Spatio-Temporal Parameters: The Case of the MAP Kinase Pathway

  • Véronique Volmat
  • Jacques Pouysségur
Part of the Endocrine Updates book series (ENDO, volume 17)


Eucaryotic cells have developed signal transduction networks that allow them to convey extracellular signals in the nucleus to induce the proper response at the gene level. A common way for the cell to “reprogram” its genetic information is through specific protein phosphorylation. Mitogen Activated Protein Kinases (MAPKs) play a key role in this action. MAPK pathways are activated in response to a large array of stimuli from growth factors to environmental stress [1–2]. Furthermore, they are evolutionarily conserved from yeast to human [3]. These pathways are organized around a core signaling module composed of three kinases that are sequentially activated (Fig. 1). The first kinase is a serine/threonine kinase called MAP kinase kinase kinase or MKKK. When activated, it phosphorylates a dual specificity kinase (MAP kinase kinase or MKK) on two serine or threonine residues. Phosphorylated MKK activates in turn the serine/threonine kinase MAP kinase or MAPK on the threonine and tyrosine residues of the consensus motif TXY (where T is threonine, X is glutamic acid, glycine or proline, and Y is tyrosine) [4]. Finally, activated MAPK phosphorylates diverse substrates including nuclear transcription factors, membrane proteins and cytoplasmic substrates which are all modified on the threonine or serine of the PX(T/S)P consensus motif (where P is proline, X an indifferent amino acid and S is serine). Considering that MAPK pathways have been duplicated within the same cell to deliver specific biological responses, the cell has evolved various means that prevent inappropriate crosstalk between the different MAPK modules that possess a strong degree of homology. Two mechanisms ensure the specificity of activation: i) insulation of the protein kinases of a same module by scaffold proteins, and ii) presence of specific docking sites on the kinases and their substrates. Furthermore, anchor proteins and specific MAPK phosphatases have been characterized that regulate the spatio-temporal activation of the MAPK pathways. In the first part of this chapter we will rapidly review the currently known mammalian MAPK pathways. In the second part we will discuss the factors controlling the specificity in the MAPK modules and how these mechanisms have evolved from yeast to human. Finally, the key elements controlling the spatio-temporal activity of the growth factor response will be highlighted with a special emphasis at the level of the p42/p44 MAPK pathway.

Figure 1

The MAPK modules in the Budding yeast Saccharomyces cerevisiae.


MAPK Pathway Scaffold Protein Dual Specificity Phosphatase MAPK Phosphatase MAPKAP Kinase 
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.
    Schaeffer H.J., Weber M.J.. 1999 Mitogen-activated protein kinases: specific messages from ubiquitous messengers. Mol Cell Biol 19: 2435–44.PubMedGoogle Scholar
  2. 2.
    Robinson M.J., Cobb M.H.. 1997 Mitogen-activated protein kinase pathways. Curr Opin Cell Biol 9: 180–6.PubMedCrossRefGoogle Scholar
  3. 3.
    Widmann C, Gibson S, Jarpe M.B., Johnson G.L., 1999 Mitogen-activated protein kinase: conservation of a three-kinase module from yeast to human. Physiol Rev 79: 143–180.PubMedGoogle Scholar
  4. 4.
    Dhanasekaran N, Premkumar Reddy E. 1998 Signaling by dual specificity kinases. Oncogene 17: 1447–55.PubMedCrossRefGoogle Scholar
  5. 5.
    Ichijo H. 1999 From receptors to stress-activated MAP kinases. Oncogene 18: 6087–6093.PubMedCrossRefGoogle Scholar
  6. 6.
    Fanger G.R., Gerwins P, Widmann C, Jarpe M.B., Johnson G.L., 1997 MEKKs, GCKs, MLKs, PAKs, TAKs, and tpls: upstream regulators of the c-Jun amino-terminal kinases? Cuff Opin Genet Dev 7: 67–74.CrossRefGoogle Scholar
  7. 7.
    Ip Y.T., Davis RJ. 1998 Signal transduction by the c-Jun N-terminal kinase ( JNK)-from inflammation to development. Cuff Opin Cell Biol 10: 205–219.Google Scholar
  8. 8.
    Tibbles L.A., Woodgett J.R., 1999 The stress-activated protein kinase pathways. Cell Mol Life Sci 55: 1230–1254.PubMedCrossRefGoogle Scholar
  9. 9.
    Whitmarsh A.J., Davis R.J., 1998 Structural organization of MAP-kinase signaling modules by scaffold proteins in yeast and mammals. Trends Biochem Sci 23: 481–485.PubMedCrossRefGoogle Scholar
  10. 10.
    Elion E.A., 1995 SteS: a meeting place for MAP kinases and their associates. Trends Cell Biol 5: 322–327.PubMedCrossRefGoogle Scholar
  11. 11.
    Posas F, Saito H. 1997 Osmotic activation of the HOG MAPK pathway via Ste 1 1 p MAPKKK: scaffold role of Pbs2p MAPKK. Science 276: 1702–1705.PubMedCrossRefGoogle Scholar
  12. 12.
    Garrington T.P. Johnson G.L., 1999 Organization and regulation of mitogen-activated protein kinase signaling pathways. Curr Opin Cell Biol 11: 211–218.Google Scholar
  13. 13.
    Whitmarsh A.J., Cavanagh J, Tournier C, Yasuda J, Davis R.J., 1998 A mammalian scaffold complex that selectively mediates MAP kinase activation. Science 281: 1671–16714.PubMedCrossRefGoogle Scholar
  14. 14.
    Yasuda J, Whitmarsh A.J., Cavanagh J, Sharma M, Davis R.J., 1999 The JIP group of mitogen-activated protein kinase scaffold proteins. Mol Cell Biol 19: 7245–7254.PubMedGoogle Scholar
  15. 15.
    Ito M, Yoshioka K, Akechi M, Yamashita S, Takamatsu N, Sugiyama K, Hibi M, Nakabeppu Y, Shiba T, Yamamoto K.I., 1999 JSAP1, a novel jun N-terminal protein kinase ( JNK)-binding protein that functions as a Scaffold factor in the JNK signaling pathway. Mol Cell Biol 19: 7539–7548.Google Scholar
  16. 16.
    McDonald P.H., Chow C.W., Miller W.E., Laporte S.A, Field M.E., Lin F.T., Davis R.J., Lefkowitz R.J., 2000 beta-arrestin 2: A receptor-regulated MAPK scaffold for the activation of JNK3. Science 290: 1574–1577.Google Scholar
  17. 17.
    Schaeffer H.J., Catling A.D., Eblen S.T., Collier L.S., Krauss A, Weber M.J., 1998 MPI: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. Science 281: 1668–1671.PubMedCrossRefGoogle Scholar
  18. 18.
    Yu W, Fantl W.J., Harrowe G, Williams L.T., 1998 Regulation of the MAP kinase pathway by mammalian Ksr through direct interaction with MEK and ERK. Curr Biol 8: 56–64.PubMedCrossRefGoogle Scholar
  19. 19.
    Stewart S, Sundaram M, Zhang Y, Lee J, Han M, Guan K.L., 1999 Kinase suppressor of Ras forms a multiprotein signaling complex and modulates MEK localization. Mol Cell Biol 19: 5523–5534.PubMedGoogle Scholar
  20. 20.
    Yablonski D, Marbach I, Levitzki A. 1996 Dimerization of SteS, a mitogen-activated protein kinase cascade scaffold protein, is required for signal transduction. Proc Natl Acad Sci U S A 93: 13864–13869.PubMedCrossRefGoogle Scholar
  21. 21.
    Mahanty S.K., Wang Y, Farley F.W., Elion E.A., 1999 Nuclear shuttling of yeast scaffold SteS is required for its recruitment to the plasma membrane and activation of the mating MAPK cascade. Cell 98: 501–512.PubMedCrossRefGoogle Scholar
  22. 22.
    Camps M, Nichols A, Gillieron C, Antonsson B, Muda M, Chabert C, Boschert U, Arkinstall S. 1998 Catalytic activation of the phosphatase MKP-3 by ERK2 mitogenactivated protein kinase. Science 280: 1262–1265.PubMedCrossRefGoogle Scholar
  23. 23.
    Smith J.A., Poteet-Smith C.E., Malarkey K, Sturgill T.W., 1999 Identification of an extracellular signal-regulated kinase (ERK) docking site in ribosomal S6 kinase, a sequence critical for activation by ERK in vivo. J Biol Chem 274: 2893–2898.PubMedCrossRefGoogle Scholar
  24. 24.
    Tanoue T, Adachi M, Moriguchi T, Nishida E. 2000 A conserved docking motif in MAP kinases common to substrates, activators and regulators. Nat Cell Biol 2: 110–116.PubMedCrossRefGoogle Scholar
  25. 25.
    Brunet A, Pouyssegur J. 1996 Identification of MAP kinase domains by redirecting stress signals into growth factor responses. Science 272: 1652–1655.PubMedCrossRefGoogle Scholar
  26. 26.
    Gupta S, Barrett T, Whitmarsh A.J., Cavanagh J, Sluss H.K., Derijard B, Davis R.J., 1996 Selective interaction of JNK protein kinase isoforms with transcription factors. EMBO J 15: 2760–7270.PubMedGoogle Scholar
  27. 27.
    Yang S.H., Whitmarsh A.J., Davis R.J., Sharrocks A.D., 1998 Differential targeting of MAP kinases to the ETS-domain transcription factor Elk-1. EMBO J 17: 1740–1749.PubMedCrossRefGoogle Scholar
  28. 28.
    Sharrocks A.D., Yang S.H., Galanis A. 2000 Docking domains and substrate-specificity determination for MAP kinases. Trends Biochem Sci 25: 448–453.PubMedCrossRefGoogle Scholar
  29. 29.
    Zuniga A, Torres J, Ubeda J, Pulido R. 1999 Interaction of mitogen-activated protein kinases with the kinase interaction motif of the tyrosine phosphatase PTP-SL provides substrate specificity and retains ERK2 in the cytoplasm. J Biol Chem 274: 21900–21907.PubMedCrossRefGoogle Scholar
  30. 30.
    Yang S.H., Yates P.R., Whitmarsh A.J., Davis R.J., Sharrocks A.D., 1998 The Elk-1 ETSdomain transcription factor contains a mitogen-activated protein kinase targeting motif. Mol Cell Biol 18: 710–720.PubMedGoogle Scholar
  31. 31.
    Meloche S, Pages G, Pouyssegur J. 1992 Functional expression and growth factor activation of an epitope-tagged p44 mitogen-activated protein kinase, p44mapk. Mol Biol Cell 3: 63–71.PubMedGoogle Scholar
  32. 32.
    Vouret-Craviari V, Obberghen-Schilling E, Scimeca J.C., Obberghen E, Pouyssegur J. 1993 Differential activation of p44mapk (ERK1) by alpha-thrombin and thrombin-receptor peptide agonist. Biochem J 289: 209–214.PubMedGoogle Scholar
  33. 33.
    Brondello J.M., McKenzie F.R., Sun H, Tonks N.K., Pouyssegur J. 1995 Constitutive MAP kinase phosphatase (MKP-1) expression blocks G1 specific gene transcription and -phase entry in fibroblasts. Oncogene 10: 1895–1904.PubMedGoogle Scholar
  34. 34.
    Pages G, Lenormand P, L’Allemain G, Chambard J.C., Meloche S, Pouyssegur J. 1993 Mitogen-activated protein kinases p42mapk and p44mapk are required for fibroblast proliferation. Proc Natl Acad Sci U S A 90: 8319–8323.PubMedCrossRefGoogle Scholar
  35. 35.
    Traverse S, Seedorf K, Paterson H, Marshall C.J., Cohen P, Ullrich A. 1994 EGF triggers neuronal differentiation of PC12 cells that overexpress the EGF receptor. Curr Biol 4: 694–701.PubMedCrossRefGoogle Scholar
  36. 36.
    Keyse S.M.. 1998 Protein phosphatases and the regulation of MAP kinase activity. Semin Cell Dev Biol 9: 143–152.PubMedCrossRefGoogle Scholar
  37. 37.
    Alessi D.R., Gomez N, Moorhead G, Lewis T, Keyse S.M., Cohen P. 1995 Inactivation of p42 MAP kinase by protein phosphatase 2A and a protein tyrosine phosphatase, but not CL100, in various cell lines. C T Biol 5: 283–295.CrossRefGoogle Scholar
  38. 38.
    Pulido R, Zuniga A, Ullrich A. 1998 PTP-SL and STEP protein tyrosine phosphatases regulate the activation of the extracellular signal-regulated kinases ERK1 and ERK2 by association through a kinase interaction motif. EMBO J 17: 7337–7350.PubMedCrossRefGoogle Scholar
  39. 39.
    Keyse S.M., 2000 Protein phosphatases and the regulation of mitogen-activated protein kinase signalling. Curr Opin Cell Biol 12: 186–92.PubMedCrossRefGoogle Scholar
  40. 40.
    Brondello J.M., Brunet A, Pouyssegur J, McKenzie F.R., 1997 The dual specificity mitogen-activated protein kinase phosphatase-1 and -2 are induced by the p42/p44MAPK cascade. J Biol Chem 272: 1368–1376.PubMedCrossRefGoogle Scholar
  41. 41.
    Camps M, Nichols A, Arkinstall S. 2000 Dual specificity phosphatases: a gene family for control of MAP kinase function. Faseb J 14: 6–16.PubMedGoogle Scholar
  42. 42.
    Lenormand P, Sardet C, Pages G, L’Allemain G, Brunet A, Pouyssegur J. 1993 Growth factors induce nuclear translocation of MAP kinases (p42mapk and p44mapk) but not of their activator MAP kinase kinase (p45mapkk) in fibroblasts. J Cell Biol 122: 1079–1088.PubMedCrossRefGoogle Scholar
  43. 43.
    Adachi M, Fukuda M, Nishida E. 1999 Two co-existing mechanisms for nuclear import of MAP kinase: passive diffusion of a monomer and active transport of a dimer. EMBO J 18: 5347–5358.PubMedCrossRefGoogle Scholar
  44. 44.
    Fukuda M, Gotoh I, Adachi M, Gotoh Y, Nishida E. 1997 A novel regulatory mechanism in the mitogen-activated protein (MAP) kinase cascade. Role of nuclear export signal of MAP kinase kinase. J Biol Chem 272: 32642–32648.Google Scholar
  45. 45.
    Khokhlatchev A.V., Canagarajah B, Wilsbacher J, Robinson M, Atkinson M, Goldsmith E, Cobb M.H., 1998 Phosphorylation of the MAP kinase ERK2 promotes its honl_xdimerization and nuclear translocation. Cell 93: 605–615.PubMedCrossRefGoogle Scholar
  46. 46.
    Brun t A, Roux D, Lenormand P, Dowd S, Keyse S, Pouyssegur J. 1999 Nuclear translocation of p42/p44 mitogen-activated protein kinase is required for growth factor-induced gene expression and cell cycle entry. EMBO J 18: 664–674.CrossRefGoogle Scholar
  47. 47.
    Fukuda M, Gotoh Y, Nishida E. 1997 Interaction of MAP kinase with MAP kinase kinase: its possible role in the control of nucleocytoplasmic transport of MAP kinase. EMBO J 16: 1901–1908.PubMedCrossRefGoogle Scholar
  48. 48.
    Lenormand P, Brondello J.M., Brunet A, Pouyssegur J. 1998 Growth factor-induced p42/p44 MAPK nuclear translocation and retention requires both MAPK activation and neosynthesis of nuclear anchoring proteins. J Cell Biol 142: 625–633.PubMedCrossRefGoogle Scholar
  49. 49.
    Yung Y, Dolginov Y, Yao Z, Rubinfeld H, Michael D, Hanoch T, Roubini E, Lando Z, Zharhary D, Seger R. 1997 Detection of ERK activation by a novel monoclonal antibody. FEBS Lett 408: 292–296.PubMedCrossRefGoogle Scholar
  50. 50.
    Volmat V, Camps M, Arkinstall S, Pouysségur J, Lenormand P. 2001 The nucleus, a site for signal termination by sequestration and inactivation of p42/p44 MAP Kinases. J Cell Sci, in press.Google Scholar
  51. 51.
    Adachi M, Fukuda M, Nishida E. 2000 Nuclear export of MAP kinase (ERK) involves a MAP kinase kinase ( MEK)-dependent active transport mechanism. J Cell Biol 148: 849–850Google Scholar
  52. 52.
    Cavigelli M, Dolfi F, Claret F.X., Karin M. 1995 Induction of c-fos expression through JNK-mediated TCF/Elk-1 phosphorylation. EMBO J 14: 5957–5964.PubMedGoogle Scholar
  53. 53.
    Engel K, Kotlyarov A, Gaestel M. 1998 Leptomycin B-sensitive nuclear export of MAPKAP kinase 2 is regulated by phosphorylation. EMBO J 17: 3363–3371.PubMedCrossRefGoogle Scholar
  54. 54.
    Mattison C.P., Ota I.M.. 2000 Two protein tyrosine phosphatases, Ptp2 and Ptp3, modulate the subcellular localization of the Hog1 MAP kinase in yeast. Genes Dev 14: 1229–1235.PubMedGoogle Scholar
  55. 55.
    Brondello J.M., Pouyssegur J, McKenzie F.R., 1999 Reduced MAP kinase phosphatase-1 degradation after p42/p44MAPK-dependent phosphorylation. Science 286: 2514–2517.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2002

Authors and Affiliations

  • Véronique Volmat
    • 1
  • Jacques Pouysségur
    • 1
  1. 1.Institute of SignalingDevelopmental Biology and Cancer Research CNRS UMR-6543 Centre Antoine LacassagneNice, Cedex 2France

Personalised recommendations