MAP Kinase Signaling Protocols pp 3-38

Part of the Methods in Molecular Biology book series (MIMB, volume 661)

The MAP Kinase Signaling Cascades: A System of Hundreds of Components Regulates a Diverse Array of Physiological Functions

Protocol

Abstract

Sequential activation of kinases within the mitogen-activated protein (MAP) kinase (MAPK) cascades is a common, and evolutionary-conserved mechanism of signal transduction. Four MAPK cascades have been identified in the last 20 years and those are usually named according to the MAPK components that are the central building blocks of each of the cascades. These are the extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-Terminal kinase (JNK), p38, and ERK5 cascades. Each of these cascades consists of a core module of three tiers of protein kinases termed MAPK, MAPKK, and MAP3K, and often two additional tiers, the upstream MAP4K and the downstream MAPKAPK, which can complete five tiers of each cascade in certain cell lines or stimulations. The transmission of the signal via each cascade is mediated by sequential phosphorylation and activation of the components in the sequential tiers. These cascades cooperate in transmitting various extracellular signals and thus control a large number of distinct and even opposing cellular processes such as proliferation, differentiation, survival, development, stress response, and apoptosis. One way by which the specificity of each cascade is regulated is through the existence of several distinct components in each tier of the different cascades. About 70 genes, which are each translated to several alternatively spliced isoforms, encode the entire MAPK system, and allow the wide array of cascade’s functions. These components, their regulation, as well as their involvement together with other mechanisms in the determination of signaling specificity by the MAPK cascade is described in this review. Mis-regulation of the MAPKs signals usually leads to diseases such as cancer and diabetes; therefore, studying the mechanisms of specificity-determination may lead to better understanding of these signaling-related diseases.

Key words

ERK JNK p38 Signaling cascades Phosphorylation 

References

  1. 1.
    Campbell, J. S., Seger, R., Graves, J. D., Graves, L. M., Jensen, A. M., and Krebs, E. G. (1995) The MAP kinase cascade. Recent Prog Horm Res 50, 131–59.PubMedGoogle Scholar
  2. 2.
    Dhanasekaran, D. N., and Johnson, G. L. (2007) MAPKs: function, regulation, role in cancer and therapeutic targeting. Oncogene 26, 3097–9.PubMedCrossRefGoogle Scholar
  3. 3.
    Avruch, J. (2007) MAP kinase pathways: the first twenty years. Biochim Biophys Acta 1773, 1150–60.PubMedCrossRefGoogle Scholar
  4. 4.
    Raman, M., Chen, W., and Cobb, M. H. (2007) Differential regulation and properties of MAPKs. Oncogene 26, 3100–12.PubMedCrossRefGoogle Scholar
  5. 5.
    Shaul, Y. D., and Seger, R. (2007) The MEK/ERK cascade: from signaling specificity to diverse functions. Biochim Biophys Acta 1773, 1213–26.PubMedCrossRefGoogle Scholar
  6. 6.
    Pimienta, G., and Pascual, J. (2007) Canonical and alternative MAPK signaling. Cell Cycle 6, 2628–32.PubMedCrossRefGoogle Scholar
  7. 7.
    Krishna, M., and Narang, H. (2008) The complexity of mitogen-activated protein kinases (MAPKs) made simple. Cell Mol Life Sci 65, 3525–44.PubMedCrossRefGoogle Scholar
  8. 8.
    Tidyman, W. E., and Rauen, K. A. (2009) The RASopathies: developmental syndromes of Ras/MAPK pathway dysregulation. Curr Opin Genet Dev 19, 230–6.PubMedCrossRefGoogle Scholar
  9. 9.
    Boulton, T. G., Nye, S. H., Robbins, D. J., Ip, N. Y., Radziejewska, E., Morgenbesser, S. D., et al. (1991) ERK’s: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell 65, 663–75.PubMedCrossRefGoogle Scholar
  10. 10.
    Derijard, B., Hibi, M., Wu, I. H., Barrett, T., Su, B., Deng, T., et al. (1994) JNK1: a protein kinase stimulated by UV light and Ha-Ras that binds and phosphorylates the c-Jun activation domain. Cell 76, 1025–7.PubMedCrossRefGoogle Scholar
  11. 11.
    Kyriakis, J. M., Banerjee, P., Nikolakaki, E., Dai, T., Rubie, E. A., Ahmad, M. F., et al. (1994) The stress-activated protein kinase subfamily of c-Jun kinases. Nature 369, 156–60.PubMedCrossRefGoogle Scholar
  12. 12.
    Freshney, N. W., Rawlinson, L., Guesdon, F., Jones, E., Cowley, S., Hsuan, J., and Saklatvala, J. (1994) Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. Cell 78, 1039–49.PubMedCrossRefGoogle Scholar
  13. 13.
    Han, J., Lee, J. D., Bibbs, L., and Ulevitch, R. J. (1994) A MAP kinase targeted by endotoxin and hyperosmolarity in mammalian cells. Science 265, 808–11.PubMedCrossRefGoogle Scholar
  14. 14.
    Rouse, J., Cohen, P., Trigon, S., Morange, M., Alonso-Llamazares, A., Zamanillo, D., et al. (1994) A novel kinase cascade triggered by stress and heat shock that stimulates MAPKAP kinase-2 and phosphorylation of the small heat shock proteins. Cell 78, 1027–37.PubMedCrossRefGoogle Scholar
  15. 15.
    Zhou, G., Bao, Z. Q., and Dixon, J. E. (1995) Components of a new human protein kinase signal transduction pathway. J Biol Chem 270, 12665–9.PubMedGoogle Scholar
  16. 16.
    Lee, J. D., Ulevitch, R. J., and Han, J. (1995) Primary structure of BMK1: a new mammalian map kinase. Biochem Biophys Res Commun 213, 715–24.PubMedCrossRefGoogle Scholar
  17. 17.
    Coulombe, P., and Meloche, S. (2007) Atypical mitogen-activated protein kinases: structure, regulation and functions. Biochim Biophys Acta 1773, 1376–87.PubMedCrossRefGoogle Scholar
  18. 18.
    Bacus, S. S., Gudkov, A. V., Lowe, M., Lyass, L., Yung, Y., Komarov, A. P., et al. (2001) Taxol-induced apoptosis depends on MAP kinase pathways (ERK and p38) and is independent of p53. Oncogene 20, 147–55.PubMedCrossRefGoogle Scholar
  19. 19.
    Schwabe, R. F., Bradham, C. A., Uehara, T., Hatano, E., Bennett, B. L., Schoonhoven, R., and Brenner, D. A. (2003) c-Jun-N-terminal kinase drives cyclin D1 expression and proliferation during liver regeneration. Hepatology 37, 824–32.PubMedCrossRefGoogle Scholar
  20. 20.
    Dhillon, A. S., Hagan, S., Rath, O., and Kolch, W. (2007) MAP kinase signalling pathways in cancer. Oncogene 26, 3279–90.PubMedCrossRefGoogle Scholar
  21. 21.
    Zick, Y. (2005) Ser/Thr phosphorylation of IRS proteins: a molecular basis for insulin resistance. Sci STKE 2005, pe4.PubMedCrossRefGoogle Scholar
  22. 22.
    Jeffrey, K. L., Camps, M., Rommel, C., and Mackay, C. R. (2007) Targeting dual-specificity phosphatases: manipulating MAP kinase signalling and immune responses. Nat Rev Drug Discov 6, 391–403.PubMedCrossRefGoogle Scholar
  23. 23.
    Torii, S., Nakayama, K., Yamamoto, T., and Nishida, E. (2004) Regulatory mechanisms and function of ERK MAP kinases. J Biochem (Tokyo) 136, 557–61.CrossRefGoogle Scholar
  24. 24.
    McCubrey, J. A., Milella, M., Tafuri, A., Martelli, A. M., Lunghi, P., Bonati, A., et al. (2008) Targeting the Raf/MEK/ERK pathway with small-molecule inhibitors. Curr Opin Investig Drugs 9, 614–30.PubMedGoogle Scholar
  25. 25.
    Aoki, Y., Niihori, T., Narumi, Y., Kure, S., and Matsubara, Y. (2008) The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum Mutat 29, 992–1006.PubMedCrossRefGoogle Scholar
  26. 26.
    Mebratu, Y., and Tesfaigzi, Y. (2009) How ERK1/2 activation controls cell proliferation and cell death is subcellular localization the answer? Cell Cycle 8, 1168–75.PubMedCrossRefGoogle Scholar
  27. 27.
    Marmor, M. D., Skaria, K. B., and Yarden, Y. (2004) Signal transduction and oncogenesis by ErbB/HER receptors. Int J Radiat Oncol Biol Phys 58, 903–13.PubMedCrossRefGoogle Scholar
  28. 28.
    Naor, Z., Benard, O., and Seger, R. (2000) Activation of MAPK cascades by G-protein-coupled receptors: the case of gonadotropin-releasing hormone receptor. Trends Endocrinol Metab 11, 91–9.PubMedCrossRefGoogle Scholar
  29. 29.
    Rane, S. G. (1999) Ion channels as physiological effectors for growth factor receptor and Ras/ERK signaling pathways. Adv Second Messenger Phosphoprotein Res 33, 107–27.PubMedCrossRefGoogle Scholar
  30. 30.
    Kyriakis, J. M., App, H., Zhang, F. X., Banerjee, P., Brautigan, D. L., Rapp, U. R., and Avruch, J. (1992) Raf-1 activates MAP kinase-kinase. Nature 358, 417–21.PubMedCrossRefGoogle Scholar
  31. 31.
    Barkoff, A., Ballantyne, S., and Wickens, M. (1998) Meiotic maturation in Xenopus requires polyadenylation of multiple mRNAs. EMBO J 17, 3168–75.PubMedCrossRefGoogle Scholar
  32. 32.
    Wellbrock, C., Karasarides, M., and Marais, R. (2004) The RAF proteins take centre stage. Nat Rev Mol Cell Biol 5, 875–85.PubMedCrossRefGoogle Scholar
  33. 33.
    Kolch, W., Heidecker, G., Kochs, G., Hummel, R., Vahidi, H., Mischak, H., et al. (1993) Protein kinase C alpha activates RAF-1 by direct phosphorylation. Nature 364, 249–52.PubMedCrossRefGoogle Scholar
  34. 34.
    Chadee, D. N., and Kyriakis, J. M. (2004) MLK3 is required for mitogen activation of B-Raf, ERK and cell proliferation. Nat Cell Biol 6, 770–6. Epub 2004 Jul 18.PubMedCrossRefGoogle Scholar
  35. 35.
    Ahn, N. G., Seger, R., Bratlien, R. L., Diltz, C. D., Tonks, N. K., and Krebs, E. G. (1991) Multiple components in an epidermal growth factor-stimulated protein kinase cascade. In vitro activation of myelin basic protein/microtubule-associated protein-2 kinase. J Biol Chem 266, 4220–7.PubMedGoogle Scholar
  36. 36.
    Gomez, N., and Cohen, P. (1991) Dissection of the protein kinase cascade by which nerve growth factor activates MAP kinases. Nature 353, 170–3.PubMedCrossRefGoogle Scholar
  37. 37.
    Crews, C. M., Alessandrini, A., and Erikson, R. L. (1992) The primary structure of MEK, a protein kinase that phosphorylates the ERK gene product. Science 258, 478–80.PubMedCrossRefGoogle Scholar
  38. 38.
    Seger, R., Seger, D., Lozeman, F. J., Ahn, N. G., Graves, L. M., Campbell, J. S., et al. (1992) Human T-cell Map kinase kinases are related to yeast signal transduction kinases. J Biol Chem 267, 25628–31.PubMedGoogle Scholar
  39. 39.
    Zheng, C. F., and Guan, K. L. (1993) Properties of MEKs, the kinases that phosphorylate and activate the extracellular signal-regulated kinases. J Biol Chem 268, 23933–9.PubMedGoogle Scholar
  40. 40.
    Alessi, D. R., Saito, Y., Campbell, D. G., Cohen, P., Sithanandam, G., Rapp, U., et al. (1994) Identification of the sites in MAP kinase kinase-1 phosphorylated by p74raf-1. EMBO J 13, 1610–9.PubMedGoogle Scholar
  41. 41.
    Seger, R., Seger, D., Reszka, A. A., Munar, E. S., Eldar-Finkelman, H., Dobrowolska, G., et al. (1994) Over-expression of Mitogen-Activated Protein Kinase Kinase (MAPKK) and its mutants in NIH-3T3 cells: evidence that MAPKK’s involvement in cellular proliferation is regulated by phosphorylation of serine residues in its kinase subdomains VII and VIII. J Biol Chem 269, 25699–709.PubMedGoogle Scholar
  42. 42.
    Seger, R., Ahn, N. G., Posada, J., Munar, E. S., Jensen, A. M., Cooper, J. A., et al. (1992) Purification and characterization of MAP kinase activator(s) from epidermal growth factor stimulated A431 cells. J Biol Chem 267, 14373–81.PubMedGoogle Scholar
  43. 43.
    Shaul, Y. D., Gibor, G., Plotnikov, A., and Seger, R. (2009) Specific phosphorylation and activation of ERK1c by MEK1b: a unique route in the ERK cascade. Genes Dev 23, 1779–90.PubMedCrossRefGoogle Scholar
  44. 44.
    Ray, L. B., and Sturgill, T. W. (1987) Characterization of insulin-stimulated microtubule-associated protein kinase. Rapid isolation and stabilization of a novel serine/threonine kinase from 3T3-L1 cells. Proc Natl Acad Sci U S A 84, 1502–6.PubMedCrossRefGoogle Scholar
  45. 45.
    Yung, Y., Yao, Z., Hanoch, T., and Seger, R. (2000) ERK1b, a 46-kDa ERK isoform that is differentially regulated by MEK. J Biol Chem 275, 15799–808.PubMedCrossRefGoogle Scholar
  46. 46.
    Aebersold, D. M., Shaul, Y. D., Yung, Y., Yarom, N., Yao, Z., Hanoch, T., and Seger, R. (2004) Extracellular signal-regulated kinase 1c (ERK1c), a novel 42-kilodalton ERK, demonstrates unique modes of regulation, localization, and function. Mol Cell Biol 24, 10000–15.PubMedCrossRefGoogle Scholar
  47. 47.
    Gonzalez, F. A., Raden, D. L., Rigby, M. R., and Davis, R. J. (1992) Heterogeneous expression of four MAP kinase isoforms in human tissues. FEBS Lett 304, 170–8.PubMedCrossRefGoogle Scholar
  48. 48.
    Yoon, S., and Seger, R. (2006) The extracellular signal-regulated kinase: multiple substrates regulate diverse cellular functions. Growth Factors 24, 21–44.PubMedCrossRefGoogle Scholar
  49. 49.
    Roux, P. P., and Blenis, J. (2004) ERK and p38 MAPK-Activated Protein Kinases: a Family of Protein Kinases with Diverse Biological Functions. Microbiol Mol Biol Rev 68, 320–44.PubMedCrossRefGoogle Scholar
  50. 50.
    Sturgill, T. W., Ray, L. B., Erikson, E., and Maller, J.L. (1988) Insulin-stimulated MAP-2 kinase phosphorylates and activates ribosomal protein S6 kinase II. Nature 334, 715–8.PubMedCrossRefGoogle Scholar
  51. 51.
    Deak, M., Clifton, A. D., Lucocq, L. M., and Alessi, D. R. (1998) Mitogen- and stress-activated protein kinase-1 (MSK1) is directly activated by MAPK and SAPK2/p38, and may mediate activation of CREB. EMBO J 17, 4426–41.PubMedCrossRefGoogle Scholar
  52. 52.
    Fukunaga, R., and Hunter, T. (1997) MNK1, a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase substrates. EMBO J 16, 1921–33.PubMedCrossRefGoogle Scholar
  53. 53.
    Waskiewicz, A. J., Flynn, A., Proud, C. G., and Cooper, J. A. (1997) Mitogen-activated protein kinases activate the serine/threonine kinases Mnk1 and Mnk2. EMBO J 16, 1909–20.PubMedCrossRefGoogle Scholar
  54. 54.
    Eldar-Finkelman, H., Seger, R., Vanden­heede, J. R., and Krebs, E. G. (1995) Inactivation of glycogen synthase kinase-3 by epidermal growth factor is mediated by mitogen-activated protein kinase/p90 ribosomal protein S6 kinase signaling pathway in NIH/3T3 cells. J Biol Chem 270, 987–90.PubMedCrossRefGoogle Scholar
  55. 55.
    Sapkota, G. P., Kieloch, A., Lizcano, J. M., Lain, S., Arthur, J. S., Williams, M. R., et al. (2001) Phosphorylation of the protein kinase mutated in Peutz-Jeghers Cancer syndrome, LKB1/STK11, at Ser431 by p90RSK and cAMP-dependent protein kinase, but not its farnesylation at Cys433, is essential for LKB1 to suppress cell growth. J Biol Chem 276, 19469–82.PubMedCrossRefGoogle Scholar
  56. 56.
    Cuenda, A., and Rousseau, S. (2007) p38 MAP-kinases pathway regulation, function and role in human diseases. Biochim Biophys Acta 1773, 1358–75.PubMedCrossRefGoogle Scholar
  57. 57.
    Han, J., and Sun, P. (2007) The pathways to tumor suppression via route p38. Trends Biochem Sci 32, 364–71.PubMedCrossRefGoogle Scholar
  58. 58.
    Loesch, M., and Chen, G. (2008) The p38 MAPK stress pathway as a tumor suppressor or more? Front Biosci 13, 3581–93.PubMedCrossRefGoogle Scholar
  59. 59.
    Thornton, T. M., and Rincon, M. (2009) Non-classical p38 map kinase functions: cell cycle checkpoints and survival. Int J Biol Sci 5, 44–51.PubMedCrossRefGoogle Scholar
  60. 60.
    Cohen, P. (2009) Targeting protein kinases for the development of anti-inflammatory drugs. Curr Opin Cell Biol 21, 317–24.PubMedCrossRefGoogle Scholar
  61. 61.
    Cohen, D. M. (2005) SRC family kinases in cell volume regulation. Am J Physiol Cell Physiol 288, C483–93.PubMedCrossRefGoogle Scholar
  62. 62.
    Hall, A. (2005) Rho GTPases and the control of cell behaviour. Biochem Soc Trans 33, 891–5.PubMedCrossRefGoogle Scholar
  63. 63.
    Dan, I., Watanabe, N. M., and Kusumi, A. (2001) The Ste20 group kinases as regulators of MAP kinase cascades. Trends Cell Biol 11, 220–30.PubMedCrossRefGoogle Scholar
  64. 64.
    Uhlik, M. T., Abell, A. N., Cuevas, B. D., Nakamura, K., and Johnson, G. L. (2004) Wiring diagrams of MAPK regulation by MEKK1, 2, and 3. Biochem Cell Biol 82, 658–63.PubMedCrossRefGoogle Scholar
  65. 65.
    Derijard, B., Raingeaud, J., Barrett, T., Wu, I. H., Han, J., Ulevitch, R. J., and Davis, R. J. (1995) Independent human MAP-kinase signal transduction pathways defined by MEK and MKK isoforms [published erratum appears in Science 1995 Jul 7;269(5220):17]. Science 267, 682–5.PubMedCrossRefGoogle Scholar
  66. 66.
    Han, J., Lee, J. D., Jiang, Y., Li, Z., Feng, L., and Ulevitch, R. J. (1996) Characterization of the structure and function of a novel MAP kinase kinase (MKK6). J Biol Chem 271, 2886–91.PubMedCrossRefGoogle Scholar
  67. 67.
    Cuenda, A., Alonso, G., Morrice, N., Jones, M., Meier, R., Cohen, P., and Nebreda, A. R. (1996) Purification and cDNA cloning of SAPKK3, the major activator of RK/p38 in stress- and cytokine-stimulated monocytes and epithelial cells. EMBO J 15, 4156–64.PubMedGoogle Scholar
  68. 68.
    Dashti, S. R., Efimova, T., and Eckert, R. L. (2001) MEK7-dependent activation of p38 MAP kinase in keratinocytes. J Biol Chem 276, 8059–63.PubMedCrossRefGoogle Scholar
  69. 69.
    Lee, J. C., Laydon, J. T., McDonnell, P. C., Gallagher, T. F., Kumar, S., Green, D., et al. (1994) A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372, 739–46.PubMedCrossRefGoogle Scholar
  70. 70.
    Jiang, Y., Chen, C., Li, Z., Guo, W., Gegner, J. A., Lin, S., and Han, J. (1996) Characterization of the structure and function of a new mitogen-activated protein kinase (p38beta). J Biol Chem 271, 17920–6.PubMedCrossRefGoogle Scholar
  71. 71.
    Li, Z., Jiang, Y., Ulevitch, R. J., and Han, J. (1996) The primary structure of p38 gamma: a new member of p38 group of MAP kinases. Biochem Biophys Res Commun 228, 334–40.PubMedCrossRefGoogle Scholar
  72. 72.
    Mertens, S., Craxton, M., and Goedert, M. (1996) SAP kinase-3, a new member of the family of mammalian stress-activated protein kinases. FEBS Lett 383, 273–6.PubMedCrossRefGoogle Scholar
  73. 73.
    Goedert, M., Cuenda, A., Craxton, M., Jakes, R., and Cohen, P. (1997) Activation of the novel stress-activated protein kinase SAPK4 by cytokines and cellular stresses is mediated by SKK3 (MKK6); comparison of its substrate specificity with that of other SAP kinases. EMBO J 16, 3563–71.PubMedCrossRefGoogle Scholar
  74. 74.
    Stokoe, D., Campbell, D. G., Nakielny, S., Hidaka, H., Leevers, S. J., Marshall, C., and Cohen, P. (1992) MAPKAP kinase-2; a novel protein kinase activated by mitogen-activated protein kinase. EMBO J 11, 3985–94.PubMedGoogle Scholar
  75. 75.
    McLaughlin, M. M., Kumar, S., McDonnell, P. C., Van Horn, S., Lee, J. C., Livi, G. P., and Young, P. R. (1996) Identification of mitogen-activated protein (MAP) kinase-activated protein kinase-3, a novel substrate of CSBP p38 MAP kinase. J Biol Chem 271, 8488–92.PubMedCrossRefGoogle Scholar
  76. 76.
    New, L., Jiang, Y., Zhao, M., Liu, K., Zhu, W., Flood, L. J., et al. (1998) PRAK, a novel protein kinase regulated by the p38 MAP kinase. EMBO J 17, 3372–84.PubMedCrossRefGoogle Scholar
  77. 77.
    Ni, H., Wang, X. S., Diener, K., and Yao, Z. (1998) MAPKAPK5, a novel mitogen-activated protein kinase (MAPK)-activated protein kinase, is a substrate of the extra-cellular-regulated kinase (ERK) and p38 kinase. Biochem Biophys Res Commun 243, 492–6.PubMedCrossRefGoogle Scholar
  78. 78.
    Kramer, R. M., Roberts, E. F., Um, S. L., Borsch-Haubold, A. G., Watson, S. P., Fisher, M. J., and Jakubowski, J. A. (1996) p38 mitogen-activated protein kinase phosphorylates cytosolic phospholipase A2 (cPLA2) in thrombin-stimulated platelets. Evidence that proline-directed phosphorylation is not required for mobilization of arachidonic acid by cPLA2. J Biol Chem 271, 27723–9.PubMedCrossRefGoogle Scholar
  79. 79.
    Ben-Levy, R., Hooper, S., Wilson, R., Paterson, H. F., and Marshall, C. J. (1998) Nuclear export of the stress-activated protein kinase p38 mediated by its substrate MAPKAP kinase-2. Curr Biol 8, 1049–57.PubMedCrossRefGoogle Scholar
  80. 80.
    Johnson, G. L., and Nakamura, K. (2007) The c-jun kinase/stress-activated pathway: regulation, function and role in human disease. Biochim Biophys Acta 1773, 1341–8.PubMedCrossRefGoogle Scholar
  81. 81.
    Wang, X., Destrument, A., and Tournier, C. (2007) Physiological roles of MKK4 and MKK7: insights from animal models. Biochim Biophys Acta 1773, 1349–57.PubMedCrossRefGoogle Scholar
  82. 82.
    Weston, C. R., and Davis, R. J. (2007) The JNK signal transduction pathway. Curr Opin Cell Biol 19, 142–9.PubMedCrossRefGoogle Scholar
  83. 83.
    Bogoyevitch, M. A., and Arthur, P. G. (2008) Inhibitors of c-Jun N-terminal kinases: JuNK no more? Biochim Biophys Acta 1784, 76–93.PubMedCrossRefGoogle Scholar
  84. 84.
    Dhanasekaran, D.N., and Reddy, E.P. (2008) JNK signaling in apoptosis. Oncogene 27, 6245–51.PubMedCrossRefGoogle Scholar
  85. 85.
    Baker, S.J., and Reddy, E.P. (1998) Modulation of life and death by the TNF receptor superfamily. Oncogene 17, 3261–70.PubMedCrossRefGoogle Scholar
  86. 86.
    Coso, O.A., Chiariello, M., Yu, J.C., Teramoto, H., Crespo, P., Xu, N., et al. (1995) The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell 81, 1137–46.PubMedCrossRefGoogle Scholar
  87. 87.
    Strange, K., Denton, J., and Nehrke, K. (2006) Ste20-type kinases: evolutionarily conserved regulators of ion transport and cell volume. Physiology (Bethesda) 21, 61–8.CrossRefGoogle Scholar
  88. 88.
    Craig, E. A., Stevens, M. V., Vaillancourt, R. R., and Camenisch, T. D. (2008) MAP3Ks as central regulators of cell fate during development. Dev Dyn 237, 3102–14.PubMedCrossRefGoogle Scholar
  89. 89.
    Sanchez, I., Hughes, R. T., Mayer, B. J., Yee, K., Woodgett, J. R., Avruch, J., et al. (1994) Role of SAPK/ERK kinase-1 in the stress-activated pathway regulating transcription factor c-Jun. Nature 372, 794–8.PubMedGoogle Scholar
  90. 90.
    Yan, M., Dai, T., Deak, J. C., Kyriakis, J. M., Zon, L. I., Woodgett, J. R., and Templeton, D. J. (1994) Activation of stress-activated protein kinase by MEKK1 phosphorylation of its activator SEK1. Nature 372, 798–800.PubMedGoogle Scholar
  91. 91.
    Tournier, C., Whitmarsh, A. J., Cavanagh, J., Barrett, T., and Davis, R. J. (1997) Mitogen-activated protein kinase kinase 7 is an activator of the c-Jun NH2-terminal kinase. Proc Natl Acad Sci U S A 94, 7337–42.PubMedCrossRefGoogle Scholar
  92. 92.
    Holland, P. M., Suzanne, M., Campbell, J. S., Noselli, S., and Cooper, J. A. (1997) MKK7 is a stress-activated mitogen-activated protein kinase kinase functionally related to hemipterous. J Biol Chem 272, 24994–8.PubMedCrossRefGoogle Scholar
  93. 93.
    Toyoshima, F., Moriguchi, T., and Nishida, E. (1997) Fas induces cytoplasmic apoptotic responses and activation of the MKK7-JNK/SAPK and MKK6-p38 pathways independent of CPP32-like proteases. J Cell Biol 139, 1005–15.PubMedCrossRefGoogle Scholar
  94. 94.
    Tournier, C., Whitmarsh, A. J., Cavanagh, J., Barrett, T., and Davis, R. J. (1999) The MKK7 gene encodes a group of c-Jun NH2-terminal kinase kinases. Mol Cell Biol 19, 1569–81.PubMedGoogle Scholar
  95. 95.
    Gupta, S., Barrett, T., Whitmarsh, A. J., Cavanagh, J., Sluss, H. K., Derijard, B., and Davis, R. J. (1996) Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J 15, 2760–70.PubMedGoogle Scholar
  96. 96.
    Dreskin, S. C., Thomas, G. W., Dale, S. N., and Heasley, L. E. (2001) Isoforms of Jun kinase are differentially expressed and activated in human monocyte/macrophage (THP-1) cells. J Immunol 166, 5646–53.PubMedGoogle Scholar
  97. 97.
    Zakowski, V., Keramas, G., Kilian, K., Rapp, U. R., and Ludwig, S. (2004) Mitogen-activated 3p kinase is active in the nucleus. Exp Cell Res 299, 101–9.PubMedCrossRefGoogle Scholar
  98. 98.
    Zhang, Y., Zhong, S., Dong, Z., Chen, N., Bode, A. M., and Ma, W. (2001) UVA induces Ser381 phosphorylation of p90RSK/MAPKAP-K1 via ERK and JNK pathways. J Biol Chem 276, 14572–80.PubMedCrossRefGoogle Scholar
  99. 99.
    Deng, X., Xiao, L., Lang, W., Gao, F., Ruvolo, P., and May, W. S., Jr. (2001) Novel role for JNK as a stress-activated Bcl2 kinase. J Biol Chem 276, 25.Google Scholar
  100. 100.
    Gdalyahu, A., Ghosh, I., Levy, T., Sapir, T., Sapoznik, S., Fishler, Y., et al. (2004) DCX, a new mediator of the JNK pathway. EMBO J 23, 823–32.PubMedCrossRefGoogle Scholar
  101. 101.
    Davis, R. J. (2000) Signal transduction by the JNK group of MAP kinases. Cell 103, 239–52.PubMedCrossRefGoogle Scholar
  102. 102.
    Hayashi, M., and Lee, J. D. (2004) Role of the BMK1/ERK5 signaling pathway: lessons from knockout mice. J Mol Med 82, 800–8.PubMedCrossRefGoogle Scholar
  103. 103.
    Cavanaugh, J. E. (2004) Role of extracellular signal regulated kinase 5 in neuronal survival. Eur J Biochem 271, 2056–9.PubMedCrossRefGoogle Scholar
  104. 104.
    Wang, X., and Tournier, C. (2006) Regulation of cellular functions by the ERK5 signalling pathway. Cell Signal 18, 753–60.PubMedCrossRefGoogle Scholar
  105. 105.
    Nishimoto, S., and Nishida, E. (2006) MAPK signalling: ERK5 versus ERK1/2. EMBO Rep 7, 782–6.PubMedCrossRefGoogle Scholar
  106. 106.
    Sumimoto, H., Kamakura, S., and Ito, T. (2007) Structure and function of the PB1 domain, a protein interaction module conserved in animals, fungi, amoebas, and plants. Sci STKE 2007, re6.PubMedCrossRefGoogle Scholar
  107. 107.
    Kato, Y., Tapping, R. I., Huang, S., Watson, M. H., Ulevitch, R. J., and Lee, J. D. (1998) Bmk1/Erk5 is required for cell proliferation induced by epidermal growth factor. Nature 395, 713–6.PubMedCrossRefGoogle Scholar
  108. 108.
    Kato, Y., Chao, T. H., Hayashi, M., Tapping, R. I., and Lee, J. D. (2000) Role of BMK1 in regulation of growth factor-induced cellular responses. Immunol Res 21, 233–7.PubMedCrossRefGoogle Scholar
  109. 109.
    Abe, J., Takahashi, M., Ishida, M., Lee, J. D., and Berk, B. C. (1997) c-Src is required for oxidative stress-mediated activation of big mitogen-activated protein kinase 1. J Biol Chem 272, 20389–94.PubMedCrossRefGoogle Scholar
  110. 110.
    Sun, W., Wei, X., Kesavan, K., Garrington, T. P., Fan, R., Mei, J., et al. (2003) MEK kinase 2 and the adaptor protein Lad regulate extracellular signal-regulated kinase 5 activation by epidermal growth factor via Src. Mol Cell Biol 23, 2298–308.PubMedCrossRefGoogle Scholar
  111. 111.
    Xu, B. E., Stippec, S., Lenertz, L., Lee, B. H., Zhang, W., Lee, Y. K., and Cobb, M. H. (2004) WNK1 activates ERK5 by an MEKK2/3-dependent mechanism. J Biol Chem 279, 7826–31.PubMedCrossRefGoogle Scholar
  112. 112.
    Chao, T. H., Hayashi, M., Tapping, R. I., Kato, Y., and Lee, J. D. (1999) MEKK3 directly regulates MEK5 activity as part of the big mitogen-activated protein kinase 1 (BMK1) signaling pathway. J Biol Chem 274, 36035–8.PubMedCrossRefGoogle Scholar
  113. 113.
    Garrington, T. P., Ishizuka, T., Papst, P. J., Chayama, K., Webb, S., Yujiri, T., et al. (2000) MEKK2 gene disruption causes loss of cytokine production in response to IgE and c-Kit ligand stimulation of ES cell-derived mast cells. EMBO J 19, 5387–95.PubMedCrossRefGoogle Scholar
  114. 114.
    Chiariello, M., Marinissen, M. J., and Gutkind, J. S. (2000) Multiple mitogen-activated protein kinase signaling pathways connect the cot oncoprotein to the c-jun promoter and to cellular transformation. Mol Cell Biol 20, 1747–58.PubMedCrossRefGoogle Scholar
  115. 115.
    Gotoh, I., Adachi, M., and Nishida, E. (2001) Identification and characterization of a novel MAP kinase kinase kinase, MLTK. J Biol Chem 276, 4276–86. Epub 2000 Oct 19.PubMedCrossRefGoogle Scholar
  116. 116.
    English, J. M., Vanderbilt, C. A., Xu, S., Marcus, S., and Cobb, M. H. (1995) Isolation of MEK5 and differential expression of alternatively spliced forms. J Biol Chem 270, 28897–902.PubMedCrossRefGoogle Scholar
  117. 117.
    Yan, C., Luo, H., Lee, J. D., Abe, J., and Berk, B. C. (2001) Molecular cloning of mouse ERK5/BMK1 splice variants and characterization of ERK5 functional domains. J Biol Chem 276, 10870–8.PubMedCrossRefGoogle Scholar
  118. 118.
    Kondoh, K., Terasawa, K., Morimoto, H., and Nishida, E. (2006) Regulation of nuclear translocation of extracellular signal-regulated kinase 5 by active nuclear import and export mechanisms. Mol Cell Biol 26, 1679–90.PubMedCrossRefGoogle Scholar
  119. 119.
    Raviv, Z., Kalie, E., and Seger, R. (2004) MEK5 and ERK5 are localized in the nuclei of resting as well as stimulated cells, while MEKK2 translocates from the cytosol to the nucleus upon stimulation. J Cell Sci 117, 1773–84.PubMedCrossRefGoogle Scholar
  120. 120.
    Hayashi, M., Tapping, R. I., Chao, T. H., Lo, J. F., King, C. C., Yang, Y., and Lee, J. D. (2001) BMK1 mediates growth factor-induced cell proliferation through direct cellular activation of serum and glucocorticoid-inducible kinase. J Biol Chem 276, 8631–34.PubMedCrossRefGoogle Scholar
  121. 121.
    English, J. M., Pearson, G., Baer, R., and Cobb, M. H. (1998) Identification of substrates and regulators of the mitogen-activated protein kinase ERK5 using chimeric protein kinases. J Biol Chem 273, 3854–60.PubMedCrossRefGoogle Scholar
  122. 122.
    Yang, C. C., Ornatsky, O. I., McDermott, J. C., Cruz, T. F., and Prody, C. A. (1998) Interaction of myocyte enhancer factor 2 (MEF2) with a mitogen-activated protein kinase, ERK5/BMK1. Nucleic Acids Res 26, 4771–7.PubMedCrossRefGoogle Scholar
  123. 123.
    Kato, Y., Kravchenko, V. V., Tapping, R. I., Han, J., Ulevitch, R. J., and Lee, J. D. (1997) BMK1/ERK5 regulates serum-induced early gene expression through transcription factor MEF2C. EMBO J 16, 7054–66.PubMedCrossRefGoogle Scholar
  124. 124.
    Kamakura, S., Moriguchi, T., and Nishida, E. (1999) Activation of the protein kinase ERK5/BMK1 by receptor tyrosine kinases. Identification and characterization of a signaling pathway to the nucleus. J Biol Chem 274, 26563–71.PubMedCrossRefGoogle Scholar
  125. 125.
    Suzaki, Y., Yoshizumi, M., Kagami, S., Koyama, A. H., Taketani, Y., Houchi, H., et al. (2002) Hydrogen peroxide stimulates c-Src-mediated big mitogen-activated protein kinase 1 (BMK1) and the MEF2C signaling pathway in PC12 cells: potential role in cell survival following oxidative insults. J Biol Chem 277, 9614–21.PubMedCrossRefGoogle Scholar
  126. 126.
    Kasler, H. G., Victoria, J., Duramad, O., and Winoto, A. (2000) ERK5 is a novel type of mitogen-activated protein kinase containing a transcriptional activation domain. Mol Cell Biol 20, 8382–9.PubMedCrossRefGoogle Scholar
  127. 127.
    Abe, M. K., Kuo, W. L., Hershenson, M. B., and Rosner, M. R. (1999) Extracellular signal-regulated kinase 7 (ERK7), a novel ERK with a C-terminal domain that regulates its activity, its cellular localization, and cell growth. Mol Cell Biol 19, 1301–12.PubMedGoogle Scholar
  128. 128.
    Abe, M. K., Saelzler, M. P., Espinosa, R., 3rd, Kahle, K. T., Hershenson, M. B., Le Beau, M. M., and Rosner, M. R. (2002) ERK8, a new member of the mitogen-activated protein kinase family. J Biol Chem 277, 16733–43.PubMedCrossRefGoogle Scholar
  129. 129.
    Klevernic, I. V., Stafford, M. J., Morrice, N., Peggie, M., Morton, S., and Cohen, P. (2006) Characterization of the reversible phosphorylation and activation of ERK8. Biochem J 394, 365–73.PubMedCrossRefGoogle Scholar
  130. 130.
    Abe, M. K., Kahle, K. T., Saelzler, M. P., Orth, K., Dixon, J. E., and Rosner, M. R. (2001) ERK7 is an autoactivated member of the MAP kinase family. J Biol Chem 276, 21272–9.PubMedCrossRefGoogle Scholar
  131. 131.
    Kuo, W. L., Duke, C. J., Abe, M. K., Kaplan, E. L., Gomes, S., and Rosner, M. R. (2004) ERK7 expression and kinase activity is regulated by the ubiquitin-proteosome pathway. J Biol Chem 279, 23073–81.PubMedCrossRefGoogle Scholar
  132. 132.
    Iavarone, C., Acunzo, M., Carlomagno, F., Catania, A., Melillo, R. M., Carlomagno, S. M., et al. (2006) Activation of the Erk8 mitogen-activated protein (MAP) kinase by RET/PTC3, a constitutively active form of the RET proto-oncogene. J Biol Chem 281, 10567–76.PubMedCrossRefGoogle Scholar
  133. 133.
    Klevernic, I. V., Martin, N. M., and Cohen, P. (2009) Regulation of the activity and expression of ERK8 by DNA damage. FEBS Lett 583, 680–4.PubMedCrossRefGoogle Scholar
  134. 134.
    Alvarez, E., Northwood, I. C., Gonzalez, F. A., Latour, D. A., Seth, A., Abate, C., et al. (1991) Pro-Leu-Ser/Thr-Pro is a consensus primary sequence for substrate protein phosphorylation. Characterization of the phosphorylation of c-myc and c-jun proteins by an epidermal growth factor receptor threonine 669 protein kinase. J Biol Chem 266, 15277–85.PubMedGoogle Scholar
  135. 135.
    Henrich, L. M., Smith, J. A., Kitt, D., Errington, T. M., Nguyen, B., Traish, A. M., and Lannigan, D. A. (2003) Extracellular signal-regulated kinase 7, a regulator of hormone-dependent estrogen receptor destruction. Mol Cell Biol 23, 5979–88.PubMedCrossRefGoogle Scholar
  136. 136.
    Saelzler, M. P., Spackman, C. C., Liu, Y., Martinez, L. C., Harris, J. P., and Abe, M. K. (2006) ERK8 down-regulates transactivation of the glucocorticoid receptor through Hic-5. J Biol Chem 281, 16821–32.PubMedCrossRefGoogle Scholar
  137. 137.
    Cheng, M., Zhen, E., Robinson, M. J., Ebert, D., Goldsmith, E., and Cobb, M. H. (1996) Characterization of a protein kinase that phosphorylates serine 189 of the mitogen-activated protein kinase homolog ERK3. J Biol Chem 271, 12057–62.PubMedCrossRefGoogle Scholar
  138. 138.
    Zimmermann, J., Lamerant, N., Grossenbacher, R., and Furst, P. (2001) Proteasome- and p38-dependent regulation of ERK3 expression. J Biol Chem 276, 10759–66.PubMedCrossRefGoogle Scholar
  139. 139.
    Seternes, O. M., Mikalsen, T., Johansen, B., Michaelsen, E., Armstrong, C. G., Morrice, N. A., et al. (2004) Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway. EMBO J 23, 4780–91.PubMedCrossRefGoogle Scholar
  140. 140.
    Schumacher, S., Laass, K., Kant, S., Shi, Y., Visel, A., Gruber, A. D., et al. (2004) Scaffolding by ERK3 regulates MK5 in development. EMBO J 23, 4770–9.PubMedCrossRefGoogle Scholar
  141. 141.
    Perander, M., Keyse, S. M., and Seternes, O. M. (2008) Does MK5 reconcile classical and atypical MAP kinases? Front Biosci 13, 4617–24.PubMedCrossRefGoogle Scholar
  142. 142.
    Zhu, A. X., Zhao, Y., Moller, D. E., and Flier, J. S. (1994) Cloning and characterization of p97MAPK, a novel human homolog of rat ERK-3. Mol Cell Biol 14, 8202–11.PubMedGoogle Scholar
  143. 143.
    Boulton, T. G., and Cobb, M. H. (1991) Identification of multiple extracellular signal-regulated kinases (ERKs) with antipeptide antibodies. Cell Regul 2, 357–71.PubMedGoogle Scholar
  144. 144.
    Miyata, Y., and Nishida, E. (1999) Distantly related cousins of MAP kinase: biochemical properties and possible physiological functions. Biochem Biophys Res Commun 266, 291–5.PubMedCrossRefGoogle Scholar
  145. 145.
    O’Neill, E., and Kolch, W. (2004) Conferring specificity on the ubiquitous Raf/MEK signalling pathway. Br J Cancer 90, 283–8.PubMedCrossRefGoogle Scholar
  146. 146.
    Bardwell, L. (2006) Mechanisms of MAPK signalling specificity. Biochem Soc Trans 34, 837–41.PubMedCrossRefGoogle Scholar
  147. 147.
    Murphy, L. O., and Blenis, J. (2006) MAPK signal specificity: the right place at the right time. Trends Biochem Sci 31, 268–75.PubMedCrossRefGoogle Scholar
  148. 148.
    Zehorai, E., Yao, Z., Plotnikov, A., and Seger, R. (2010) The subcellular localization of MEK and ERK-A novel nuclear translocation signal (NTS) paves a way to the nucleus. Mol Cell Endocrinol 314, 213–20.Google Scholar
  149. 149.
    Songyang, Z., Lu, K. P., Kwon, Y. T., Tsai, L. H., Filhol, O., Cochet, C., et al. (1996) A structural basis for substrate specificities of protein Ser/Thr kinases: primary sequence preference of casein kinases I and II, NIMA, phosphorylase kinase, calmodulin-dependent kinase II, CDK5, and Erk1. Mol Cell Biol 16, 6486–93.PubMedGoogle Scholar
  150. 150.
    Tanoue, T., Adachi, M., Moriguchi, T., and Nishida, E. (2000) A conserved docking motif in MAP kinases common to substrates, activators and regulators. Nat Cell Biol 2, 110–6.PubMedCrossRefGoogle Scholar
  151. 151.
    Marshall, C. J. (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179–85.PubMedCrossRefGoogle Scholar
  152. 152.
    Yao, Z., and Seger, R. (2004) The molecular mechanism of MAPK/ERK inactivation. Curr Genomics 5, 385–93.CrossRefGoogle Scholar
  153. 153.
    Peraldi, P., Scimeca, J., Filloux, C., and Van Obberghen, E. (1993) Regulation of extracellular signal regulated protein kinase-1 (ERK1; pp44/mitogen-activated protein kinase) by epidermal growth factor and nerve growth factor in PC12 cells: implication of ERK1 inhibitory activities. Endocrinology 132, 2578–85.PubMedCrossRefGoogle Scholar
  154. 154.
    Owens, D. M., and Keyse, S. M. (2007) Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene 26, 3203–13.PubMedCrossRefGoogle Scholar
  155. 155.
    Turner, C. E. (2000) Paxillin interactions. J Cell Sci 113 Pt 23, 4139–40.PubMedGoogle Scholar
  156. 156.
    Kolch, W. (2005) Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol 6, 827–37.PubMedCrossRefGoogle Scholar
  157. 157.
    Pullikuth, A. K., and Catling, A. D. (2007) Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: a perspective. Cell Signal 19, 1621–32.PubMedCrossRefGoogle Scholar
  158. 158.
    Whitmarsh, A. J. (2006) The JIP family of MAPK scaffold proteins. Biochem Soc Trans 34, 828–32.PubMedCrossRefGoogle Scholar
  159. 159.
    Morrison, D. K., and Davis, R. J. (2003) Regulation of MAP kinase signaling modules by scaffold proteins in mammals. Annu Rev Cell Dev Biol 19, 91–118.PubMedCrossRefGoogle Scholar
  160. 160.
    Casar, B., Pinto, A., and Crespo, P. (2009) ERK dimers and scaffold proteins: unexpected partners for a forgotten (cytoplasmic) task. Cell Cycle 8, 1007–13.PubMedCrossRefGoogle Scholar
  161. 161.
    Takaesu, G., Kang, J. S., Bae, G. U., Yi, M. J., Lee, C. M., Reddy, E. P., and Krauss, R. S. (2006) Activation of p38alpha/beta MAPK in myogenesis via binding of the scaffold protein JLP to the cell surface protein Cdo. J Cell Biol 175, 383–8.PubMedCrossRefGoogle Scholar
  162. 162.
    Casar, B., Pinto, A., and Crespo, P. (2008) Essential role of ERK dimers in the activation of cytoplasmic but not nuclear substrates by ERK-scaffold complexes. Mol Cell 31, 708–21.PubMedCrossRefGoogle Scholar
  163. 163.
    Raman, M., and Cobb, M. H. (2003) MAP kinase modules: many roads home. Curr Biol 13, R886–8.PubMedCrossRefGoogle Scholar
  164. 164.
    Junttila, M. R., Li, S. P., and Westermarck, J. (2008) Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival. FASEB J 22, 954–65.PubMedCrossRefGoogle Scholar
  165. 165.
    Frost, J. A., Steen, H., Shapiro, P., Lewis, T., Ahn, N., Shaw, P. E., and Cobb, M. H. (1997) Cross-cascade activation of ERKs and ternary complex factors by Rho family proteins. EMBO J 16, 6426–38.PubMedCrossRefGoogle Scholar
  166. 166.
    Rommel, C., Clarke, B. A., Zimmermann, S., Nunez, L., Rossman, R., Reid, K., et al. (1999) Differentiation stage-specific inhibition of the Raf-MEK-ERK pathway by Akt. Science 286, 1738–41.PubMedCrossRefGoogle Scholar
  167. 167.
    Zimmermann, S., and Moelling, K. (1999) Phosphorylation and regulation of Raf by Akt (protein kinase B). Science 286, 1741–4.PubMedCrossRefGoogle Scholar
  168. 168.
    Crispin, J. C., and Tsokos, G. C. (2009) Transcriptional regulation of IL-2 in health and autoimmunity. Autoimmun Rev 8, 190–5.PubMedCrossRefGoogle Scholar
  169. 169.
    Kondoh, K., Torii, S., and Nishida, E. (2005) Control of MAP kinase signaling to the nucleus. Chromosoma 114, 86–91.PubMedCrossRefGoogle Scholar
  170. 170.
    Chuderland, D., Konson, A., and Seger, R. (2008) Identification and characterization of a general nuclear translocation signal in signaling proteins. Mol Cell 31, 850–61.PubMedCrossRefGoogle Scholar
  171. 171.
    Inder, K., Harding, A., Plowman, S. J., Philips, M. R., Parton, R. G., and Hancock, J. F. (2008) Activation of the MAPK module from different spatial locations generates distinct system outputs. Mol Biol Cell 19, 4776–84.PubMedCrossRefGoogle Scholar
  172. 172.
    Casar, B., Arozarena, I., Sanz-Moreno, V., Pinto, A., Agudo-Ibanez, L., Marais, R., et al. (2009) Ras subcellular localization defines extracellular signal-regulated kinase 1 and 2 substrate specificity through distinct utilization of scaffold proteins. Mol Cell Biol 29, 1338–53.PubMedCrossRefGoogle Scholar
  173. 173.
    Lefloch, R., Pouyssegur, J., and Lenormand, P. (2009) Total ERK1/2 activity regulates cell proliferation. Cell Cycle 8, 705–11.PubMedCrossRefGoogle Scholar
  174. 174.
    Handley, M. E., Rasaiyaah, J., Chain, B. M., and Katz, D. R. (2007) Mixed lineage kinases (MLKs): a role in dendritic cells, inflammation and immunity? Int J Exp Pathol 88, 111–26.PubMedCrossRefGoogle Scholar
  175. 175.
    Lee, C. M., Onesime, D., Reddy, C. D., Dhanasekaran, N., and Reddy, E. P. (2002) JLP: a scaffolding protein that tethers JNK/p38MAPK signaling modules and transcription factors. Proc Natl Acad Sci U S A 99, 14189–94.PubMedCrossRefGoogle Scholar
  176. 176.
    Song, J. J., and Lee, Y. J. (2007) Differential activation of the JNK signal pathway by UV irradiation and glucose deprivation. Cell Signal 19, 563–72.PubMedCrossRefGoogle Scholar
  177. 177.
    Buchsbaum, R. J., Connolly, B. A., and Feig, L. A. (2002) Interaction of Rac exchange factors Tiam1 and Ras-GRF1 with a scaffold for the p38 mitogen-activated protein kinase cascade. Mol Cell Biol 22, 4073–85.PubMedCrossRefGoogle Scholar
  178. 178.
    Seger, R., and Krebs, E. G. (1995) The MAPK signaling cascade. FASEB J 9, 726–35.PubMedGoogle Scholar
  179. 179.
    Rubinfeld, H., and Seger, R. (2005) The ERK cascade: a prototype of MAPK signaling. Mol Biotechnol 31, 151–74.PubMedCrossRefGoogle Scholar
  180. 180.
    Dhillon, A. S., von Kriegsheim, A., Grindlay, J., and Kolch, W. (2007) Phosphatase and feedback regulation of Raf-1 signaling. Cell Cycle 6, 3–7.PubMedCrossRefGoogle Scholar
  181. 181.
    Borysova, M. K., Cui, Y., Snyder, M., and Guadagno, T. M. (2008) Knockdown of B-Raf impairs spindle formation and the mitotic checkpoint in human somatic cells. Cell Cycle 7, 2894–901.PubMedCrossRefGoogle Scholar
  182. 182.
    Rossomando, A. J., Dent, P., Sturgill, T. W., and Marshak, D. R. (1994) Mitogen-activated protein kinase kinase 1 (MKK1) is negatively regulated by threonine phosphorylation. Mol Cell Biol 14, 1594–602.PubMedGoogle Scholar
  183. 183.
    Beeser, A., Jaffer, Z. M., Hofmann, C., and Chernoff, J. (2005) Role of group A p21-activated kinases in activation of extracellular-regulated kinase by growth factors. J Biol Chem 280, 36609–15.PubMedCrossRefGoogle Scholar
  184. 184.
    Catalanotti, F., Reyes, G., Jesenberger, V., Galabova-Kovacs, G., de Matos Simoes, R., Carugo, O., and Baccarini, M. (2009) A Mek1-Mek2 heterodimer determines the strength and duration of the Erk signal. Nat Struct Mol Biol 16, 294–303.PubMedCrossRefGoogle Scholar
  185. 185.
    Shaul, Y. D., and Seger, R. (2005) Methods in MAPK signaling. Curr Protoc Cell Biol 14.3, Suppl 28, 1–33.Google Scholar
  186. 186.
    Pages, G., Guerin, S., Grall, D., Bonino, F., Smith, A., Anjuere, F., et al. (1999) Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice. Science 286, 1374–7.PubMedCrossRefGoogle Scholar
  187. 187.
    Saba-El-Leil, M. K., Vella, F. D., Vernay, B., Voisin, L., Chen, L., Labrecque, N., et al. (2003) An essential function of the mitogen-activated protein kinase Erk2 in mouse trophoblast development. EMBO Rep 4, 964–8.PubMedCrossRefGoogle Scholar
  188. 188.
    Hatano, N., Mori, Y., Oh-hora, M., Kosugi, A., Fujikawa, T., Nakai, N., et al. (2003) Essential role for ERK2 mitogen-activated protein kinase in placental development. Genes Cells 8, 847–56.PubMedCrossRefGoogle Scholar
  189. 189.
    Yao, Y., Li, W., Wu, J., Germann, U. A., Su, M. S., Kuida, K., and Boucher, D. M. (2003) Extracellular signal-regulated kinase 2 is necessary for mesoderm differentiation. Proc Natl Acad Sci U S A 100, 12759–64.PubMedCrossRefGoogle Scholar
  190. 190.
    Liu, X., Yan, S., Zhou, T., Terada, Y., and Erikson, R. L. (2004) The MAP kinase pathway is required for entry into mitosis and cell survival. Oncogene 23, 763–76.PubMedCrossRefGoogle Scholar
  191. 191.
    Vantaggiato, C., Formentini, I., Bondanza, A., Bonini, C., Naldini, L., and Brambilla, R. (2006) ERK1 and ERK2 mitogen-activated protein kinases affect Ras-dependent cell signaling differentially. J Biol 5, 14.PubMedCrossRefGoogle Scholar
  192. 192.
    Lefloch, R., Pouyssegur, J., and Lenormand, P. (2008) Single and combined silencing of ERK1 and ERK2 reveals their positive contribution to growth signaling depending on their expression levels. Mol Cell Biol 28, 511–27.PubMedCrossRefGoogle Scholar
  193. 193.
    Shaul, Y. D., and Seger, R. (2006) ERK1c regulates Golgi fragmentation during mitosis. J Cell Biol 172, 885–97.PubMedCrossRefGoogle Scholar
  194. 194.
    Zervos, A. S., Faccio, L., Gatto, J. P., Kyriakis, J. M., and Brent, R. (1995) Mxi2, a mitogen-activated protein kinase that recognizes and phosphorylates Max protein. Proc Natl Acad Sci U S A 92, 10531–4.PubMedCrossRefGoogle Scholar
  195. 195.
    Cameron, S. J., Abe, J., Malik, S., Che, W., and Yang, J. (2004) Differential role of MEK5alpha and MEK5beta in BMK1/ERK5 activation. J Biol Chem 279, 1506–12.PubMedCrossRefGoogle Scholar
  196. 196.
    Pombo, C. M., Kehrl, J. H., Sanchez, I., Katz, P., Avruch, J., Zon, L. I., et al. (1995) Activation of the SAPK pathway by the human STE20 homologue germinal centre kinase. Nature 377, 750–4.PubMedCrossRefGoogle Scholar
  197. 197.
    Shi, C. S., and Kehrl, J. H. (1997) Activation of stress-activated protein kinase/c-Jun N-terminal kinase, but not NF-kappaB, by the tumor necrosis factor (TNF) receptor 1 through a TNF receptor-associated factor 2- and germinal center kinase related-dependent pathway. J Biol Chem 272, 32102–7.PubMedCrossRefGoogle Scholar
  198. 198.
    Diener, K., Wang, X. S., Chen, C., Meyer, C. F., Keesler, G., Zukowski, M., et al. (1997) Activation of the c-Jun N-terminal kinase pathway by a novel protein kinase related to human germinal center kinase. Proc Natl Acad Sci U S A 94, 9687–92.PubMedCrossRefGoogle Scholar
  199. 199.
    Kiefer, F., Tibbles, L. A., Anafi, M., Janssen, A., Zanke, B. W., Lassam, N., et al. (1996) HPK1, a hematopoietic protein kinase activating the SAPK/JNK pathway. EMBO J 15, 7013–25.PubMedGoogle Scholar
  200. 200.
    Dan, I., Watanabe, N. M., Kobayashi, T., Yamashita-Suzuki, K., Fukagaya, Y., Kajikawa, E., et al. (2000) Molecular cloning of MINK, a novel member of mammalian GCK family kinases, which is up-regulated during postnatal mouse cerebral development. FEBS Lett 469, 19–23.PubMedCrossRefGoogle Scholar
  201. 201.
    Graves, J. D., Gotoh, Y., Draves, K. E., Ambrose, D., Han, D. K., Wright, M., et al. (1998) Caspase-mediated activation and induction of apoptosis by the mammalian Ste20-like kinase Mst1. EMBO J 17, 2224–34.PubMedCrossRefGoogle Scholar
  202. 202.
    Lin, J. L., Chen, H. C., Fang, H. I., Robinson, D., Kung, H. J., and Shih, H. M. (2001) MST4, a new Ste20-related kinase that mediates cell growth and transformation via modulating ERK pathway. Oncogene 20, 6559–69.PubMedCrossRefGoogle Scholar
  203. 203.
    Nakano, K., Yamauchi, J., Nakagawa, K., Itoh, H., and Kitamura, N. (2000) NESK, a member of the germinal center kinase family that activates the c-Jun N-terminal kinase pathway and is expressed during the late stages of embryogenesis. J Biol Chem 275, 20533–9.PubMedCrossRefGoogle Scholar
  204. 204.
    Su, Y. C., Han, J., Xu, S., Cobb, M., and Skolnik, E. Y. (1997) NIK is a new Ste20-related kinase that binds NCK and MEKK1 and activates the SAPK/JNK cascade via a conserved regulatory domain. EMBO J 16, 1279–90.PubMedCrossRefGoogle Scholar
  205. 205.
    Chen, W., Yazicioglu, M., and Cobb, M. H. (2004) Characterization of OSR1, a member of the mammalian Ste20p/GCK subfamily. J Biol Chem 279, 11129–36.PubMedCrossRefGoogle Scholar
  206. 206.
    Zhang, S., Han, J., Sells, M. A., Chernoff, J., Knaus, U. G., Ulevitch, R. J., and Bokoch, G. M. (1995) Rho family GTPases regulate p38 mitogen-activated protein kinase through the downstream mediator Pak1. J Biol Chem 270, 23934–6.PubMedCrossRefGoogle Scholar
  207. 207.
    Dan, C., Nath, N., Liberto, M., and Minden, A. (2002) PAK5, a new brain-specific kinase, promotes neurite outgrowth in N1E-115 cells. Mol Cell Biol 22, 567–77.PubMedCrossRefGoogle Scholar
  208. 208.
    Liu, Z. G., Hsu, H., Goeddel, D. V., and Karin, M. (1996) Dissection of TNF receptor 1 effector functions: JNK activation is not linked to apoptosis while NF-kappaB activation prevents cell death. Cell 87, 565–76.PubMedCrossRefGoogle Scholar
  209. 209.
    Johnston, A. M., Naselli, G., Gonez, L. J., Martin, R. M., Harrison, L. C., and DeAizpurua, H. J. (2000) SPAK, a STE20/SPS1-related kinase that activates the p38 pathway. Oncogene 19, 4290–7.PubMedCrossRefGoogle Scholar
  210. 210.
    Sabourin, L. A., and Rudnicki, M. A. (1999) Induction of apoptosis by SLK, a Ste20-related kinase. Oncogene 18, 7566–75.PubMedCrossRefGoogle Scholar
  211. 211.
    Fu, C. A., Shen, M., Huang, B. C., Lasaga, J., Payan, D. G., and Luo, Y. (1999) TNIK, a novel member of the germinal center kinase family that activates the c-Jun N-terminal kinase pathway and regulates the cytoskeleton. J Biol Chem 274, 30729–37.PubMedCrossRefGoogle Scholar
  212. 212.
    Ichijo, H., Nishida, E., Irie, K., ten Dijke, P., Saitoh, M., Moriguchi, T., et al. (1997) Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science 275, 90–4.PubMedCrossRefGoogle Scholar
  213. 213.
    Wang, X. S., Diener, K., Tan, T. H., and Yao, Z. (1998) MAPKKK6, a novel mitogen-activated protein kinase kinase kinase, that associates with MAPKKK5. Biochem Biophys Res Commun 253, 33–7.PubMedCrossRefGoogle Scholar
  214. 214.
    Fan, G., Merritt, S. E., Kortenjann, M., Shaw, P. E., and Holzman, L. B. (1996) Dual leucine zipper-bearing kinase (DLK) activates p46SAPK and p38mapk but not ERK2. J Biol Chem 271, 24788–93.PubMedCrossRefGoogle Scholar
  215. 215.
    Sakuma, H., Ikeda, A., Oka, S., Kozutsumi, Y., Zanetta, J. P., and Kawasaki, T. (1997) Molecular cloning and functional expression of a cDNA encoding a new member of mixed lineage protein kinase from human brain. J Biol Chem 272, 28622–9.PubMedCrossRefGoogle Scholar
  216. 216.
    Deacon, K., and Blank, J. L. (1997) Characterization of the mitogen-activated protein kinase kinase 4 (MKK4)/c-Jun NH2-terminal kinase 1 and MKK3/p38 pathways regulated by MEK kinases 2 and 3. MEK kinase 3 activates MKK3 but does not cause activation of p38 kinase in vivo. J Biol Chem 272, 14489–96.PubMedCrossRefGoogle Scholar
  217. 217.
    Blank, J. L., Gerwins, P., Elliott, E. M., Sather, S., and Johnson, G. L. (1996) Molecular cloning of mitogen-activated protein/ERK kinase kinases (MEKK) 2 and 3. Regulation of sequential phosphorylation pathways involving mitogen-activated protein kinase and c-Jun kinase. J Biol Chem 271, 5361–8.PubMedCrossRefGoogle Scholar
  218. 218.
    Gerwins, P., Blank, J. L., and Johnson, G. L. (1997) Cloning of a novel mitogen-activated protein kinase kinase kinase, MEKK4, that selectively regulates the c-Jun amino terminal kinase pathway. J Biol Chem 272, 8288–95.PubMedCrossRefGoogle Scholar
  219. 219.
    Xu, Z., Maroney, A. C., Dobrzanski, P., Kukekov, N. V., and Greene, L. A. (2001) The MLK family mediates c-Jun N-terminal kinase activation in neuronal apoptosis. Mol Cell Biol 21, 4713–24.PubMedCrossRefGoogle Scholar
  220. 220.
    Hirai, S., Katoh, M., Terada, M., Kyriakis, J. M., Zon, L. I., Rana, A., et al. (1997) MST/MLK2, a member of the mixed lineage kinase family, directly phosphorylates and activates SEK1, an activator of c-Jun N-terminal kinase/stress-activated protein kinase. J Biol Chem 272, 15167–73.PubMedCrossRefGoogle Scholar
  221. 221.
    Rana, A., Gallo, K., Godowski, P., Hirai, S., Ohno, S., Zon, L., et al. (1996) The mixed lineage kinase SPRK phosphorylates and activates the stress-activated protein kinase activator, SEK-1. J Biol Chem 271, 19025–8.PubMedCrossRefGoogle Scholar
  222. 222.
    Gallo, K. A., and Johnson, G. L. (2002) Mixed-lineage kinase control of JNK and p38 MAPK pathways. Nat Rev Mol Cell Biol 3, 663–72.PubMedCrossRefGoogle Scholar
  223. 223.
    Posada, J., Yew, N., Ahn, N. G., Vande-Woude, G. F., and Cooper, J. A. (1993) Mos stimulates MAP kinase in Xenopus oocytes and activates a MAP kinase kinase in vitro. Mol Cell Biol 13, 2546–52.PubMedGoogle Scholar
  224. 224.
    Hagemann, C., and Rapp, U. R. (1999) Isotype-specific functions of Raf kinases. Exp Cell Res 253, 34–46.PubMedCrossRefGoogle Scholar
  225. 225.
    Peraldi, P., Frodin, M., Barnier, J. V., Calleja, V., Scimeca, J. C., Filloux, C., et al. (1995) Regulation of the MAP kinase cascade in PC12 cells: B-Raf activates MEK-1 (MAP kinase or ERK kinase) and is inhibited by cAMP. FEBS Lett 357, 290–6.PubMedCrossRefGoogle Scholar
  226. 226.
    Moriguchi, T., Kuroyanagi, N., Yamaguchi, K., Gotoh, Y., Irie, K., Kano, T., et al. (1996) A novel kinase cascade mediated by mitogen-activated protein kinase kinase 6 and MKK3. J Biol Chem 271, 13675–9.PubMedCrossRefGoogle Scholar
  227. 227.
    Hutchison, M., Berman, K. S., and Cobb, M. H. (1998) Isolation of TAO1, a protein kinase that activates MEKs in stress- activated protein kinase cascades [In Process Citation]. J Biol Chem 273, 28625–32.PubMedCrossRefGoogle Scholar
  228. 228.
    Chen, Z., Hutchison, M., and Cobb, M. H. (1999) Isolation of the protein kinase TAO2 and identification of its mitogen-activated protein kinase/extracellular signal-regulated kinase kinase binding domain. J Biol Chem 274, 28803–7.PubMedCrossRefGoogle Scholar
  229. 229.
    Manning, G., Whyte, D. B., Martinez, R., Hunter, T., and Sudarsanam, S. (2002) The protein kinase complement of the human genome. Science 298, 1912–34.PubMedCrossRefGoogle Scholar
  230. 230.
    Salmeron, A., Ahmad, T. B., Carlile, G. W., Pappin, D., Narsimhan, R. P., and Ley, S. C. (1996) Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAP kinase kinase kinase. EMBO J 15, 817–26.PubMedGoogle Scholar
  231. 231.
    Boulton, T. G., Yancopoulos, G. D., Gregory, J. S., Slaughter, C., Moomaw, C., Hsu, J., and Cobb, M. H. (1990) An insulin-­stimulated protein kinase similar to yeast kinases involved in cell cycle control. Science 249, 64–7.PubMedCrossRefGoogle Scholar
  232. 232.
    Qian, Z., Okuhara, D., Abe, M. K., and Rosner, M. R. (1999) Molecular cloning and characterization of a mitogen-activated protein kinase-associated intracellular chloride channel. J Biol Chem 274, 1621–7.PubMedCrossRefGoogle Scholar
  233. 233.
    Hibi, M., Lin, A., Smeal, T., Minden, A., and Karin, M. (1993) Identification of an oncoprotein- and UV-responsive protein kinase that binds and potentiates the c-Jun activation domain. Genes Dev 7, 2135–48.PubMedCrossRefGoogle Scholar
  234. 234.
    Kallunki, T., Su, B., Tsiegelny, I., Sluss, H. K., Derijard, B., Moore, G., et al. (1994) JNK2 contains a specificity-determining region responsible for efficient c-Jun binding and phosphorylation. Genes Dev 8, 2996–3007.PubMedCrossRefGoogle Scholar
  235. 235.
    Yntema, H. G., van den Helm, B., Kissing, J., van Duijnhoven, G., Poppelaars, F., Chelly, J., et al. (1999) A novel ribosomal S6-kinase (RSK4; RPS6KA6) is commonly deleted in patients with complex X-linked mental retardation. Genomics 62, 332–43.PubMedCrossRefGoogle Scholar
  236. 236.
    Caivano, M., and Cohen, P. (2000) Role of mitogen-activated protein kinase cascades in mediating lipopolysaccharide-stimulated induction of cyclooxygenase-2 and IL-1 beta in RAW264 macrophages. J Immunol 164, 3018–25.PubMedGoogle Scholar
  237. 237.
    Jones, S. W., Erikson, E., Blenis, J., Maller, J. L., and Erikson, R. L. (1988) A Xenopus ribosomal protein S6 kinase has two apparent kinase domains that are each similar to distinct protein kinases. Proc Natl Acad Sci U S A 85, 3377–81.PubMedCrossRefGoogle Scholar
  238. 238.
    Alcorta, D. A., Crews, C. M., Sweet, L. J., Bankston, L., Jones, S. W., and Erikson, R. L. (1989) Sequence and expression of chicken and mouse rsk: homologs of Xenopus laevis ribosomal S6 kinase. Mol Cell Biol 9, 3850–9.PubMedGoogle Scholar
  239. 239.
    Lavoinne, A., Erikson, E., Maller, J. L., Price, D. J., Avruch, J., and Cohen, P. (1991) Purification and characterisation of the insulin-stimulated protein kinase from rabbit skeletal muscle; close similarity to S6 kinase II. Eur J Biochem 199, 723–8.PubMedCrossRefGoogle Scholar
  240. 240.
    Zhao, Y., Bjorbaek, C., Weremowicz, S., Morton, C. C., and Moller, D. E. (1995) RSK3 encodes a novel pp90rsk isoform with a unique N-terminal sequence: growth factor-stimulated kinase function and nuclear translocation. Mol Cell Biol 15, 4353–63.PubMedGoogle Scholar
  241. 241.
    Webster, M. K., Goya, L., Ge, Y., Maiyar, A. C., and Firestone, G. L. (1993) Characterization of sgk, a novel member of the serine/threonine protein kinase gene family which is transcriptionally induced by glucocorticoids and serum. Mol Cell Biol 13, 2031–40.PubMedGoogle Scholar

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© Springer Science+Business Meida, LLC 2010

Authors and Affiliations

  1. 1.Department of Biological RegulationThe Weizmann Institute of ScienceRehovotIsrael

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