Coordinating ERK/MAPK signalling through scaffolds and inhibitors

Nature Reviews Molecular Cell Biology

Volumn 6, Issue 11, 2005, Pages 827-837

  Kolch, Walter ^a,b  

^a BEATSON INSTITUTE FOR CANCER RESEARCH   (United Kingdom)

^b UNIVERSITY OF GLASGOW   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

ADAPTOR PROTEIN; BETA ARRESTIN; BINDING PROTEIN; CONNECTOR ENHANCER OF KSR; FOCAL ADHESION KINASE; KINASE SUPPRESSOR OF RAS 1; MITOGEN ACTIVATED PROTEIN KINASE; MITOGEN ACTIVATED PROTEIN KINASE INHIBITOR; PAXILLIN; PHOSPHATIDYLETHANOLAMINE BINDING PROTEIN; PROTEIN INHIBITOR; RAF PROTEIN; RAS PROTEIN; REGULATOR PROTEIN; RHO FACTOR; SCAFFOLD PROTEIN; SPROUTY PROTEIN; SPROUTY RELATED PROTEIN WITH AN EVH1 DOMAIN; UNCLASSIFIED DRUG;

APOPTOSIS; CELL ADHESION; CELL COMPARTMENTALIZATION; CELL FUNCTION; CELL NUCLEUS; CELLULAR DISTRIBUTION; CYTOSKELETON; CYTOSOL; ENZYME INHIBITION; KNOCKOUT MOUSE; MAMMAL; MATHEMATICAL MODEL; NONHUMAN; PRIORITY JOURNAL; PROTEIN LOCALIZATION; PROTEIN PROTEIN INTERACTION; PROTEIN TARGETING; REGULATORY MECHANISM; REVIEW; SIGNAL TRANSDUCTION;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; ANIMALS; DROSOPHILA PROTEINS; EXTRACELLULAR SIGNAL-REGULATED MAP KINASES; MAP KINASE SIGNALING SYSTEM; MICE; MITOGEN-ACTIVATED PROTEIN KINASE KINASES; PROTEIN KINASES; PROTO-ONCOGENE PROTEINS C-RAF; RAS PROTEINS;

MAMMALIA;

EID: 27644575157     PISSN: 14710072     EISSN: 14710080     Source Type: Journal    
DOI: 10.1038/nrm1743     Document Type: Review

References (109)

1. O'Neill, E. & Kolch, W. Conferring specificity on the ubiquitous Raf/MEK signalling pathway. Br. J. Cancer 90, 283-288 (2004).
2. Wellbrock, C., Karasarides, M. & Marais, R. The RAF proteins take centre stage. Nature Rev. Mol. Cell Biol. 5, 875-885 (2004).
3. Chong, H., Vikis, H. G. & Guan, K. L. Mechanisms of regulating the Raf kinase family. Cell Signal. 15, 463-469 (2003).
4. Huser, M. et al. MEK kinase activity is not necessary for Raf-1 function. EMBO J. 20, 1940-1951 (2001).
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.
6. Marshall, C. J. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179-185 (1995).
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).
8. O'Neill, E., Rushworth, L., Baccarini, M. & Kolch, W. Role of the kinase MST2 in suppression of apoptosis by the protooncogene 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.
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).
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.
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.
12. Schwartz, M. Rho signalling at a glance. J. Cell Sci. 117, 5457-5458 (2004).
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).
14. Morrison, D. K. KSR: a MARK scaffold of the Ras pathway? J. Cell Sci. 114, 1609-1612. (2001).
15. Therrien, M., Michaud, N. R., Rubin, G. M. & Morrison, D. K. KSR modulates signal propagation within the MARK 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.
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).
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).
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).
19. Lozano, J. et al. Deficiency of kinase suppressor of Ras1 prevents oncogenic ras signaling in mice. Cancer Res. 63, 4232-4238 (2003).
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).
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.
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).
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).
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.
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.
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).
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).
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.
29. Douziech, M. et al. Bimodal regulation of RAF by CNK in Drosophila. EMBO J. 22, 5068-5078 (2003).
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).
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).
32. Gonfloni, S., Waijland, 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).
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).
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).
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).
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).
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).
39. Jaffe, A. B., Aspenstrom, R & Hall, A. Human CNK1 acts as a scaffold protein, linking Rho and Ras signal transduction pathways. Mol. Cell Biol 24, 1736-1746 (2004).
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 Leff. 579, 648-654 (2005).
41. Jackson, P. K. Linking tumor suppression, DNA damage and the anaphase-promoting complex. Trends Cell Biol. 14, 331-334 (2004).
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).
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).
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.
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).
46. Vial, E., Sahai, E. & Marshall, C. J. ERK-MAPK signaling coordinately regulates activity of Rad and RhoA for tumor cell motility. Cancer Cell 4, 67-79 (2003).
47. Lefkowitz, R. J. & Whalen, E. J. β-arrestins: traffic cops of cell signaling. Curr. Opin. Cell Biol. 16, 162-168 (2004).
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).
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.
50. DeFea, K. A. et al. α-arrestin-dependent endocytosis of proteinase-activated receptor 2 is required for intracellular targeting of activated ERK1/2. J. Cell Biol. 148, 1267-1282 (2000).
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).
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).
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).
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).
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).
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).
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).
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).
59. Tsang, M. & Dawid, I. B. Promotion and attenuation of FGF signaling through the Ras-MAPK pathway. Sci. STKE. 2004, e17 (2004).
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.
61. Bivona, T. G. et al. Phospholipase Cgamma activates Ras on the Golgi apparatus by means of RasGRP1. Nature 424, 694-698 (2003).
62. Briggs, M. W. & Sacks, D. B. IQGAP proteins are integral components of cytoskeletal regulation. EMBO Rep. 4, 571-574 (2003).
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).
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).
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).
66. Roy, M., Li, Z. & Sacks, D. B. IQGAP1 binds ERK2 and modulates its activity. J. Biol. Chem. 279, 17329-17337 (2004).
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).
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).
69. Huang, C., Jacobson, K. & Schaller, M. D. MAP kinases and cell migration. J. Cell Sci. 117, 4619-4628 (2004).
70. Turner, C. E. Paxillin interactions. J. Cell Sci. 113, 4139-4140 (2000).
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).
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.
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.
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).
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).
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.
77. Sharma, C. et al. MEK partner 1 (MP1): regulation of oligomerization in MAP kinase signaling. J. Cell Biochem. 94, 708-719 (2005).
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).
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).
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.
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).
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).
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).
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.
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).
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).
87. Chatterjee, D. et al. RKIP sensitizes prostate and breast cancer cells to drug-induced apoptosis. J. Biol. Chem. 279, 17515-17523 (2004).
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.
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).
90. Yamazaki, T. et al. Differentiation induction of human keratinocytes by phosphatidylethanolamine-binding protein. J. Biol. Chem. 279, 32191-32195 (2004).
91. Kazuki, Y. et al. Human chromosome 21 q22.2-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).
92. Agha, M. M. et al. Congenital abnormalities and childhood cancer. Cancer 103, 1939-1948 (2005).
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.
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).
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).
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).
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).
98. Sasaki, A. et al. Mammalian Sprouty4 suppresses Ras-independent ERK activation by binding to Raf1. Nature Cell Biol. 5, 427-432 (2003).
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).
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).
101. Burack, W. R. & Sturgill, T. W. The activating dual phosphorylation of MARK by MEK is nonprocessive. Biochemistry 36, 5929-5933 (1997).
102. Ferrell, J. E. Jr. Self-perpetuating states in signal transduction: positive feedback, double-negative feedback and testability. Curr. Opin. Cell Biol. 14, 140-148 (2002).
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).
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.
105. Colicelli, J. Human RAS superfamily proteins and related GTPases. Sci. STKE. 2004, RE13 (2004).
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).
107. Garnett, M. J. & Marais, R. Guilty as charged: B-RAF is a human oncogene. Cancer Cell 6, 313-319 (2004).
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).