IκB kinase regulation of the TPL-2/ERK MAPK pathway

Immunological Reviews

Volumn 246, Issue 1, 2012, Pages 168-182

  Gantke, Thorsten ^a   Sriskantharajah, Srividya ^a,b   Sadowski, Michael ^a   Ley, Steven C ^a  

^a NATIONAL INSTITUTE FOR MEDICAL RESEARCH   (United Kingdom)

^b Cellzome Ltd   (United Kingdom)

Author keywords

ABIN 2; IKK; MAPK; NF B1; TLR; TPL 2 COT

Indexed keywords

1,7 NAPHTHYRIDINE 3 CARBONITRILE; ABIN 2 PROTEIN; BINDING PROTEIN; I KAPPA B; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; INDAZOLE DERIVATIVE; MITOGEN ACTIVATED PROTEIN KINASE; ONCOPROTEIN; PROTEIN P105; PROTEIN SERINE THREONINE KINASE INHIBITOR; THIENOPYRIDINE DERIVATIVE; TUMOR PROGRESSION LOCUS 2 PROTEIN; UNCLASSIFIED DRUG;

AUTOIMMUNITY; CANCER GROWTH; CELL NUCLEUS; DRUG TARGETING; ENZYME ACTIVATION; ENZYME PHOSPHORYLATION; ENZYME REGULATION; GENE EXPRESSION; HUMAN; IMMUNE RESPONSE; INFLAMMATION; NONHUMAN; PRIORITY JOURNAL; PROTEIN BINDING; PROTEIN DEGRADATION; PROTEIN FUNCTION; PROTEIN STABILITY; REVIEW; SIGNAL TRANSDUCTION; STOICHIOMETRY;

ADAPTOR PROTEINS, SIGNAL TRANSDUCING; ANIMALS; AUTOIMMUNITY; EXTRACELLULAR SIGNAL-REGULATED MAP KINASES; HUMANS; I-KAPPA B KINASE; INFLAMMATION; MAP KINASE SIGNALING SYSTEM; NEOPLASMS; PHOSPHORYLATION; PROTEIN STABILITY; PROTO-ONCOGENE PROTEINS;

EID: 84858738072     PISSN: 01052896     EISSN: 1600065X     Source Type: Journal    
DOI: 10.1111/j.1600-065X.2012.01104.x     Document Type: Review

References (128)

1. Medzhitov R. Toll-like receptors and innate immunity. Nat Rev Immunol 2001;1:135-145.
2. Kawai T, Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 2010;11:373-384.
3. Medzhitov R, Horng T. Transcriptional control of the inflammatory response. Nat Rev Immunol 2009;9:692-703.
4. Smale ST. Selective transcription in response to an inflammatory stimulus. Cell 2010;140:833-844.
5. Marshall CJ. MAPK kinase kinase, MAPK kinase and MAPK. Curr Opin Gene Dev 1994;4:82-89.
6. Dhillon AS, Hagan S, Rath O, Kolch W. MAPK signalling pathways in cancer. Oncogene 2007;26:3279-3290.
7. Wellbrock C, Karasarides M, Marais R. The Raf proteins take centre stage. Nat Rev Mol Cell Biol 2004;5:875-885.
8. Cantrell DA. GTPase and T cell activation. Immunol Rev 2003;192:122-130.
9. Kurosaki T, Shinohara H, Baba Y. B cell signaling and fate decision. Annu Rev Immunol 2009;28:21-55.
10. Pappin DJ, Hojrup P, Bleasby AJ. Rapid identification of proteins by peptide-mass fingerprinting. Curr Biol 1993;3:327-332.
11. Patriotis C, Makris A, Bear SE, Tsichlis PN. Tumor progression locus 2 (Tpl-2) encodes a protein kinase involved in the progression of rodent T cell lymphomas and in T cell activation. Proc Natl Acad Sci USA 1993;90:2251-2255.
12. Miyoshi J, Higashi T, Mukai H, Ohuchi T, Kakunaga T. Structure and transforming potential of the human cot oncogene encoding a putative protein kinase. Mol Cell Biol 1991;11:4088-4096.
13. Salmeron A, Ahmad TB, Carlile GW, Pappin D, Narsimhan RP, Ley SC. Activation of MEK-1 and SEK-1 by Tpl-2 proto-oncoprotein, a novel MAPK kinase kinase. EMBO J 1996;15:817-826.
14. Chiariello M, Marinissen MJ, Gutkind JS. Multiple mitogen-activated protein kinase signaling pathways connect the Cot oncoprotein to the c-Jun promoter and to cellular transformation. Mol Cell Biol 2000;20:1747-1758.
15. Hagemann D, Troppmair J, Rapp UR. Cot protooncoprotein activates the dual specificity kinases MEK-1 and SEK-1 and induces differentiation of PC12 cells. Oncogene 1999;18:1391-1400.
16. Gantke T, Sriskantharajah S, Ley SC. Regulation and function of TPL-2, an IκB kinase-regulated MAPK kinase kinase. Cell Res 2010;21:131-145.
17. Dumitru CD, et al. TNFα induction by LPS is regulated post-transcriptionally via a TPL2/ERK-dependent pathway. Cell 2000;103:1071-1083.
18. Beinke S, Robinson MJ, Salmeron A, Hugunin M, Allen H, Ley SC. Lipopolysaccharide activation of the TPL-2/MEK/Extracellular signal-regulated kinase mitogen-activated protein kinase cascade is regulated by IκB kinase-induced proteolysis of NF-κB1 p105. Mol Cell Biol 2004;24:9658-9667.
19. Waterfield M, Jin W, Reiley W, Zhang MY, Sun S-C. IKKβ is an essential component of the TPL-2 signaling pathway. Mol Cell Biol 2004;24:6040-6048.
20. Eliopoulos AG, Wang C-C, Dumitru CD, Tsichlis PN. TPL-2 transduces CD40 and TNF signals that activate ERK and regulates IgE induction by CD40. EMBO J 2003;22:3855-3864.
21. Kaiser F, et al. TPL-2 negatively regulates interferon-beta production in macrophages and myeloid dendritic cells. J Exp Med. 2009; 206:1863-1871.
22. Mielke LA, et al. Tumor progression locus 2 (Map3k8) is critical for host defense against Listeria monocytogenes and IL-1 production. J Immunol 2009;183:7984-7993.
23. Banerjee A, Gugasyan R, McMahon M, Gerondakis S. Diverse Toll-like receptors utilize Tpl2 to activate extracellular signal-regulated kinase (ERK) in hemopoietic cells. Proc Natl Acad Sci USA 2006;103:3274-3279.
24. Das S, et al. Tpl2/Cot signals activate ERK, JNK and NF-κB in a cell-type and stimulus-specific manner. J Biol Chem 2005;280:23748-23757.
25. Belich MP, Salmeron A, Johnston LH, Ley SC. TPL-2 kinase regulates the proteolysis of the NF-κB inhibitory protein NF-κB1 p105. Nature 1999;397:363-368.
26. Lang V, et al. ABIN-2 forms a ternary complex with TPL-2 and NF-κB1 p105 and is essential for TPL-2 protein stability. Mol Cell Biol 2004;24:5235-5248.
27. Yang HT, et al. NF-κB1 inhibits TLR-induced IFN-β production in macrophages through TPL-2-dependent ERK activation. J Immunol.2011; 186:1989-1996.
28. Waterfield MR, Zhang M, Norman LP, Sun S-C. NF-κB1/p105 regulates lipopolysaccharide-stimulated MAPK signaling by governing the stability and function of the TPL-2 kinase. Mol Cell 2003;11:685-694.
29. Beinke S, et al. NF-κB p105 negatively regulates TPL-2 MEK kinase activity. Mol Cell Biol 2003;23:4739-4752.
30. Savinova OV, Hoffmann A, Ghosh G. The Nfkb1 and Nfkb2 proteins p105 and p100 function as the core of high-molecular-weight heterogeneous complexes. Mol Cell 2009;34:591-602.
31. Lang V, et al. βTrCP-mediated proteolysis of NF-κB1 p105 requires phosphorylation of p105 serines 927 and 932. Mol Cell Biol 2003;23:402-413.
32. Salmeron A, et al. Direct phosphorylation of NF-κB p105 by the IκB kinase complex on serine 927 is essential for signal-induced p105 proteolysis. J Biol Chem 2001;276:22215-22222.
33. Heissmeyer V, Krappmann D, Wulczyn FG, Scheidereit C. NF-κB p105 is a target of IκB kinases and controls signal induction of BCL-3-p50 complexes. EMBO J 1999;18:4766-4788.
34. βTrCP ubiquitin ligase-mediated processing of NF-κB p105 requires phosphorylation of its C-terminus by IκB kinase. EMBO J 2000;19:2580-2591.
35. Kanarek N, Ben-Neriah Y. Regulation of NF-κB by ubiquitination and degradation of the IκBs. Immunol Rev 2012;246:77-94.
36. Verstrepen L, Carpentier I, Verhelst K, Beyaert R. ABINs: A20 binding inhibitors of NF-kappa B and apoptosis signaling. Biochem Pharmacol 2009;78:105-114.
37. Komander D, Reyes-Turcu F, Licchesi JD, Odenwaelder P, Wilkinson KD, Barford D. Molecular discrimination of structurally equivalent Lys 63-linked and linear polyubiquitin chains. EMBO Rep 2009;10:466-473.
38. Papoutsopoulou S, et al. ABIN-2 is required for optimal activation of the TPL-2/ERK MAPK pathway in innate immune responses. Nat Immunol 2006;7:606-615.
39. Handoyo H, Stafford MJ, McManus E, Baltzis D, Peggie M, Cohen P. IRAK1-independent pathways required for the interleukin 1-stimulated activation of the TPL-2 catalytic subunit and its dissociation from ABIN-2. Biochem J 2009;424:109-118.
40. Babu GR, et al. Phosphorylation of NF-κB1/p105 by oncoprotein kinase Tpl2: implications for a novel mechanism of Tpl2 regulation. Biochim Biophys Acta 2006;1763:174-181.
41. Robinson MJ, Beinke S, Kouroumalis A, Tsichlis PN, Ley SC. Phosphorylation of TPL-2 on serine 400 is essential for lipopolysaccharide activation of extracellular signal-regulated kinase in macrophages. Mol Cell Biol 2007;27:7355-7364.
42. Cohen P. Targeting protein kinases for the development of anti-inflammatory drugs. Curr Opin Cell Biol 2009;21:1-8.
43. Luciano BS, Hsu S, Channavajhala PL, Lin L-L, Cuozzo JW. Phoshorylation of threonine 290 in the activation loop of Tpl2/Cot is necessary but not sufficient for kinase activity. J Biol Chem 2004;279:52117-52123.
44. Cho J, Melnick M, Solidakis GP, Tsichlis PN. Tpl2 (Tumor Progression Locus 2) phosphorylation at Thr290 is induced by lipopolysaccharide via an IκB kinase-β-dependent pathway and is required for Tpl2 activation by external signals. J Biol Chem 2005;280:20442-20448.
45. Nolen B, Taylor S, Ghosh G. Regulation of protein kinases: controlling activity through activation segment conformation. Mol Cell 2004;15:661-675.
46. Symons A, Beinke S, Ley SC. MAPK kinase kinases and innate immunity. Trends Immunol 2006;27:40-48.
47. Yang J, Cron P, Good VM, Thompson V, Hemmings BA, Barford D. Crystal structure of an activated Akt/protein kinase B ternary complex with GSK3-peptide and AMP-PNP. Nat Struct Biol 2002;9:940-944.
48. Mieulet V, et al. TPL-2-mediated activation of MAPK downstream of TLR4 signaling is coupled to arginine availability. Sci Signaling 2010;3:1-8.
49. Yan L, Lamb RF. Signalling by amino acid nutrients. Biochem Soc Trans 2011;39:443-445.
50. Morris SM. Arginine: master and commander in innate immune responses. Sci Signaling 2010;3:pe27.
51. Rousseau S, et al. TPL2-mediated activation of ERK1 and ERK2 regulates the processing of pre-TNF alpha in LPS-stimulated macrophages. J Cell Sci 2008;121:149-154.
52. Stow JL, Low PC, Offenhauser C, Sangermani D. Cytokine secretion in macrophages and other cells: pathways and mediators. Immunobiology 2009;214:601-612.
53. Liu C, Xu P, Lamouille S, Xu J, Derynck R. TACE-mediated ectodomain shedding of the type I TGF-β receptor downregulates TGF-β signaling. Mol Cell 2009;35:26-36.
54. Soond SM, Everson B, Riches DWH, Murphy G. ERK-mediated phosphorylation of Thr735 in TNFα-converting enzyme and its potential role in TACE protein trafficking. J Cell Sci 2005;118:2371-2380.
55. Tomczak MF, et al. Defective activation of ERK in macrophages lacking the p50/p105 Subunit of NF-kB Is responsible for elevated expression of IL-12 p40 observed after challenge with Helicobacter hepaticus. J Immunol 2006;176:1244-1251.
56. Kontoyiannis D, et al. Genetic dissection of the cellular pathways and signaling mechanisms in modeled tumor necrosis factor-induced Crohn's-like inflammatory bowel disease. J Exp Med 2002;196:1563-1574.
57. Kontoyiannis D, Pasparakis M, Pizarro TT, Cominelli F, Kollias G. Impaired on/off regulation of TNF biosynthesis in mice lacking TNF AU-rich elements: implications for joint and gut-associated immunopathologies. Immunity 1999;10:387-398.
58. Perfield JW, et al. Tumor progression locus 2 (TPL2) regulates obesity-associated inflammation and insulin resistance. Diabetes 2011;60:1168-1176.
59. Rothe J, et al. Mice lacking tumour necrosis factor receptor 1 are resistant to TNF-mediated toxicity but highly susceptible to infection by Listeria monocytogenes. Nature 1993;364:798-802.
60. Gringhuis SI, et al. Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-κB activation through Raf-1 and Syk. Nat Immunol 2009;10:203-213.
61. Havell EA, Moldawer LI, Halfgott D, Kilian PL, Sehgal PB. Type I IL-1 receptor blockade exacerbates murine listeriosis. J Immunol 1992;148:1486-1492.
62. Rogers HW, Sheehan KCF, Brunt LM, Dower SK, Unanue ER, Schreiber RD. Interleukin 1 participates in the development of anti-listerial responses in normal and SCID mice. Proc Natl Acad Sci USA 1992;89:1011-1015.
63. Watford WT, et al. Ablation of tumor progression locus 2 promotes a type 2 Th cell response in ovalbumin-immunized mice. J Immunol 2009;184:105-113.
64. Watford WT, et al. Tpl2 kinase regulates T cell interferon-γ production and host resistance to Toxoplasma gondii. J Exp Med 2008;205:2803-2812.
65. Glimcher LH, Murphy KM. Lineage commitment in the immune system: the T helper lymphocyte grows up. Genes Dev 2000;14:1693-1711.
66. Yap GS, Sher A. Cell-mediated immunity to Toxoplasma gondii: initiation, regulation and effector function. Immunobiology 1999;201:240-247.
67. Sugimoto K, et al. A serine/threonine kinase, Cot/Tpl2, modulates bacterial DNA-induced IL-12 production and Th cell differentiation. J Clin Invest 2004;114:857-866.
68. De Gregorio E, D'Oro U, Wack A. Immunology of TLR-independent vaccine adjuvants. Curr Opin Immunol 2009;21:339-345.
69. Kakimoto K, Musikacharoen T, Chiba N, Bandow K, Ohnishi T, Matsuguchi T. Cot/Tpl2 regulates IL-23 p19 expression in LPS-stimulated macrophages through ERK activation. J Physiol Biochem 2010;66:47-53.
70. Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector functions of TH17 cells. Nat Rev Immunol 2008;453:1051-1057.
71. Erny KM, Peli J, Lambert J-F, Muller V, Diggelmann H. Involvement of the TPL-2/COT oncogene in MMTV tumorigenesis. Oncogene 1996;13:2015-2020.
72. Ceci JD, et al. TPL-2 is an oncogenic kinase that is activated by carboxy-terminal truncation. Gene Dev 1997;11:688-700.
73. Gandara ML, Lopez P, Hernando R, Castano JG, Alemany S. The COOH-terminal domain of wild-type Cot regulates its stability and kinase specific activity. Mol Cell Biol 2003;23:7377-7390.
74. Vougioukalaki M, Kanellis DC, Gkouskou K, Eliopoulos AG. Tpl2 kinase signal transduction in inflammation and cancer. Cancer Lett 2011;304:80-89.
75. Ding L, et al. Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 2010;464:999-1005.
76. Parsons DW, et al. An integrated genomic analysis of human glioblastoma multiforme. Science. 2008; 321:1807-1812.
77. Clark AM, Reynolds SH, Anderson M, Wiest JS. Mutational activation of the MAP3K8 proto-oncogene in lung cancer. Genes Chromosom Cancer 2004;41:99-108.
78. Christoforidou AV, Papadaki HA, Margioris AN, Eliopoulos AG, Tsatsanis C. Expression of the Tpl2/Cot oncogene in human T-cell neoplasias. Mol Cancer 2004;3:34.
79. Sourvinos G, Tsichlis PN, Spandidos DA. Overexpression of the Tpl-2/Cot oncogene in human breast cancer. Oncogene 1999;18:4968-4973.
80. Eliopoulos AG, et al. The oncogenic protein kinase Tpl-2/Cot contributes to Epstein-Barr virus-encoded later infection membrane protein 1-induced NF-κB signaling downstream of TRAF2. J Virol 2002;76:4567-4579.
81. Fernandez M, Manso R, Bernaldez F, Lopez P, Martin-Duce A, Alemany S. Involvement of Cot activity in the proliferation of ALCL lymphoma cells. Biochem Biophys Res Commun 2011;411:655-660.
82. Johannessen CM, et al. COT drives resistance to RAF inhibition through MAPK pathway reactivation. Nature 2010;468:968-972.
83. Babu G, Waterfield M, Chang M, Wu X, Sun S-C. Deregulated activation of oncoprotein kinase Tpl2/Cot in HTLV-1-transformed T cells. J Biol Chem 2006;281:14041-14047.
84. DeCicco-Skinner KL, Trovato EL, Simmons JK, Lepage PK, Wiest JS. Loss of tumor progression locus 2 (tpl2) enhances tumorgenesis and inflammation in two-stage skin carcinogenesis. Oncogene 2010;30:389-397.
85. Tsatsanis C, et al. Tpl2 and ERK transduce anti-proliferative T cell receptor signals and inhibit transformation of chronically stimulated T cells. Proc Natl Acad Sci USA 2008;105:2987-2992.
86. Staudt LM. Oncogenic activation of NF-κB. Cold Spring Harb Perspect Biol. 2010; 2(6):a000109.
87. Annunziata CM, et al. A mechanistic rationale for MEK inhibitor therapy in myeloma based on blockade of MAF oncogene expression. Blood 2011;117:2396-2404.
88. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation and cancer. Cell 2010;140:883-899.
89. Aggarwal BB, Vijayalekshmi RV, Sung B. Targeting inflammatory pathways for prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer Res 2009;15:425-430.
90. Greten FR, et al. IKKβ links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell 2004;118:285-296.
91. Ben-Neriah Y, Karin M. Inflammation meets cancer, with NF-κB as the matchmaker. Nat Immunol 2011;12:715-723.
92. Mantovani A, Sica A. Macrophages, innate immunity and cancer: balance, tolerance and diversity. Curr Opin Immunol 2010;22:231-237.
93. Hagemann T, et al. 'Re-educating' tumor-associated macrophages by targeting NF-κB. J Exp Med 2008;205:1261-1268.
94. Porta C, et al. Tolerance and M2 (alternative) macrophage polarization are related processes orchestrated by p50 nuclear factor κB. Proc Natl Acad Sci USA 2009;106:14978-14983.
95. Saccani A, et al. p50 nuclear factor kappa B overexpression in tumor-associated macrophages inhibits M1 inflammatory responses and antitumor reesistance. Cancer Res. 2006; 66:11432-11440.
96. Lopez-Pelaez M, Soria Castro I, Bosca L, Fernandez M, Alemany S. Cot/Tpl2 activity is required for TLR-induced activation of the Akt p70 S6K pathway in macrophages: implications for NO synthase 2 expression. Eur J Immunol 2011;41:1733-1741.
97. Maeda S, Kamata H, Leffert H, Karin M. IKK-β couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell 2005;121:977-990.
98. Apostolaki M, Armaka M, Victoratos P, Kollias G. Cellular mechanisms of TNF function in models of inflammation and autoimmunity. Curr Dir Autoimmun 2010;11:1-26.
99. Strand V, Kimberly R, Isaacs JD. Biologic therapies in rheumatology: lessons learned, future directions. Nat Rev Drug Discov 2007;6:75-92.
100. Hanauer SB, et al. Maintenance infliximab for Crohn's disease: the ACCENT I randomised trial. Lancet 2002;359:1541-1549.
101. Scholl FA, et al. MEK1/2 MAPK kinases are essential for mammalian development, homeostasis, and Raf-induced hyperplasia. Dev Cell 2007;12:615-629.
102. Manning G, Whyte DB, Martinez R, Hunter T, Sudarsanam S. The protein kinase complement of the human genome. Science. 2002; 298:1912-1934.
103. Adams JA. Kinetic and catalytic mechanisms of protein kinases. Chem Rev. 2001; 101:2271-2290.
104. Cohen P. Protein kinases - the major drugs targets of the twenty-first century? Nat Rev Drug Discov 2002;1:309-315.
105. Jia Y, et al. Purification and kinetic characterization of recombinant human mitogen-activated protein kinase kinase kinase COT and the complexes with its cellular partner NF-κB1 p105. Arch Biochem Biophys 2005;441:64-74.
106. George D, Salmeron A. Cot/TPL-2 protein kinase as a target for the treatment of inflammatory disease. Curr Topics Med Chem 2009;9:611-622.
107. Hu Y, et al. Discovery of indazoles as inhibitors of TPL-2 kinase. Bioorg Med Chem Lett 2011;21:4758-4761.
108. George D, et al. Discovery of thieno [2, 3-c]pyridines as potent COT inhibitors. Bioorg Med Chem Lett 2008;18:4952-4955.
109. Hall JP, et al. Pharmacologic inhibition of TPL-2 blocks inflammatory responses in primary human monocytes, synoviocytes, and blood. J Biol Chem 2007;282:33295-33304.
110. Hu Y, et al. Inhibition of Tpl2 kinase and TNFα production with quinoline-3-carbonitriles for the treatment of rheumatoid arthritis. Bioorg Med Chem Lett 2006;16:6067-6072.
111. Janeway CA, Medzhitov R. Innate immune recognition. Annu Rev Immunol 2002;20:197-216.
112. Hatziapostolou M, et al. Tumor progression locus 2 mediates signal-induced increases in cytoplasmic calcium and cell migration. Sci Signal. 2011; 4(187):ra55.
113. Kane LP, Mollenauer MN, Xu Z, Turck CW, Weiss A. Akt-dependent phosphorylation specifically regulates Cot induction of NF-κB-dependent transcription. Mol Cell Biol 2002;22:5962-5974.
114. Dong D, et al. A20, ABIN-1/2 and CARD11 mutations and their prognostic value in gastointestinal diffuse large B-cell lymphomas. Clin Cancer Res 2011;17:1440-1451.
115. Compagno M, et al. Mutations of multiple genes cause deregulation of NF-κB in diffuse large B-cell lymphoma. Nature 2009;459:717-721.
116. Karin M, Yamamoto Y, Wang QM. The IKK NF-κB system: a treasure trove for drug development. Nat Rev Drug Discov 2004;3:17-26.
117. DiDonato JA, Mercurio F, Karin M. NF-jB and the link between inflammation and cancer. Immunol Rev 2012;246:379-400.
118. Greten FR, et al. NF-κB is a negative regulator of IL-1β secretion as revealed by genetic and pharmacological inhibition of IKKβ. Cell 2007;130:918-931.
119. Fong CHY, et al. An anti-inflammatory role for IKKβ through inhibition of 'classical' macrophage activation. J Exp Med 2008;205:1269-1276.
120. Record CJ, et al. Structural comparison of human mammalian ste20-like kinases. PLoS ONE. 2010; 5:e11905.
121. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol 1990;215:403-410.
122. Papadopoulos JS, Agarwala R. COBALT: constraint-based alignment tool for multiple protein sequences. Bioinformatics 2007;23:1073-1079.
123. Sali A, Blundell TL. Comparative protein modelling by satisfaction of spatial restraints. J Mol Biol 1993;234:779-815.
124. DeLano WL. The PyMOL User's Manual. San Carlos, CA, USA: DeLano Scientific, 2002.
125. Stafford MJ, Morrice N, Peggie MW, Cohen P. Interleukin-1 stimulated activation of the COT catalytic subunit through the phosphorylation of Thr290 and Ser62. FEBS Lett 2006;580:4010-4014.
126. Black TM, Andrews CL, Kilili G, Ivan M, Tsichlis PN, Vouros P. Characterization of phosphorylation sites on Tpl2 using IMAC enrichment and a linear ion trap mass spectrometer. J Proteome Res 2007;6:2269-2276.
127. Weintz G, et al. The phosphoproteome of toll-like receptor-activated macrophages. Mol Syst Biol 2010;6:371.
128. Cho J, Tsichlis PN. Phosphorylation at T290 regulates Tpl2 binding to NF-jB1/p105 and Tpl2 activation and degradation by lipopolysaccharide. Proc Natl Acad Sci USA 2005;102:2350-2355.