Skip to main content
SpringerLink
Log in

Protein-protein interactions in the regulation of the extracellular signal-regulated kinase

  • Review
  • Published:
Molecular Biotechnology Aims and scope Submit manuscript

Abstract

The extracellular signal-regulated kinase (ERK) cascade is a central intracellular signaling pathway that is activated by a variety of extracellular stimuli, and thereby regulates cellular processes such as proliferation, differentiation, and oncogenic transformation. To execute these functions, the signals of those stimuli are transmitted to the cytosolic and nuclear targets in a rapid and specific manner. In the last few years it has become clear that the specificity and the rapid function of the ERK cascade is largely determined by protein-protein interactions with various signaling components and substrates. This review describes interactions of ERK with its immediate regulators, scaffold proteins, substrates, and localizing proteins, and shows their involvement in the functioning of the ERK cascade. Understanding the full scope of ERK-interactions is important for the development of new drugs for the treatment of cancer and other diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Seger, R., and Krebs, E. G. (1995) The MAPK signaling cascade. Faseb. J 9, 726–735.

    PubMed  CAS  Google Scholar 

  2. Pearson, G., Robinson, F., Beers Gibson, T., et al. (2001) Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr. Rev. 22, 153–183.

    Article  PubMed  CAS  Google Scholar 

  3. Chen, Z., Gibson, T. B., Robinson, F., et al. (2001) MAP kinases. Chem. Rev. 101, 2449–2476.

    Article  PubMed  CAS  Google Scholar 

  4. Rubinfeld, H. and Seger, R. (2004) The ERK cascade as a prototype of MAPK signaling pathways. Methods. Mol. Biol. 250, 1–28.

    PubMed  CAS  Google Scholar 

  5. Boulton, T. G., Yancopoulos, G. D., Gregory, J. S., et al. (1990) An insulin-stimulated protein kinase similar to yeast kinases involved in cell cycle control. Science 249, 64–67.

    Article  PubMed  CAS  Google Scholar 

  6. 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, 2135–2148.

    Article  PubMed  CAS  Google Scholar 

  7. Kyriakis, J. M., Banerjee, P., Nikolakaki, E., et al. (1994) The stress-activated protein kinase subfamily of c-Jun kinases. Nature 369, 156–160.

    Article  PubMed  CAS  Google Scholar 

  8. Freshney, N. W., Rawlinson, L., Guesdon, F., et al. (1994) Interleukin-1 activates a novel protein kinase cascade that results in the phosphorylation of Hsp27. Cell 78, 1039–1049.

    Article  PubMed  CAS  Google Scholar 

  9. 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, 808–811.

    Article  PubMed  CAS  Google Scholar 

  10. Lee, J. C., Laydon, J. T., McDonnell, P. C., et al. (1994) A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature 372, 739–746.

    Article  PubMed  CAS  Google Scholar 

  11. Zhou, G., Bao, Z. Q., and Dixon, J. E. (1995) Components of a new human protein kinase signal transduction pathway. J. Biol. Chem. 270, 12665–12669.

    PubMed  CAS  Google Scholar 

  12. Kyriakis, J. M., Force, T. L., Rapp, U. R., Bonventre, J. V., and Avruch, J. (1993) Mitogen regulation of c-Raf-1 protein kinase activity toward mitogen-activated protein kinase-kinase. J. Biol. Chem. 268, 16009–16019.

    PubMed  CAS  Google Scholar 

  13. Kyriakis, J. M., App, H., Zhang, X. F., Banerjee, P., Brautigan, D. L., Rapp, U. R., and Avruch, J. (1992) Raf-1 activates MAPKK. Nature 358, 417–421.

    Article  PubMed  CAS  Google Scholar 

  14. Saito, Y., Gomez, N., Campbell, D. G., Ashworth, A., Marshall, C. J., and Cohen, P. (1994) The threonine residues in MAPKK 1 phosphorylated by MAP kinase in vitro are also phosphorylated in nerve growth factor-stimulated rat phaeochromocytoma (PC12) cells. FEBS Lett. 341, 119–124.

    Article  PubMed  CAS  Google Scholar 

  15. Payne, D. M., Rossomando, A. J., Martino, P., et al. (1991) Identification of the regulatory phosphorylation sites in pp42/mitogen-activated protein kinase (MAP kinase). EMBO J. 10, 885–892.

    PubMed  CAS  Google Scholar 

  16. 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, 715–718.

    Article  PubMed  CAS  Google Scholar 

  17. 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, 4426–4441.

    Article  PubMed  CAS  Google Scholar 

  18. 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, 1921–1933.

    Article  PubMed  CAS  Google Scholar 

  19. 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, 1909–1920.

    Article  PubMed  CAS  Google Scholar 

  20. Marais, R., Wynne, J., and Treisman, R. (1993) The SRF accessory protein Elk-1 contains a growth factor-regulated transcriptional activation domain. Cell 73, 381–393.

    Article  PubMed  CAS  Google Scholar 

  21. Chen, R. H., Abate, C., and Blenis, J. (1993) Phosphorylation of the c-Fos transrepression domain by mitogen-activated protein kinase and 90-kDa ribosomal S6 kinase. Proc. Natl. Acad. Sci. USA 90, 10952–10956.

    Article  PubMed  CAS  Google Scholar 

  22. Murphy, L. O., Smith, S., Chen, R. H., Fingar, D. C., and Blenis, J. (2002) Molecular interpretation of ERK signal duration by immediate early gene products. Nat. Cell. Biol. 4, 556–564.

    PubMed  CAS  Google Scholar 

  23. Morton, S., Davis, R. J., McLaren, A., and Cohen, P. (2003) A reinvestigation of the multisite phosphorylation of the transcription factor c-Jun. EMBO J. 22, 3876–3886.

    Article  PubMed  CAS  Google Scholar 

  24. Lin, L. L., Wartmann, M., Lin, A. Y., Knopf, J. L., Seth, A., and Davis, R. J. (1993) cPLA2 is phosphorylated and activated by MAP kinase. Cell 72, 269–278.

    Article  PubMed  CAS  Google Scholar 

  25. Lewis, T. S., Hunt, J. B., Aveline, L. D., et al. (2000) Identification of novel MAP kinase pathway signaling targets by functional proteomics and mass spectrometry. Mol. Cell. 6, 1343–1354.

    Article  PubMed  CAS  Google Scholar 

  26. Northwood, I. C., Gonzalez, F. A., Wartmann, M., Raden, D. L., and Davis, R.J. (1991) Isolation and characterization of two growth factor-stimulated protein kinases that phosphorylate the epidermal growth factor receptor at threonine 669. J. Biol. Chem. 266, 15266–15276.

    PubMed  CAS  Google Scholar 

  27. 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, 15799–15808.

    Article  PubMed  CAS  Google Scholar 

  28. Aebersold, D. M., Shaul, Y., Yung, Y., et al. (2004) ERK1c, a 42-kDa ERK with a unique mode of regulation by phosphorylation, dephosphorylation and ubiquitination. Mol. Cell Biol. 24, 10,000–10,015.

    Article  CAS  Google Scholar 

  29. 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, 170–178.

    Article  PubMed  CAS  Google Scholar 

  30. Boulton, T. G., Nye, S. H., Robbins, D. J., et al. (1991) ERKs: a family of protein-serine/threonine kinases that are activated and tyrosine phosphorylated in response to insulin and NGF. Cell 65, 663–675.

    Article  PubMed  CAS  Google Scholar 

  31. Boulton, T. G., and Cobb, M. H. (1991) Identification of multiple extracellular signal-regulated kinases (ERKs) with antipeptide antibodies. Cell. Regul. 2, 357–371.

    PubMed  CAS  Google Scholar 

  32. Boulton, T. G., Gregory, J. S., and Cobb, M. H. (1991) Purification and properties of extracellular signal-regulated kinase 1, an insulin-stimulated microtubule-associated protein 2 kinase. Biochemistry 30, 278–286.

    Article  PubMed  CAS  Google Scholar 

  33. Yung, Y., Yao, Z., Aebersold, D. M., Hanoch, T., and Seger, R. (2001) Altered regulation of ERK1b by MEK1 and PTP-SL and modified Elk1 phosphorylation by ERK1b are caused by abrogation of the regulatory C-terminal sequence of ERKs. J. Biol. Chem. 276, 35280–35289.

    Article  PubMed  CAS  Google Scholar 

  34. Zhang, F., Strand, A., Robbins, D., Cobb, M. H., and Goldsmith, E. J. (1994) Atomic structure of the MAP kinase ERK2 at 2.3 A resolution. Nature 367, 704–711.

    Article  PubMed  CAS  Google Scholar 

  35. Canagarajah, B. J., Khokhlatchev, A., Cobb, M. H., and Goldsmith, E. J. (1997) Activation mechanism of the MAP kinase ERK2 by dual phosphorylation. Cell 90, 859–869.

    Article  PubMed  CAS  Google Scholar 

  36. Rubinfeld, H., Hanoch, T., and Seger, R. (1999) Identification of a cytoplasmic-retention sequence in ERK2. J. Biol. Chem. 274, 30349–30352.

    Article  PubMed  CAS  Google Scholar 

  37. 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, 110–116.

    Article  PubMed  CAS  Google Scholar 

  38. Bott, C. M., Thorneycroft, S. G., and Marshall, C. J. (1994) The sevenmaker gain-of-function mutation in p42 MAP kinase leads to enhanced signalling and reduced sensitivity to dual specificity phosphatase action. FEBS Lett. 352, 201–205.

    Article  PubMed  CAS  Google Scholar 

  39. Bardwell, A. J., Abdollahi, M., and Bardwell, L. (2003) Docking sites on mitogen-activated protein kinase (MAPK) kinases, MAPK phosphatases and the Elk-1 transcription factor compete for MAPK binding and are crucial for enzymic activity. Biochem J 370, 1077–1085.

    Article  PubMed  CAS  Google Scholar 

  40. Gille, H., Sharrocks, A. D., and Shaw, P. E. (1992) Phosphorylation of transcription factor p62TCF by MAP kinase stimulates ternary complex formation at c-fos promoter. Nature 358, 414–417.

    Article  PubMed  CAS  Google Scholar 

  41. Tanoue, T., Maeda, R., Adachi, M., and Nishida, E. (2001) Identification of a docking groove on ERK and p38 MAP kinases that regulates the specificity of docking interactions. EMBO J. 20, 466–479.

    Article  PubMed  CAS  Google Scholar 

  42. Reszka, A. A., Seger, R., Diltz, C. D., Krebs, E. G., and Fischer, E. H. (1995) Association of mitogen-activated protein kinase with the microtubule cytoskeleton. Proc. Natl. Acad. Sci. USA 92, 8881–8885.

    Article  PubMed  CAS  Google Scholar 

  43. Wilsbacher, J. L., Goldsmith, E. J., and Cobb, M. H. (1999) Phosphorylation of MAP kinases by MAP/ERK involves multiple regions of MAP kinases. J. Biol. Chem. 274, 16988–16994.

    Article  PubMed  CAS  Google Scholar 

  44. Lee, T., Hoofnagle, A. N., Kabuyama, Y., et al. (2004) Docking Motif Interactions in MAP Kinases Revealed by Hydrogen Exchange Mass Spectrometry. Mol. Cell 14, 43–55.

    Article  PubMed  CAS  Google Scholar 

  45. Eblen, S. T., Catling, A. D., Assanah, M. C., and Weber, M. J. (2001) Biochemical and biological functions of the N-terminal, noncatalytic domain of extracellular signal-regulated kinase 2. Mol. Cell. Biol. 21, 249–259.

    Article  PubMed  CAS  Google Scholar 

  46. Robinson, F. L., Whitehurst, A. W., Raman, M., and Cobb, M. H. (2002) Identification of novel point mutations in ERK2 that selectively disrupt binding to MEK1. J. Biol. Chem. 277, 14844–14852.

    Article  PubMed  CAS  Google Scholar 

  47. Fukuda, M., Gotoh, Y., and 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.

    Article  PubMed  CAS  Google Scholar 

  48. Wolf, I., Rubinfeld, H., Yoon, S., Marmor, G., Hanoch, T., and Seger, R. (2001) Involvement of the activation loop of ERK in the detachment from cytosolic anchoring. J. Biol. Chem. 276, 24490–24497.

    Article  PubMed  CAS  Google Scholar 

  49. Adachi, M., Fukuda, M., and Nishida, E. (2000) Nuclear export of MAP kinase (ERK) involves a MAP kinase kinase (MEK)-dependent active transport mechanism. J. Cell. Biol. 148, 849–856.

    Article  PubMed  CAS  Google Scholar 

  50. Bardwell, A. J., Flatauer, L. J., Matsukuma, K., Thorner, J., and Bardwell, L. (2001) A conserved docking site in MEKs mediates high-affinity binding to MAP kinases and cooperates with a scaffold protein to enhance signal transmission. J. Biol. Chem. 276, 10374–10386.

    Article  PubMed  CAS  Google Scholar 

  51. Marshall, C. J. (1995) Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179–185.

    Article  PubMed  CAS  Google Scholar 

  52. Yao, Z., and Seger, a. R. (2004) The molecular Mechanism of MAPK/ERK inactivation. Current genomics, in press.

  53. Camps, M., Nichols, A., Gillieron, C., et al. (1998) Catalytic activation of the phosphatase MKP-3 by ERK2 mitogen-activated protein kinase. Science 280, 1262–1265.

    Article  PubMed  CAS  Google Scholar 

  54. Zhou, B., Wu, L., Shen, K., Zhang, J., Lawrence, D. S., and Zhang, Z. Y. (2001) Multiple regions of MAP kinase phosphatase 3 are involved in its recognition and activation by ERK2. J. Biol. Chem. 276, 6506–6515.

    Article  PubMed  CAS  Google Scholar 

  55. Nichols, A., Camps, M., Gillieron, C., et al. (2000) Substrate recognition domains within extracellular signal-regulated kinase mediate binding and catalytic activation of mitogen-activated protein kinase phosphatase-3. J. Biol. Chem. 275, 24613–24621.

    Article  PubMed  CAS  Google Scholar 

  56. Zhang, J., Zhou, B., Zheng, C. F., and Zhang, Z. Y. (2003) A bipartite mechanism for ER2 recognition by its cognate regulators and substrates. J. Biol. Chem. 278, 29901–29912.

    Article  PubMed  CAS  Google Scholar 

  57. Wente, S. R. (2000) Gatekeepers of the nucleus. Science 288, 1374–1377.

    Article  PubMed  CAS  Google Scholar 

  58. Cobb, M. H., and Goldsmith, E. J. (2000) Dimerization in MAP-kinase signaling. Trends Biochem. Sci. 25, 7–9.

    Article  PubMed  CAS  Google Scholar 

  59. Matsubayashi, Y., Fukuda, M., and Nishida, E. (2001) Evidence for existence of a nuclear pore complex-mediated, cytosol-independent pathway of nuclear translocation of ERK MAP kinase in permeabilized cells. J. Biol. Chem. 276, 41755–41760.

    Article  PubMed  CAS  Google Scholar 

  60. Whitehurst, A. W., Wilsbacher, J. L., You, Y., Luby-Phelps, K., Moore, M. S., and Cobb, M. H. (2002) ERK2 enters the nucleus by a carrier-independent mechanism. Proc. Natl. Acad. Sci. USA 99, 7496–7501.

    Article  PubMed  CAS  Google Scholar 

  61. Levchenko, A., Bruck, J., and Sternberg, P. W. (2000) Scaffold proteins may biphasically affect the levels of mitogen-activated protein kinase signaling and reduce its threshold properties. Proc. Natl. Acad. Sci. USA 97, 5818–5823.

    Article  PubMed  CAS  Google Scholar 

  62. Whitmarsh, A. J., and Davis, R. J. (1998) Structural organization of MAP-kinase signaling modules by scaffold proteins in yeast and mammals. Trends Biochem. Sci. 23, 481–485.

    Article  PubMed  CAS  Google Scholar 

  63. Garrington, T. P., and Johnson, G. L. (1999) Organization and regulation of mitogen-activated protein kinase signaling pathways. Curr. Opin. Cell Biol. 11, 211–218.

    Article  PubMed  CAS  Google Scholar 

  64. Schaeffer, H. J., Catling, A. D., Eblen, S. T., Collier, L. S., Krauss, A., and Weber, M. J. (1998) MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. Science 281, 1668–1671.

    Article  PubMed  CAS  Google Scholar 

  65. Morrison, D. K. (2001) KSR: a MAPK scaffold of the Ras pathway? J. Cell Sci. 114, 1609–1612.

    PubMed  CAS  Google Scholar 

  66. Tohgo, A., Pierce, K. L., Choy, E. W., Lefkowitz, R. J., and Luttrell, L. M. (2002) beta-Arrestin scaffolding of the ERK cascade enhances cytosolic ERK activity but inhibits ERK-mediated transcription following angiotensin AT1a receptor stimulation. J. Biol. Chem. 277, 9429–9436.

    Article  PubMed  CAS  Google Scholar 

  67. Woods, A. J., Roberts, M. S., Choudhary, J., et al. (2002) Paxillin associates with poly(A)-binding protein 1 at the dense endoplasmic reticulum and the leading edge of migrating cells. J. Biol. Chem. 277, 6428–6437.

    Article  PubMed  CAS  Google Scholar 

  68. Choi, K. Y., Satterberg, B., Lyons, D. M., and Elion, E. A. (1994) Ste5 tethers multiple protein kinases in the MAP kinase cascade required for mating in S. cerevisiae. Cell 78, 499–512.

    Article  PubMed  CAS  Google Scholar 

  69. Marcus, S., Polverino, A., Barr, M., and Wigler, M. (1994) Complexes between STE5 and components of the pheromone-responsive mitogen-activated protein kinase module. Proc. Natl. Acad. Sci. USA 91, 7762–7766.

    Article  PubMed  CAS  Google Scholar 

  70. Elion, E. A. (2001) The Ste5p scaffold. J. Cell. Sci. 114, 3967–3978.

    PubMed  CAS  Google Scholar 

  71. Park, S. H., Zarrinpar, A., and Lim, W. A. (2003) Rewiring MAP kinase pathways using alternative scaffold assembly mechanisms. Science 299, 1061–1064.

    Article  PubMed  CAS  Google Scholar 

  72. Kusari, A. B., Molina, D. M., Sabbagh, W., Jr., Lau, C. S., and Bardwell, L. (2004) A conserved protein interaction network involving the yeast MAP kinases Fus3 and Kss1. J. Cell. Biol. 164, 267–277.

    Article  PubMed  CAS  Google Scholar 

  73. Tedford, K., Kim, S., Sa, D., Stevens, K., and Tyers, M. (1997) Regulation of the mating pheromone and invasive growth responses in yeast by two MAP kinase substrates. Curr. Biol. 7, 228–238.

    Article  PubMed  CAS  Google Scholar 

  74. Madhani, H. D., Styles, C. A., and Fink, G. R. (1997) MAP kinases with distinct inhibitory functions impart signaling specificity during yeast differentiation. Cell 91, 673–684.

    Article  PubMed  CAS  Google Scholar 

  75. Bardwell, L., Cook, J.G., Voora, D., Baggott, D. M., Martinez, A. R., and Thorner, J. (1998) Repression of yeast Ste12 transcription factor by direct binding of unphosphorylated Kss1 MAPK and its regulation by the Ste7 MEK. Genes Dev. 12, 2887–2898.

    PubMed  CAS  Google Scholar 

  76. Zeitlinger, J., Simon, I., Harbison, C. T., et al. (2003) Program-specific distribution of a transcription factor dependent on partner transcription factor and MAPK signaling. Cell 113, 395–404.

    Article  PubMed  CAS  Google Scholar 

  77. Posas, F., and Saito, H. (1997) Osmotic activation of the HOG MAPK pathway via Ste 11p MAPKKK: scaffold role of Pbs2p MAPKK. Science 276, 1702–1705.

    Article  PubMed  CAS  Google Scholar 

  78. O’Rourke, S. M., Herskowitz, I., and O’Shea, E. K. (2002) Yeast go the whole HOG for the hyperosmotic response. Trends Genet. 18, 405–412.

    Article  PubMed  CAS  Google Scholar 

  79. Schuller, C., Brewster, J. L., Alexander, M. R., Gustin, M. C., and Ruis, H. (1994) The HOG pathway controls osmotic regulation of transcription via the stress response element (STRE) of the Saccharomyces cerevisiae CTT1 gene. EMBO J. 13, 4382–4389.

    PubMed  CAS  Google Scholar 

  80. Maeda, T., Takekawa, M., and Saito, H. (1995) Activation of yeast PBS2 MAPKK by MAPKKKs or by binding of an SH3-containing osmosensor. Science 269, 554–558.

    Article  PubMed  CAS  Google Scholar 

  81. Tatebayashi, K., Takekawa, M., and Saito, H. (2003) A docking site determining specificity of Pbs2 MAPKK for Ssk2/Ssk22 MAPKKKs in the yeast HOG pathway. EMBO J. 22, 3624–3634.

    Article  PubMed  CAS  Google Scholar 

  82. Wunderlich, W., Fialka, I., Teis, D., et al. (2001) A novel 14-kilodalton protein interacts with the mitogen-activated protein kinase scaffold mp1 on a late endosomal/lysosomal compartment. J. Cell. Biol. 152, 765–776.

    Article  PubMed  CAS  Google Scholar 

  83. Therrien, M., Chang, H. C., Solomon, N. M., Karim, F. D., Wassarman, D. A., and Rubin, G. M. (1995) KSR, a novel protein kinase required for RAS signal transduction. Cell 83, 879–888.

    Article  PubMed  CAS  Google Scholar 

  84. Sundaram, M., and Han, M. (1995) The C. elegans ksr-1 gene encodes a novel Raf-related kinase involved in Ras-mediated signal transduction. Cell 83, 889–901.

    Article  PubMed  CAS  Google Scholar 

  85. Kornfeld, K., Hom, D. B., and Horvitz, H. R. (1995) The ksr-1 gene encodes a novel protein kinase involved in Ras-mediated signaling in C. elegans. Cell 83, 903–913.

    Article  PubMed  CAS  Google Scholar 

  86. Xing, H. R., Campodonico, L., and Kolesnick, R. N. (2004) The kinase activity of kinase suppressor of Ras1 (KSR1) is independent of bound MEK. J. Biol. Chem. 279, 26,210–26,214.

    CAS  Google Scholar 

  87. Stewart, S., Sundaram, M., Zhang, Y., Lee, J., Han, M., and Guan, K. L. (1999) Kinase suppressor of Ras forms a multiprotein signaling complex and modulates MEK localization. Mol. Cell. Biol. 19, 5523–5534.

    PubMed  CAS  Google Scholar 

  88. Yu, W., Fantl, W. J., Harrowe, G., and 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.

    Article  PubMed  CAS  Google Scholar 

  89. Denouel-Galy, A., Douville, E. M., Warne, P. H., et al. (1998) Murine Ksr interacts with MEK and inhibits Ras-induced transformation. Curr. Biol. 8, 46–55.

    Article  PubMed  CAS  Google Scholar 

  90. Muller, J., Ory, S., Copeland, T., Piwnica-Worms, H., and Morrison, D. K. (2001) C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, KSR1. Mol. Cell 8, 983–993.

    Article  PubMed  CAS  Google Scholar 

  91. Fantz, D. A., Jacobs, D., Glossip, D., and Kornfeld, K. (2001) Docking sites on substrate proteins direct extracellular signal-regulated kinase to phosphorylate specific residues. J. Biol. Chem. 276, 27256–27265.

    Article  PubMed  CAS  Google Scholar 

  92. Roy, F., Laberge, G., Douziech, M., Ferland-McCollough, D., and Therrien, M. (2002) KSR is a scaffold required for activation of the ERK/MAPK module. Genes Dev. 16, 427–438.

    Article  PubMed  CAS  Google Scholar 

  93. 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.

    Article  PubMed  CAS  Google Scholar 

  94. Sugimoto, T., Stewart, S., Han, M., and Guan, K. L. (1998) The kinase suppressor of Ras (KSR) modulates growth factor and Ras signaling by uncoupling Elk-1 phosphorylation from MAP kinase activation. EMBO J. 17, 1717–1727.

    Article  PubMed  CAS  Google Scholar 

  95. Ferguson, S. S., Downey, W. E., 3rd, Colapietro, A. M., Barak, L. S., Menard, L., and Caron, M. G. (1996) Role of beta-arrestin in mediating agonist-promoted G protein-coupled receptor internalization. Science 271, 363–366.

    Article  PubMed  CAS  Google Scholar 

  96. Pierce, K. L., Luttrell, L. M., and Lefkowitz, R. J. (2001) New mechanisms in heptahelical receptor signaling to mitogen activated protein kinase cascades. Oncogene 20, 1532–1539.

    Article  PubMed  CAS  Google Scholar 

  97. 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, 91–99.

    Article  PubMed  CAS  Google Scholar 

  98. Daaka, Y., Luttrell, L. M., Ahn, S., et al. (1998) Essential role for G protein-coupled receptor endocytosis in the activation of mitogen-activated protein kinase. J. Biol. Chem. 273, 685–688.

    Article  PubMed  CAS  Google Scholar 

  99. Luttrell, L. M., Roudabush, F. L., Choy, E. W., et al. (2001) Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proc. Natl. Acad. Sci. USA 98, 2449–2454.

    Article  PubMed  CAS  Google Scholar 

  100. Miller, W. E., Maudsley, S., Ahn, S., Khan, K. D., Luttrell, L. M., and Lefkowitz, R. J. (2000) beta-arrestinl interacts with the catalytic domain of the tyrosine kinase c-SRC. Role of beta-arrestin1-dependent targeting of c-SRC in receptor endocytosis. J. Biol. Chem. 275, 11312–11319.

    Article  PubMed  CAS  Google Scholar 

  101. DeFea, K. A., Vaughn, Z. D., O’Bryan, E. M., Nishijima, D., Dery, O., and Bunnett, N. W. (2000) The proliferative and antiapoptotic effects of substance P are facilitated by formation of a beta — arrestin-dependent scaffolding complex. Proc. Natl. Acad. Sci. USA 97, 11086–11091.

    Article  PubMed  CAS  Google Scholar 

  102. Tohgo, A., Choy, E. W., Gesty-Palmer, D., et al. (2003) The stability of the G protein-coupled receptor-beta-arrestin interaction determines the mechanism and functional consequence of ERK activation. J. Biol. Chem. 278, 6258–6267.

    Article  PubMed  CAS  Google Scholar 

  103. Schaller, M. D., Otey, C. A., Hildebrand, J. D., and Parsons, J. T. (1995) Focal adhesion kinase and paxillin bind to peptides mimicking beta integrin cytoplasmic domains. J. Cell. Biol. 130, 1181–1187.

    Article  PubMed  CAS  Google Scholar 

  104. Hagel, M., George, E. L., Kim, A., et al. (2002) The adaptor protein paxillin is essential for normal development in the mouse and is a critical transducer of fibronectin signaling. Mol. Cell. Biol. 22, 901–915.

    Article  PubMed  CAS  Google Scholar 

  105. Ishibe, S., Joly, D., Zhu, X., and Cantley, L. G. (2003) Phosphorylation-dependent paxillin-ERK association mediates hepatocyte growth factor-stimulated epithelial morphogenesis. Mol. Cell. 12, 1275–1285.

    Article  PubMed  CAS  Google Scholar 

  106. Chen, R. H., Sarnecki, C., and Blenis, J. (1992) Nuclear localization and regulation of erk- and rsk-encoded protein kinases. Mol. Cell. Biol. 12, 915–927.

    PubMed  CAS  Google Scholar 

  107. Lewis, T. S., Shapiro, P. S., and Ahn, N. G. (1998) Signal transduction through MAP kinase cascades. Adv. Cancer Res. 74, 49–139.

    PubMed  CAS  Google Scholar 

  108. Xing, J., Ginty, D. D., and Greenberg, M. E. (1996) Coupling of the RAS-MAPK pathway to gene activation by RSK2, a growth factor-regulated CREB kinase. Science 273, 959–963.

    Article  PubMed  CAS  Google Scholar 

  109. Shimamura, A., Ballif, B. A., Richards, S. A., and Blenis, J. (2000) Rsk1 mediates a MEK-MAP kinase cell survival signal. Curr. Biol. 10, 127–135.

    Article  PubMed  CAS  Google Scholar 

  110. Sassone-Corsi, P., Mizzen, C. A., Cheung, P., et al. (1999) Requirement of Rsk-2 for epidermal growth factor-activated phosphorylation of histone H3. Science 285, 886–891.

    Article  PubMed  CAS  Google Scholar 

  111. Roux, P. P., Richards, S. A., and Blenis, J. (2003) Phosphorylation of p90 ribosomal S6 kinase (RSK) regulates extracellular signal-regulated kinase docking and RSK activity. Mol. Cell. Biol. 23, 4796–4804.

    Article  PubMed  CAS  Google Scholar 

  112. Smith, J. A., Poteet-Smith, C. E., Malarkey, K., and 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.

    Article  PubMed  CAS  Google Scholar 

  113. Smith, J. A., Poteet-Smith, C. E., Lannigan, D. A., Freed, T. A., Zoltoski, A. J., and Sturgill, T. W. (2000) Creation of a stress-activated p90 ribosomal S6 kinase. The carboxyl-terminal tail of the MAPK-activated protein kinases dictates the signal transduction pathway in which they function. J. Biol. Chem. 275, 31588–31593.

    Article  PubMed  CAS  Google Scholar 

  114. Grevin, D., Ung, S., Denhez, F., et al. (1996) Structure and organization of the mouse elk1 gene. Gene 174, 185–188.

    Article  PubMed  CAS  Google Scholar 

  115. Griffiths, M. R., Black, E. J., Culbert, A. A., et al. (1998) Insulin-stimulated expression of c-fos, fra1 and c-jun accompanies the activation of the activator protein-1 (AP-1) transcriptional complex. Biochem. J. 335, 19–26.

    PubMed  CAS  Google Scholar 

  116. Gille, H., Kortenjann, M., Thomae, O., et al. (1995) ERK phosphorylation potentiates Elk-1-mediated ternary complex formation and transactivation. EMBO J. 14, 951–962.

    PubMed  CAS  Google Scholar 

  117. Price, M. A., Cruzalegui, F. H., and Treisman, R. (1996) The p38 and ERK MAP kinase pathways cooperate to activate Ternary Complex Factors and c-fos transcription in response to UV light. EMBO J. 15, 6552–6563.

    PubMed  CAS  Google Scholar 

  118. Cruzalegui, F. H., Cano, E., and Treisman, R. (1999) ERK activation induces phosphorylation of Elk-1 at multiple S/T-P motifs to high stoichiometry. Oncogene 18, 7948–7957.

    Article  PubMed  CAS  Google Scholar 

  119. Rao, V. N., and Reddy, E. S. (1994) elk-1 proteins interact with MAP kinases. Oncogene 9, 1855–1860.

    PubMed  CAS  Google Scholar 

  120. Jacobs, D., Glossip, D., Xing, H., Muslin, A. J., and Kornfeld, K. (1999) Multiple docking sites on substrate proteins form a modular system that mediates recognition by ERK MAP kinase. Genes Dev. 13, 163–175.

    Article  PubMed  CAS  Google Scholar 

  121. Conti, M., Richter, W., Mehats, C., Livera, G., Park, J. Y., and Jin, C. (2003) Cyclic AMP-specific PDE4 phosphodiesterases as critical components of cyclic AMP signaling. J. Biol. Chem. 278, 5493–5496.

    Article  PubMed  CAS  Google Scholar 

  122. MacKenzie, S. J., Baillie, G. S., McPhee, I., Bolger, G. B., and Houslay, M. D. (2000) ERK2 mitogen-activated protein kinase binding, phosphorylation, and regulation of the PDE4D cAMP-specific phosphodiesterases. The involvement of COOH-terminal docking sites and NH2-terminal UCR regions. J. Biol. Chem. 275, 16609–16617.

    Article  PubMed  CAS  Google Scholar 

  123. Houslay, M. D., and Kolch, W. (2000) Cell-type specific integration of crosstalk between extracellular signal-regulated kinase and cAMP signaling. Mol. Pharmacol. 58, 659–668.

    PubMed  CAS  Google Scholar 

  124. Baillie, G., MacKenzie, S. J., and Houslay, M. D. (2001) Phorbol 12-myristate 13-acetate triggers the protein kinase A-mediated phosphorylation and activation of the PDE4D5 cAMP phosphodiesterase in human aortic smooth muscle cells through a route involving extracellular signal regulated kinase (ERK). Mol. Pharmacol. 60, 1100–1111.

    PubMed  CAS  Google Scholar 

  125. Ramos, J. W., Kojima, T. K., Hughes, P. E., Fenczik, C. A., and Ginsberg, M. H. (1998) The death effector domain of PEA-15 is involved in its regulation of integrin activation. J. Biol. Chem. 273, 33897–33900.

    Article  PubMed  CAS  Google Scholar 

  126. Ramos, J. W., and Ginsberg, M. (2002) Expression cloning strategies for the identification of adhesion molecules. Methods Cell Biol. 69, 209–221.

    Article  PubMed  CAS  Google Scholar 

  127. Formstecher, E., Ramos, J. W., Fauquet, M., et al. (2001) PEA-15 mediates cytoplasmic sequestration of ERK MAP kinase. Dev. Cell. 1, 239–250.

    Article  PubMed  CAS  Google Scholar 

  128. Hill, J. M., Vaidyanathan, H., Ramos, J. W., Ginsberg, M. H., and Werner, M. H. (2002) Recognition of ERK MAP kinase by PEA-15 reveals a common docking site within the death domain and death effector domain. EMBO J. 21, 6494–6504.

    Article  PubMed  CAS  Google Scholar 

  129. Whitehurst, A. W., Robinson, F. L., Moore, M. S., and Cobb, M. H. (2004) The death effector domain protein PEA-15 prevents nuclear entry of ERK2 by inhibiting required interactions. J. Biol. Chem. 279, 12840–12847.

    Article  PubMed  CAS  Google Scholar 

  130. Stossel, T. P. (1993) On the crawling of animal cells. Science 260, 1086–1094.

    Article  PubMed  CAS  Google Scholar 

  131. Reszka, A. A., Bulinski, J. C., Krebs, E. G., and Fischer, E. H. (1997) Mitogen-activated protein kinase/extracellular signal-regulated kinase 2 regulates cytoskeletal organization and chemotaxis via catalytic and microtubule-specific interactions. Mol. Biol. Cell. 8, 1219–1232.

    PubMed  CAS  Google Scholar 

  132. Leinweber, B. D., Leavis, P. C., Grabarek, Z., Wang, C. L., and Morgan, K. G. (1999) Extracellular regulated kinase (ERK) interaction with actin and the calponin homology (CH) domain of actin-binding proteins. Biochem. J. 344 Pt 1, 117–123.

    Article  PubMed  CAS  Google Scholar 

  133. Michel, J. J., and Scott, J. D. (2002) AKAP mediated signal transduction. Annu. Rev. Pharmacol. Toxicol. 42, 235–257.

    Article  PubMed  CAS  Google Scholar 

  134. Pulido, R., Zuniga, A., and Ullrich, A. (1998) PTPSL 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.

    Article  PubMed  CAS  Google Scholar 

  135. Pettiford, S. M., and Herbst, R. (2000) The MAP-kinase ERK2 is a specific substrate of the protein tyrosine phosphatase HePTP. Oncogene 19, 858–869.

    Article  PubMed  CAS  Google Scholar 

  136. Muda, M., Theodosiou, A., Gillieron, C., et al. (1998) The mitogen-activated protein kinase phosphatase-3 N-terminal noncatalytic region is responsible for tight substrate binding and enzymatic specificity. J. Biol. Chem. 273, 9323–9329.

    Article  PubMed  CAS  Google Scholar 

  137. Zhou, B., and Zhang, Z. Y. (1999) Mechanism of mitogen-activated protein kinase phosphatase-3 activation by ERK2. J. Biol. Chem. 274, 35526–35534.

    Article  PubMed  CAS  Google Scholar 

  138. Tanoue, T., Yamamoto, T., and Nishida, E. (2002) Modular structure of a docking surface on MAPK phosphatases. J. Biol. Chem. 277, 22942–22949.

    Article  PubMed  CAS  Google Scholar 

  139. Karandikar, M., Xu, S., and Cobb, M. H. (2000) MEKK1 binds raf-1 and the ERK2 cascade components. J. Biol. Chem. 275, 40120–40127.

    Article  PubMed  CAS  Google Scholar 

  140. Yeung, K., Janosch, P., McFerran, B., et al. (2000) Mechanism of suppression of the Raf/MEK/extracellular signal-regulated kinase pathway by the raf kinase inhibitor protein. Mol. Cell. Biol 20, 3079–3085.

    Article  PubMed  CAS  Google Scholar 

  141. Vomastek, T., Schaeffer, H. J., Tarcsafalvi, A., Smolkin, M. E., Bissonette, E. A., and Weber, M. J. (2004) Modular construction of a signaling scaffold: MORG1 interacts with components of the ERK cascade and links ERK signaling to specific agonists. Proc. Natl. Acad. Sci. USA

  142. Garcia, J., Ye, Y., Arranz, V., Letourneux, C., Pezeron, G., and Porteu, F. (2002) IEX-1: a new ERK substrate involved in both ERK survival activity and ERK activation. EMBO J. 21, 5151–5163.

    Article  PubMed  CAS  Google Scholar 

  143. Pircher, T. J., Petersen, H., Gustafsson, J. A., and Haldosen, L. A. (1999) Extracellular signal-regulated kinase (ERK) interacts with signal transducer and activator of transcription (STAT) 5a. Mol. Endocrinol. 13, 555–565.

    Article  PubMed  CAS  Google Scholar 

  144. Roy, A. L. (2001) Biochemistry and biology of the inducible multifunctional transcription factor TFII-I. Gene 274, 1–13.

    Article  PubMed  CAS  Google Scholar 

  145. Kim, D. W., Cheriyath, V., Roy, A. L., and Cochran, B. H. (1998) TFII-I enhances activation of the c-fos promoter through interactions with upstream elements. Mol. Cell. Biol. 18, 3310–3320.

    PubMed  CAS  Google Scholar 

  146. Zhang, S., Fukushi, M., Hashimoto, S., et al. (2002) A new ERK2 binding protein, Naf1, attenuates the EGF/ERK2 nuclear signaling. Biochem. Biophys. Res. Commun. 297, 17–23.

    Article  PubMed  CAS  Google Scholar 

  147. Xu, R., Seger, R., and Pecht, I. (1999) Cutting edge: extracellular signal-regulated kinase activates syk: a new potential feedback regulation of Fc epsilon receptor signaling. J. Immunol. 163, 1110–1114.

    PubMed  CAS  Google Scholar 

  148. Shapiro, P. S., Whalen, A. M., Tolwinski, N. S., et al. (1999) Extracellular signal-regulated kinase activates topoisomerase IIalpha through a mechanism independent of phosphorylation. Mol. Cell. Biol. 19, 3551–3560.

    PubMed  CAS  Google Scholar 

  149. Roberts, M. S., Woods, A. J., Shaw, P. E., and Norman, J. C. (2003) ERK1 associates with alpha/beta 3 integrin and regulates cell spreading on vitronectin. J. Biol. Chem. 278, 1975–1985.

    Article  PubMed  CAS  Google Scholar 

  150. Purcell, N. H., Darwis, D., Bueno, O. F., Muller, J. M., Schule, R., and Molkentin, J. D. (2004) Extracellular Signal-Regulated Kinase 2 Interacts with and Is Negatively Regulated by the LIM-Only Protein FHL2 in Cardiomyocytes. Mol. Cell. Biol. 24, 1081–1095.

    Article  PubMed  CAS  Google Scholar 

  151. Ishihara, K., Tsutsumi, K., Kawane, S., Nakajima, M., and Kasaoka, T. (2003) The receptor for advanced glycation end-products (RAGE) directly binds to ERK by a D-domain-like docking site. FEBS Lett. 550, 107–113.

    Article  PubMed  CAS  Google Scholar 

  152. Roy, M., Li, Z., and Sacks, D. B. (2004) IQGAP1 binds ERK2 and modulates its activity. J. Biol. Chem. 279, 17329–17337.

    Article  PubMed  CAS  Google Scholar 

  153. David, M., Petricoin, E., 3rd, Benjamin, C., Pine, R., Weber, M. J., and Larner, A. C. (1995) Requirement for MAP kinase (ERK2) activity in interferon alpha-and interferon beta-stimulated gene expression through STAT proteins. Science 269, 1721–1723.

    Article  PubMed  CAS  Google Scholar 

  154. Zhang, H., Shi, X., Hampong, M., Blanis, L., and Pelech, S. (2001) Stress-induced inhibition of ERK1 and ERK2 by direct interaction with p38 MAP kinase. J. Biol. Chem. 276, 6905–6908.

    Article  PubMed  CAS  Google Scholar 

  155. Volente, C., Angelastro, J. M. and Greene, L. A. (1993) Association of protein kinases ERK1 and ERK2 with p75 nerve growth factor receptors. J. Biol. Chem. 268, 21,410–21,415.

    CAS  Google Scholar 

  156. Zhou, X., Richon, V., Wang, A., Yang, X., Rifkind, R., and Marks, P. (2000) Histone deacetylase 4 associates with extracellular signal-regulated by oncogenic Ras. Proc. Natl. Acad. Sci. USA 97, 14,329–14,333.

    CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biological Regulation, The Weizmann Institute of Science, 76100, Rehovot, Israel

    Dana Chuderland & Rony Seger

Authors
  1. Dana Chuderland
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rony Seger
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Rony Seger.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chuderland, D., Seger, R. Protein-protein interactions in the regulation of the extracellular signal-regulated kinase. Mol Biotechnol 29, 57–74 (2005). https://doi.org/10.1385/MB:29:1:57

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1385/MB:29:1:57

Index Entries

Search

Navigation