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Coordinating ERK/MAPK signalling through scaffolds and inhibitors

Key Points

  • The Ras–Raf–MEK–ERK/MAPK (ERK, extracellular signal-regulated kinase; MAPK, mitogen-activated protein kinase; MEK, MAPK and ERK kinase) pathway mediates many different biological responses. It is still unclear how response fidelity and specificity are determined, although modulations of signal amplitude and duration, spatial constraints, as well as crosstalk with other pathways, have important roles.

  • This pivotal regulation is mainly afforded through the manipulation of protein interactions by scaffolding, inhibitor and adaptor proteins that enhance, decrease or redirect the signal flux.

  • Examples of signalling enhancers are scaffolding proteins such as kinase suppressor of Ras-1 (KSR1) and MEK partner-1 (MP1), which tether components together ensuring a fast and selective response.

  • Inhibitors, such as Raf kinase inhibitor protein (RKIP), selectively disrupt the interaction between components of signalling pathways adding an additional dimension of regulation.

  • Multidomain adaptor proteins, such as connector enhancer of KSR (CNK), integrate and distribute signals by engaging multiple signalling pathways.

  • The combinatorial interplay between signalling proteins and pathways generates a rich diversity of regulation that can influence specific biochemical and biological responses. Unravelling these networks is an important challenge, which is facilitated by computational modelling.

Abstract

The pathway from Ras through Raf and MEK (MAPK and ERK kinase) to ERK/MAPK (extracellular signal-regulated kinase/mitogen-activated protein kinase) regulates many fundamental cellular processes. Recently, a number of scaffolding proteins and endogenous inhibitors have been identified, and their important roles in regulating signalling through this pathway are now emerging. Some scaffolds augment the signal flux, but also mediate crosstalk with other pathways; certain adaptors target MEK–ERK/MAPK complexes to subcellular localizations; others provide regulated inhibition. Computational modelling indicates that, together, these modulators can determine the dynamic biological behaviour of the pathway.

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Figure 1: KSR and Raf domains.
Figure 2: The KSR regulation cycle.
Figure 3: CNK interaction partners and signalling targets.
Figure 4: Paxillin connects the ERK/MAPK and FAK pathways.
Figure 5: MORG1 and MP1.
Figure 6: RKIP and ERK/MAPK activation.

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References

  1. O'Neill, E. & Kolch, W. Conferring specificity on the ubiquitous Raf/MEK signalling pathway. Br. J. Cancer 90, 283–288 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wellbrock, C., Karasarides, M. & Marais, R. The RAF proteins take centre stage. Nature Rev. Mol. Cell Biol. 5, 875–885 (2004).

    Article  CAS  Google Scholar 

  3. Chong, H., Vikis, H. G. & Guan, K. L. Mechanisms of regulating the Raf kinase family. Cell Signal. 15, 463–469 (2003).

    Article  CAS  PubMed  Google Scholar 

  4. Huser, M. et al. MEK kinase activity is not necessary for Raf-1 function. EMBO J. 20, 1940–1951 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Mikula, M. et al. Embryonic lethality and fetal liver apoptosis in mice lacking the c-raf-1 gene. EMBO J. 20, 1952–1962 (2001). References 4 and 5 describe the phenotype of Raf -1 knockout mice, demonstrating that some of the functions of Raf-1 are independent of its ability to activate the ERK/MAPK pathway.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  7. Brunet, A. et al. 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 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. O'Neill, E., Rushworth, L., Baccarini, M. & Kolch, W. Role of the kinase MST2 in suppression of apoptosis by the proto-oncogene product Raf-1. Science 306, 2267–2270 (2004). Shows that Raf-1, independently of its catalytic activity, can inhibit apoptosis by controlling the activation of the pro-apoptotic kinase MST2. Raf-1 interferes with MST2 dimerization and induces MST2 dephosphorylation.

    Article  CAS  PubMed  Google Scholar 

  9. Chen, J., Fujii, K., Zhang, L., Roberts, T. & Fu, H. Raf-1 promotes cell survival by antagonizing apoptosis signal- regulating kinase 1 through a MEK-ERK independent mechanism. Proc. Natl Acad. Sci. USA 98, 7783–7788. (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Yamaguchi, O. et al. Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis. J. Clin. Invest 114, 937–943 (2004). References 9 and 10 show that Raf-1 also can inhibit the pro-apoptotic kinase ASK1 by an unknown mechanism that does not require Raf-1 kinase activity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Ehrenreiter, K. et al. Raf-1 regulates Rho signaling and cell migration. J. Cell Biol. 168, 955–964 (2005). Describes a role for ASK1 suppression by Raf-1 during heart development and also demonstrates a role for Raf-1 in the regulation of cell migration and the actin cytoskeleton. Raf-1, independently of its kinase activity, controls Rho signalling.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Schwartz, M. Rho signalling at a glance. J. Cell Sci. 117, 5457–5458 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Pritchard, C. A. et al. B-Raf acts via the ROCKII/LIMK/cofilin pathway to maintain actin stress fibers in fibroblasts. Mol. Cell Biol 24, 5937–5952 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  15. Therrien, M., Michaud, N. R., Rubin, G. M. & Morrison, D. K. KSR modulates signal propagation within the MAPK cascade. Genes Dev. 10, 2684–2695 (1996). Genetic and biochemical analyses of KSR function show that KSR is a regulated scaffold for the Raf–MEK–ERK/MAPK pathway.

    Article  CAS  PubMed  Google Scholar 

  16. Kortum, R. L. & Lewis, R. E. The molecular scaffold KSR1 regulates the proliferative and oncogenic potential of cells. Mol. Cell Biol 24, 4407–4416 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ohmachi, M. et al. C. elegans ksr-1 and ksr-2 have both unique and redundant functions and are required for MPK-1 ERK phosphorylation. Curr. Biol. 12, 427–433 (2002).

    Article  CAS  PubMed  Google Scholar 

  18. Nguyen, A. et al. Kinase suppressor of Ras (KSR) is a scaffold which facilitates mitogen-activated protein kinase activation in vivo. Mol. Cell Biol. 22, 3035–3045 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Lozano, J. et al. Deficiency of kinase suppressor of Ras1 prevents oncogenic ras signaling in mice. Cancer Res. 63, 4232–4238 (2003).

    CAS  PubMed  Google Scholar 

  20. Channavajhala, P. L. et al. Identification of a novel human kinase supporter of Ras (hKSR-2) that functions as a negative regulator of Cot (Tpl2) signaling. J. Biol. Chem. 278, 47089–47097 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Razidlo, G. L., Kortum, R. L., Haferbier, J. L. & Lewis, R. E. Phosphorylation regulates KSR1 stability, ERK activation, and cell proliferation. J. Biol. Chem. 279, 47808–47814 (2004). Describes the effects of phosphorylation on KSR1 function.

    Article  CAS  PubMed  Google Scholar 

  22. Yan, F. et al. Kinase suppressor of Ras-1 protects intestinal epithelium from cytokine-mediated apoptosis during inflammation. J. Clin. Invest. 114, 1272–1280 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Muller, J., Cacace, A. M., Lyons, W. E., McGill, C. B. & Morrison, D. K. Identification of B-KSR1, a novel brain-specific isoform of KSR1 that functions in neuronal signaling. Mol. Cell Biol. 20, 5529–5539 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Muller, J., Ory, S., Copeland, T., Piwnica-Worms, H. & Morrison, D. K. C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, KSR1. Mol. Cell 8, 983–993 (2001). Shows that KSR1 is phosphorylated by C-TAK1 creating a 14-3-3 binding site on S392 that retains KSR1 in the cytosol.

    Article  CAS  PubMed  Google Scholar 

  25. Matheny, S. A. et al. Ras regulates assembly of mitogenic signalling complexes through the effector protein IMP. Nature 427, 256–260 (2004). Identification of IMP as a Ras-regulated inhibitor of KSR.

    Article  CAS  PubMed  Google Scholar 

  26. Hartsough, M. T. et al. Nm23-H1 metastasis suppressor phosphorylation of kinase suppressor of Ras via a histidine protein kinase pathway. J. Biol. Chem. 277, 32389–32399 (2002).

    Article  CAS  PubMed  Google Scholar 

  27. Cacace, A. M. et al. Identification of constitutive and ras-inducible phosphorylation sites of KSR: implications for 14–3-3 binding, mitogen-activated protein kinase binding, and KSR overexpression. Mol. Cell Biol. 19, 229–240 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Therrien, M., Wong, A. M. & Rubin, G. M. CNK, a RAF-binding multidomain protein required for RAS signaling. Cell 95, 343–353 (1998). This paper and reference 30 describe the identification of CNK as a multi-adaptor protein that regulates multiple signalling pathways.

    Article  CAS  PubMed  Google Scholar 

  29. Douziech, M. et al. Bimodal regulation of RAF by CNK in Drosophila. EMBO J. 22, 5068–5078 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Therrien, M., Wong, A. M., Kwan, E. & Rubin, G. M. Functional analysis of CNK in RAS signaling. Proc. Natl Acad. Sci. USA 96, 13259–13263 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Laberge, G., Douziech, M. & Therrien, M. Src42 binding activity regulates Drosophila RAF by a novel CNK-dependent derepression mechanism. EMBO J. 24, 487–498 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Gonfloni, S., Weijland, A., Kretzschmar, J. & Superti-Furga, G. Crosstalk between the catalytic and regulatory domains allows bidirectional regulation of Src. Nature Struct. Biol. 7, 281–286 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Ziogas, A., Moelling, K. & Radziwill, G. CNK1 is a scaffold protein that regulates Src-mediated Raf-1 activation. J. Biol. Chem. 24205–20211 (2005).

  34. Rabizadeh, S. et al. The scaffold protein CNK1 interacts with the tumor suppressor RASSF1A and augments RASSF1A-induced cell death. J. Biol. Chem. 279, 29247–29254 (2004).

    Article  CAS  PubMed  Google Scholar 

  35. Lanigan, T. M. et al. Human homologue of Drosophila CNK interacts with Ras effector proteins Raf and Rlf. FASEB J. 17, 2048–2060 (2003).

    Article  CAS  PubMed  Google Scholar 

  36. Bumeister, R., Rosse, C., Anselmo, A., Camonis, J. & White, M. A. CNK2 couples NGF signal propagation to multiple regulatory cascades driving cell differentiation. Curr. Biol. 14, 439–445 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Tran, Y. K. et al. A novel member of the NF2/ERM/4.1 superfamily with growth suppressing properties in lung cancer. Cancer Res. 59, 35–43 (1999).

    CAS  PubMed  Google Scholar 

  38. Ohtakara, K. et al. Densin-180, a synaptic protein, links to PSD-95 through its direct interaction with MAGUIN-1. Genes Cells 7, 1149–1160 (2002).

    Article  CAS  PubMed  Google Scholar 

  39. Jaffe, A. B., Aspenstrom, P. & Hall, A. Human CNK1 acts as a scaffold protein, linking Rho and Ras signal transduction pathways. Mol. Cell Biol 24, 1736–1746 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lopez-Ilasaca, M. A., Bernabe-Ortiz, J. C., Na, S. Y., Dzau, V. J. & Xavier, R. J. Bioluminescence resonance energy transfer identify scaffold protein CNK1 interactions in intact cells. FEBS Lett. 579, 648–654 (2005).

    Article  CAS  PubMed  Google Scholar 

  41. Jackson, P. K. Linking tumor suppression, DNA damage and the anaphase-promoting complex. Trends Cell Biol. 14, 331–334 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Sharif, A., Canton, B., Junier, M. P. & Chneiweiss, H. PEA-15 modulates TNFα intracellular signaling in astrocytes. Ann. NY Acad. Sci. 1010, 43–50 (2003).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  44. Formstecher, E. et al. PEA-15 mediates cytoplasmic sequestration of ERK MAP kinase. Dev. Cell 1, 239–250 (2001). Identification of PEA15 as an inhibitor of ERK/MAPK nuclear signalling. PEA15 sequesters ERK/MAPK in the cytosol.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  46. Vial, E., Sahai, E. & Marshall, C. J. ERK-MAPK signaling coordinately regulates activity of Rac1 and RhoA for tumor cell motility. Cancer Cell 4, 67–79 (2003).

    Article  CAS  PubMed  Google Scholar 

  47. Lefkowitz, R. J. & Whalen, E. J. β-arrestins: traffic cops of cell signaling. Curr. Opin. Cell Biol. 16, 162–168 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Shenoy, S. K. & Lefkowitz, R. J. Multifaceted roles of beta-arrestins in the regulation of seven-membrane-spanning receptor trafficking and signalling. Biochem. J. 375, 503–515 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Luttrell, L. M. et al. Activation and targeting of extracellular signal-regulated kinases by beta-arrestin scaffolds. Proc. Natl Acad. Sci. USA 98, 2449–2454 (2001). The above three papers review the complex roles of β-arrestins as multifunctional adaptor proteins and regulators of GPCR endocytosis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. DeFea, K. A. et al. β-arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2. J. Cell Biol. 148, 1267–1282 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Tohgo, A. et al. The stability of the G protein-coupled receptor-β-arrestin interaction determines the mechanism and functional consequence of ERK activation. J. Biol. Chem. 278, 6258–6267 (2003).

    Article  CAS  PubMed  Google Scholar 

  52. Wei, H. et al. Independent β-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2. Proc. Natl Acad. Sci. USA 100, 10782–10787 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Luttrell, L. M. 'Location, location, location': activation and targeting of MAP kinases by G protein-coupled receptors. J. Mol. Endocrinol. 30, 117–126 (2003).

    Article  CAS  PubMed  Google Scholar 

  54. Ahn, S., Shenoy, S. K., Wei, H. & Lefkowitz, R. J. Differential kinetic and spatial patterns of beta-arrestin and G protein-mediated ERK activation by the angiotensin II receptor. J. Biol. Chem. 279, 35518–35525 (2004).

    Article  CAS  PubMed  Google Scholar 

  55. Lin, F. T., Miller, W. E., Luttrell, L. M. & Lefkowitz, R. J. Feedback regulation of β-arrestin1 function by extracellular signal-regulated kinases. J. Biol. Chem. 274, 15971–15974 (1999).

    Article  CAS  PubMed  Google Scholar 

  56. Pitcher, J. A. et al. Feedback inhibition of G protein-coupled receptor kinase 2 (GRK2) activity by extracellular signal-regulated kinases. J. Biol. Chem. 274, 34531–34534 (1999).

    Article  CAS  PubMed  Google Scholar 

  57. Furthauer, M., Lin, W., Ang, S. L., Thisse, B. & Thisse, C. Sef is a feedback-induced antagonist of Ras/MAPK-mediated FGF signalling. Nature Cell Biol. 4, 170–174 (2002).

    Article  CAS  PubMed  Google Scholar 

  58. Tsang, M., Friesel, R., Kudoh, T. & Dawid, I. B. Identification of Sef, a novel modulator of FGF signalling. Nature Cell Biol. 4, 165–169 (2002).

    Article  CAS  PubMed  Google Scholar 

  59. Tsang, M. & Dawid, I. B. Promotion and attenuation of FGF signaling through the Ras-MAPK pathway. Sci. STKE. 2004, e17 (2004).

    Google Scholar 

  60. Torii, S., Kusakabe, M., Yamamoto, T., Maekawa, M. & Nishida, E. Sef is a spatial regulator for Ras/MAP kinase signaling. Dev. Cell 7, 33–44 (2004). Sef scaffolds a MEK–ERK/MAPK complex at the Golgi. Sef inhibits nuclear ERK/MAPK signalling, but permits the phosphorylation of cytosolic substrates by ERK/MAPK.

    Article  CAS  PubMed  Google Scholar 

  61. Bivona, T. G. et al. Phospholipase Cgamma activates Ras on the Golgi apparatus by means of RasGRP1. Nature 424, 694–698 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Briggs, M. W. & Sacks, D. B. IQGAP proteins are integral components of cytoskeletal regulation. EMBO Rep. 4, 571–574 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Hart, M. J., Callow, M. G., Souza, B. & Polakis, P. IQGAP1, a calmodulin-binding protein with a rasGAP-related domain, is a potential effector for cdc42Hs. EMBO J. 15, 2997–3005 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Brill, S. et al. The Ras GTPase-activating-protein-related human protein IQGAP2 harbors a potential actin binding domain and interacts with calmodulin and Rho family GTPases. Mol. Cell Biol. 16, 4869–4878 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Bourguignon, L. Y., Gilad, E., Rothman, K. & Peyrollier, K. Hyaluronan-CD44 interaction with IQGAP1 promotes Cdc42 and ERK signaling, leading to actin binding, Elk-1/estrogen receptor transcriptional activation, and ovarian cancer progression. J. Biol. Chem. 280, 11961–11972 (2005).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  67. King, A. J. et al. The protein kinase Pak3 positively regulates Raf-1 activity through phosphorylation of serine 338. Nature 396, 180–183 (1998).

    Article  CAS  PubMed  Google Scholar 

  68. Harrison, R. E., Sikorski, B. A. & Jongstra, J. Leukocyte-specific protein 1 targets the ERK/MAP kinase scaffold protein KSR and MEK1 and ERK2 to the actin cytoskeleton. J. Cell Sci. 117, 2151–2157 (2004).

    Article  CAS  PubMed  Google Scholar 

  69. Huang, C., Jacobson, K. & Schaller, M. D. MAP kinases and cell migration. J. Cell Sci. 117, 4619–4628 (2004).

    Article  CAS  PubMed  Google Scholar 

  70. Turner, C. E. Paxillin interactions. J. Cell Sci. 113, 4139–4140 (2000).

    CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  72. Ishibe, S., Joly, D., Liu, Z. X. & Cantley, L. G. Paxillin serves as an ERK-regulated scaffold for coordinating FAK and Rac activation in epithelial morphogenesis. Mol. Cell 16, 257–267 (2004). References 71 and 72 describe the assembly of an ERK/MAPK signalling complex at the site of focal adhesions that coordinates the turnover of focal adhesions during migration by connecting ERK/MAPK signalling with Rac activation.

    Article  CAS  PubMed  Google Scholar 

  73. Schaeffer, H. J. et al. MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. Science 281, 1668–1671 (1998). This paper and reference 76 identify and characterize the function of MP1, showing that it is a scaffold protein that localizes ERK/MAPK signalling to endosomes.

    Article  CAS  PubMed  Google Scholar 

  74. Kurzbauer, R. et al. Crystal structure of the p14/MP1 scaffolding complex: how a twin couple attaches mitogen-activated protein kinase signaling to late endosomes. Proc. Natl Acad. Sci. USA 101, 10984–10989 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Teis, D., Wunderlich, W. & Huber, L. A. Localization of the MP1-MAPK scaffold complex to endosomes is mediated by p14 and required for signal transduction. Dev. Cell 3, 803–814 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Schoeberl, B., Eichler-Jonsson, C., Gilles, E. D. & Muller, G. Computational modeling of the dynamics of the MAP kinase cascade activated by surface and internalized EGF receptors. Nature Biotechnol. 20, 370–375 (2002). One of the most exhaustive computational models of the ERK/MAPK pathway.

    Article  Google Scholar 

  77. Sharma, C. et al. MEK partner 1 (MP1): regulation of oligomerization in MAP kinase signaling. J. Cell Biochem. 94, 708–719 (2005).

    Article  CAS  PubMed  Google Scholar 

  78. Pullikuth, A., McKinnon, E., Schaeffer, H. J. & Catling, A. D. The MEK1 scaffolding protein MP1 regulates cell spreading by integrating PAK1 and Rho signals. Mol. Cell Biol 25, 5119–5133 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Vomastek, T. et al. 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 101, 6981–6986 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Yeung, K. et al. Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP. Nature 401, 173–177 (1999). Identifies RKIP as a physiological inhibitor of ERK/MAPK signalling. The mechanism of inhibition is the disruption of the Raf–MEK interaction by RKIP.

    Article  CAS  PubMed  Google Scholar 

  81. Park, S., Yeung, M. L., Beach, S., Shields, J. M. & Yeung, K. C. RKIP downregulates B-Raf kinase activity in melanoma cancer cells. Oncogene 24, 3535–3540 (2005).

    Article  CAS  PubMed  Google Scholar 

  82. Trakul, N., Menard, R. E., Schade, G. R., Qian, Z. & Rosner, M. R. Raf kinase inhibitory protein regulates Raf-1 but not B-Raf kinase activation. J. Biol. Chem. 280, 24931–24940 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Corbit, K. C. et al. Activation of Raf-1 signaling by protein kinase C through a mechanism involving Raf kinase inhibitory protein. J. Biol. Chem. 278, 13061–13068 (2003).

    Article  CAS  PubMed  Google Scholar 

  84. Lorenz, K., Lohse, M. J. & Quitterer, U. Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2. Nature 426, 574–579 (2003). PKC phosphorylation of RKIP inactivates RKIP as an inhibitor of Raf-mediated MEK phosphorylation, and turns RKIP into an inhibitor of GRK2, resulting in extended signalling by GPCRs.

    Article  CAS  PubMed  Google Scholar 

  85. Yeung, K. C. et al. Raf kinase inhibitor protein interacts with NF-κb-inducing kinase and tak1 and inhibits NF-κb activation. Mol. Cell Biol. 21, 7207–7217 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Schuierer, M. M., Bataille, F., Hagan, S., Kolch, W. & Bosserhoff, A. K. Reduction in Raf kinase inhibitor protein expression is associated with increased Ras-extracellular signal-regulated kinase signaling in melanoma cell lines. Cancer Res. 64, 5186–5192 (2004).

    Article  CAS  PubMed  Google Scholar 

  87. Chatterjee, D. et al. RKIP sensitizes prostate and breast cancer cells to drug-induced apoptosis. J. Biol. Chem. 279, 17515–17523 (2004).

    Article  CAS  PubMed  Google Scholar 

  88. Fu, Z. et al. Effects of raf kinase inhibitor protein expression on suppression of prostate cancer metastasis. J. Natl Cancer Inst. 95, 878–889 (2003). First demonstration that RKIP is a metastasis suppressor gene.

    Article  CAS  PubMed  Google Scholar 

  89. Jazirehi, A. R., Vega, M. I., Chatterjee, D., Goodglick, L. & Bonavida, B. Inhibition of the Raf-MEK1/2-ERK1/2 signaling pathway, Bcl-xL down-regulation, and chemosensitization of non-Hodgkin's lymphoma B cells by Rituximab. Cancer Res. 64, 7117–7126 (2004).

    Article  CAS  PubMed  Google Scholar 

  90. Yamazaki, T. et al. Differentiation induction of human keratinocytes by phosphatidylethanolamine-binding protein. J. Biol. Chem. 279, 32191–32195 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Kazuki, Y. et al. Human chromosome 21q22.2-qter carries a gene(s) responsible for downregulation of mlc2a and PEBP in Down syndrome model mice. Biochem. Biophys. Res. Comm. 317, 491–499 (2004).

    Article  CAS  PubMed  Google Scholar 

  92. Agha, M. M. et al. Congenital abnormalities and childhood cancer. Cancer 103, 1939–1948 (2005).

    Article  PubMed  Google Scholar 

  93. Kim, H. J. & Bar-Sagi, D. Modulation of signalling by Sprouty: a developing story. Nature Rev. Mol. Cell Biol. 5, 441–450 (2004). A recent comprehensive review on the pleiotropic functions of the Sprouty and SPRED family.

    Article  CAS  Google Scholar 

  94. Li, X., Brunton, V. G., Burgar, H. R., Wheldon, L. M. & Heath, J. K. FRS2-dependent SRC activation is required for fibroblast growth factor receptor-induced phosphorylation of Sprouty and suppression of ERK activity. J. Cell Sci. 117, 6007–6017 (2004).

    Article  CAS  PubMed  Google Scholar 

  95. Gross, I., Bassit, B., Benezra, M. & Licht, J. D. Mammalian sprouty proteins inhibit cell growth and differentiation by preventing ras activation. J. Biol. Chem. 276, 46460–46468 (2001).

    Article  CAS  PubMed  Google Scholar 

  96. Egan, J. E., Hall, A. B., Yatsula, B. A. & Bar-Sagi, D. The bimodal regulation of epidermal growth factor signaling by human Sprouty proteins. Proc. Natl Acad. Sci. USA 99, 6041–6046 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Wong, E. S. et al. Sprouty2 attenuates epidermal growth factor receptor ubiquitylation and endocytosis, and consequently enhances Ras/ERK signalling. EMBO J. 21, 4796–4808 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Sasaki, A. et al. Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1. Nature Cell Biol. 5, 427–432 (2003).

    Article  CAS  PubMed  Google Scholar 

  99. Levchenko, A., Bruck, J. & Sternberg, P. W. 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 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Alessi, D. R. et al. Identification of the sites in MAP kinase kinase-1 phosphorylated by p74raf-1. EMBO J. 13, 1610–1619 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Burack, W. R. & Sturgill, T. W. The activating dual phosphorylation of MAPK by MEK is nonprocessive. Biochemistry 36, 5929–5933 (1997).

    Article  CAS  PubMed  Google Scholar 

  102. Ferrell, J. E. Jr. Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and bistability. Curr. Opin. Cell Biol. 14, 140–148 (2002).

    Article  CAS  PubMed  Google Scholar 

  103. Xiong, W. & Ferrell, J. E. Jr. A positive-feedback-based bistable 'memory module' that governs a cell fate decision. Nature 426, 460–465 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Heinrich, R., Neel, B. G. & Rapoport, T. A. Mathematical models of protein kinase signal transduction. Mol. Cell 9, 957–970 (2002). A comprehensive theoretical analysis of the rich biochemical behaviour intrinsic to kinase cascades.

    Article  CAS  PubMed  Google Scholar 

  105. Colicelli, J. Human RAS superfamily proteins and related GTPases. Sci. STKE. 2004, RE13 (2004).

    PubMed  PubMed Central  Google Scholar 

  106. Repasky, G. A., Chenette, E. J. & Der, C. J. Renewing the conspiracy theory debate: does Raf function alone to mediate Ras oncogenesis? Trends Cell Biol. 14, 639–647 (2004).

    Article  CAS  PubMed  Google Scholar 

  107. Garnett, M. J. & Marais, R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell 6, 313–319 (2004).

    Article  CAS  PubMed  Google Scholar 

  108. Garcia, R., Dhillon, A. S. & Kolch, W. in Recent Res. Devel. Mol. Cell. Biol. 3. (Pandalai, S. G. ed.) 88–112 (Research Signpost, 2002).

  109. Roux, P. P. & Blenis, J. ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol. Mol. Biol Rev. 68, 320–344 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

I thank members of my laboratory for helpful discussions and apologize to all the authors whose work could not be cited because of space restriction.

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DATABASES

Swiss-Prot

A-Raf

B-Raf

β-arrestin-1

β-arrestin-2

CNK1

CNK2

EGF

FAK

Grb2

GRK2

HGF

IMP

KSR1

MEK

MP1

paxillin

PEA15

Raf-1

Ras

RASSF1

RhoA

RhoB

RhoC

RKIP

FURTHER INFORMATION

Walter Kolch's Laboratory

Glossary

PC12 CELLS

A clonal line of rat adrenal pheochromocytoma cells which is used as model for neuronal differentiation as the cells respond to nerve growth factor and can synthesize, store and secrete catecholamines, much like sympathetic neurons. PC12 cells contain small, clear synaptic-like vesicles and larger dense-core granules.

ACTIVATION LOOP

A 20–25-residue segment in a protein kinase that functions to modulate kinase activity.

STRESS FIBRES

Also termed 'actin-microfilament bundles', these are bundles of parallel filaments that contain F-actin and other contractile molecules, and often stretch between cell attachments as if under stress.

14-3-3 PROTEINS

A large class of proteins that are involved in cell division, apoptosis, signal transduction, transmitter release, receptor function, gene expression and enzyme activation in eukaryotes. They function by binding to a wide range of specific target proteins, usually in response to phosphorylation of these targets.

E3 UBIQUITIN LIGASE

The final enzyme complex in the ubiquitin-conjugation pathway. E3 enzymes transfer ubiquitin from previous components of the pathway to the substrate protein to form a covalently linked ubiquitin–substrate conjugate.

DOMINANT NEGATIVE

A defective protein that retains interaction capabilities and so competes with normal proteins, thereby impairing protein function.

STERILE α-MOTIF

(SAM). Domain of 70 amino acids roughly conserved in many proteins and thought to participate in protein–protein interactions.

PDZ DOMAIN

(Postsynaptic-density protein of 95 kDa, Discs large, Zona occludens-1). A protein-interaction domain that often occurs in scaffolding proteins and is named after the founding members of this protein family.

PLECKSTRIN-HOMOLOGY (PH) DOMAIN

A protein module of 100 amino acids that is present in a range of proteins. Different PH domains interact with various phospholipids and are involved in the targeting of the proteins.

EPISTASIS ANALYSIS

Epistasis is the masking of a phenotype caused by a mutation in one gene by a mutation in another gene. Epistasis analysis can therefore be used to dissect the order in which genes in a genetic pathway function.

SH2 DOMAIN

(Src-homology-2 domain). A protein motif that recognizes and binds tyrosine-phosphorylated sequences, and has a key role in relaying cascades of signal transduction.

SH3 DOMAIN

(Src-homology-3). A protein sequence of 50 amino acids that recognizes and binds sequences that are rich in proline.

FILOPODIA

Thin, transient actin protrusions that extend out from the cell surface and are formed by the elongation of bundled actin filaments in its core.

NUCLEOPORINS

Protein subunits of the nuclear pore complex.

INTEGRINS

A large family of heterodimeric transmembrane proteins that function as receptors for cell-adhesion molecules.

G-PROTEIN-COUPLED RECEPTOR

(GPCR). A seven-helix transmembrane-spanning cell-surface receptor that signals through heterotrimeric GTP-binding and GTP-hydrolysing G-proteins to stimulate or inhibit the activity of a downstream enzyme.

CLATHRIN-COATED PIT

(CCP). The initial site of invagination of a clathrin-coated vesicle.

EARLY ENDOSOME

An intracellular vesicular structure that is a precursor of the mature endosome and that has an important role in endocytosis.

HETEROTRIMERIC G PROTEIN

A protein complex of three proteins (Gα, Gβ and Gγ). Gβ and Gγ form a tight complex, and Gα is part of this complex in its inactive, GDP-bound form but dissociates in its active, GTP-bound form. Both Gα and Gβγ can transmit downstream signals after activation.

GUANINE NUCLEOTIDE-EXCHANGE FACTOR

A protein that facilitates the exchange of GDP for GTP in the nucleotide-binding pocket of a GTP-binding protein.

FOCAL ADHESION

An integrin-mediated cell–substrate adhesion structure that anchors the ends of actin filaments (stress fibres) and mediates strong attachments to substrates. It also functions as an integrin signalling platform.

RHO-FAMILY GTPASE

A family of Ras-related GTPases that are involved in controlling the dynamics of the actin cytoskeleton.

LAMELLIPODIA

Flattened, sheet-like structures — which are composed of a crosslinked F-actin meshwork — that project from the surface of a cell. They are often associated with cell migration.

LEADING EDGE

The thin margin of a lamellipodium that spans the area of the cell from the plasma membrane to a depth of about 1 μm into the lamellipodium.

LATE ENDOSOMES

These organelles mature from early endosomes and feature lower pH and different protein composition. They usually deliver cargo proteins to lysosomes for degradation.

SHORT INTERFERING RNA

A non-coding RNA (21 nucleotides) that is processed from longer double stranded RNA during RNA interference. Such non-coding RNAs hybridize with mRNA targets, and confer target specificity to the silencing complexes that contain them.

WD40 DOMAIN

A poorly conserved repeat sequence of 40–60 amino acids, which usually ends with Trp-Asp (WD). Several consecutive repeats fold into a circular structure, a so-called β-propeller, in which each 'blade' is a four-stranded β-sheet. This domain is found in proteins that have different functions.

PHORBOL ESTER

A polycyclic ester that is isolated from croton oil. The most common are phorbol-12-myristate-13-acetate (PMA) and 12-O-tetradecanoyl-phorbol-13-acetate (TPA). These are potent inflammatory agents and tumour promoters because they mimic diacylglycerol, and thereby cause sustained activation of protein kinase C.

KERATINOCYTE

An epithelial cell of the skin that has differentiated to produce keratin. Keratinocytes are the predominant cell type in the epidermis of the skin.

EVH1 DOMAIN

The Enabled/VASP homology domain-1 is a 110 amino acid sequence that — similarly to SH3 domains — interacts with polyproline-rich regions. Structurally, EVH1 is similar to the PH domain despite low sequence homology and different binding partners.

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Kolch, W. Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat Rev Mol Cell Biol 6, 827–837 (2005). https://doi.org/10.1038/nrm1743

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