.J., Berk, B.C., and Lee, J.-D. Big mitogenactivated protein kinase 1 (BMK) is a redox-sensitive kinase. J. Biol. Chem. 271: 16586 (1996).PubMedCrossRefGoogle Scholar
  42. 42.
    Pombo, CM., Bonventure, J.V., Molnar, A., Kyriakis, J., Force, T. Activation of a human Ste20-like kinase by oxidant stress defines a novel stress response pathway. EMBO J. 15:4537 (1996).PubMedGoogle Scholar
  43. 43.
    Roczniak, A., Burns, K.D. Nitric oxide stimulates guanylate cyclase and regulates sodium transport in rabbit proximal tubule. Am. J. Physiol. 270: F106 (1996).PubMedGoogle Scholar
  44. 44.
    Lander, H.M., Jacovina, A.T., Davis, R.J., and Tauras, J.M. Differntial activation of mitogen-activated protein kinases by nitric oxide. J. Biol Chem. 271: 19705 (1996).PubMedCrossRefGoogle Scholar
  45. 45.
    Yang, X., Khosravi-Far, R., Chang, H., and Baltimore, D. Daxx, a novel Fas-binding protein that activates JNK and apoptosis. Cell. 89: 1067 (1997).PubMedCrossRefGoogle Scholar
  46. 46.
    Alessi, D.R., Cuenda, A., Cohen, P., Dudley, D.T., and Saltiel, A.R. PD 098059 is a specific inhibitor of the activation of mitogen-activated protein kinase kinase in vitro and in vivo. J. Biol. Chem. 270:27489 (1995).PubMedCrossRefGoogle Scholar
  47. 47.
    Cuenda, A., Rouse, J., Doza, Y.N., Meier, R., Cohen, P., Gallagher, T.F., Young, P.R., Lee, J.C. SB 203580 is a specific inhibitior of a MAP kinase homologue which is stimulated by cellular stress and interleukin-1. FEBS Letters 364: 229 (1995).PubMedCrossRefGoogle Scholar
  48. 48.
    Gupta, S., Campbell, D., Derijard, B., Davis, RJ. Transcription factor ATF2 regulation by the JNK signal transduction pathway. Science, 267: 389 (1995).PubMedCrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1998

Authors and Affiliations

  • Paul Vichi
    • 1
  • James Posada
    • 1
  1. 1.Department of Molecular Physiology BurlingtonUniversity of Vermont College of MedicineVermontUSA

Personalised recommendations