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. 2010 Feb 23;1(3):218–226. doi: 10.1007/s13238-010-0019-9

MAPK signaling in inflammation-associated cancer development

Pengyu Huang 1, Jiahuai Han 2,✉, Lijian Hui 1,✉
PMCID: PMC4875080  PMID: 21203968

Abstract

Mitogen-activated protein (MAP) kinases comprise a family of protein-serine/threonine kinases, which are highly conserved in protein structures from unicellular eukaryotic organisms to multicellular organisms, including mammals. These kinases, including ERKs, JNKs and p38s, are regulated by a phosphorelay cascade, with a prototype of three protein kinases that sequentially phosphorylate one another. MAPKs transduce extracellular signals into a variety of cellular processes, such as cell proliferation, survival, death, and differentiation. Consistent with their essential cellular functions, MAPKs have been shown to play critical roles in embryonic development, adult tissue homeostasis and various pathologies. In this review, we discuss recent findings that reveal the profound impact of these pathways on chronic inflammation and, particularly, inflammation-associated cancer development.

Contributor Information

Jiahuai Han, Email: jhan@xmu.edu.cn.

Lijian Hui, Email: ljhui@sibs.ac.cn.

References

  1. Adams R.H., Porras A., Alonso G., Jones M., Vintersten K., Panelli S., Valladares A., Perez L., Klein R., Nebreda A.R. Essential role of p38alpha MAP kinase in placental but not embryonic cardiovascular development. Mol Cell. 2000;6:109–116. doi: 10.1016/S1097-2765(05)00014-6. [DOI] [PubMed] [Google Scholar]
  2. Allen M., Svensson L., Roach M., Hambor J., McNeish J., Gabel C.A. Deficiency of the stress kinase p38alpha results in embryonic lethality: characterization of the kinase dependence of stress responses of enzyme-deficient embryonic stem cells. J Exp Med. 2000;191:859–870. doi: 10.1084/jem.191.5.859. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Assi K., Pillai R., Gomez-Munoz A., Owen D., Salh B. The specific JNK inhibitor SP600125 targets tumour necrosis factor-alpha production and epithelial cell apoptosis in acute murine colitis. Immunology. 2006;118:112–121. doi: 10.1111/j.1365-2567.2006.02349.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Balkwill F., Mantovani A. Inflammation and cancer: back to Virchow. Lancet. 2001;357:539–545. doi: 10.1016/S0140-6736(00)04046-0. [DOI] [PubMed] [Google Scholar]
  5. Bost F., Aouadi M., Caron L., Even P., Belmonte N., Prot M., Dani C., Hofman P., Pages G., Pouyssegur J. The extracellular signal-regulated kinase isoform ERK1 is specifically required for in vitro and in vivo adipogenesis. Diabetes. 2005;54:402–411. doi: 10.2337/diabetes.54.2.402. [DOI] [PubMed] [Google Scholar]
  6. Boutros T., Chevet E., Metrakos P. Mitogen-activated protein (MAP) kinase/MAP kinase phosphatase regulation: roles in cell growth, death, and cancer. Pharmacol Rev. 2008;60:261–310. doi: 10.1124/pr.107.00106. [DOI] [PubMed] [Google Scholar]
  7. Brancho D., Tanaka N., Jaeschke A., Ventura J.J., Kelkar N., Tanaka Y., Kyuuma M., Takeshita T., Flavell R.A., Davis R. J. Mechanism of p38 MAP kinase activation in vivo. Genes Dev. 2003;17:1969–1978. doi: 10.1101/gad.1107303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bulavin D.V., Phillips C., Nannenga B., Timofeev O., Donehower L. A., Anderson C.W., Appella E., Fornace A.J., Jr. Inactivation of the Wip1 phosphatase inhibits mammary tumorigenesis through p38 MAPK-mediated activation of the p16(Ink4a)-p19(Arf) pathway. Nat Genet. 2004;36:343–350. doi: 10.1038/ng1317. [DOI] [PubMed] [Google Scholar]
  9. Chambard J.C., Lefloch R., Pouyssegur J., Lenormand P. ERK implication in cell cycle regulation. Biochim Biophys Acta. 2007;1773:1299–1310. doi: 10.1016/j.bbamcr.2006.11.010. [DOI] [PubMed] [Google Scholar]
  10. Chang L., Kamata H., Solinas G., Luo J.L., Maeda S., Venuprasad K., Liu Y.C., Karin M. The E3 ubiquitin ligase itch couples JNK activation to TNFalpha-induced cell death by inducing c-FLIP(L) turnover. Cell. 2006;124:601–613. doi: 10.1016/j.cell.2006.01.021. [DOI] [PubMed] [Google Scholar]
  11. Chang Q., Zhang Y., Beezhold K.J., Bhatia D., Zhao H., Chen J., Castranova V., Shi X., Chen F. Sustained JNK1 activation is associated with altered histone H3 methylations in human liver cancer. J Hepatol. 2009;50:323–333. doi: 10.1016/j.jhep.2008.07.037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Chen F., Castranova V. Beyond apoptosis of JNK1 in liver cancer. Cell Cycle. 2009;8:1145–1147. doi: 10.4161/cc.8.8.8200. [DOI] [PubMed] [Google Scholar]
  13. Cho Y.S., Challa S., Moquin D., Genga R., Ray T.D., Guildford M., Chan F.K. Phosphorylation-driven assembly of the RIP1-RIP3 complex regulates programmed necrosis and virusinduced inflammation. Cell. 2009;137:1112–1123. doi: 10.1016/j.cell.2009.05.037. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Chromik A.M., Muller A.M., Korner J., Belyaev O., Holland-Letz T., Schmitz F., Herdegen T., Uhl W., Mittelkotter U. Genetic deletion of JNK1 and JNK2 aggravates the DSS-induced colitis in mice. J Invest Surg. 2007;20:23–33. doi: 10.1080/08941930601126140. [DOI] [PubMed] [Google Scholar]
  15. Corcelle E., Nebout M., Bekri S., Gauthier N., Hofman P., Poujeol P., Fenichel P., Mograbi B. Disruption of autophagy at the maturation step by the carcinogen lindane is associated with the sustained mitogen-activated protein kinase/extracellular signal-regulated kinase activity. Cancer Res. 2006;66:6861–6870. doi: 10.1158/0008-5472.CAN-05-3557. [DOI] [PubMed] [Google Scholar]
  16. Das M., Sabio G., Jiang F., Rincon M., Flavell R.A., Davis R.J. Induction of hepatitis by JNK-mediated expression of TNF-alpha. Cell. 2009;136:249–260. doi: 10.1016/j.cell.2008.11.017. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Degterev A., Hitomi J., Germscheid M., Ch’en I.L., Korkina O., Teng X., Abbott D., Cuny G.D., Yuan C., Wagner G. Identification of RIP1 kinase as a specific cellular target of necrostatins. Nat Chem Biol. 2008;4:313–321. doi: 10.1038/nchembio.83. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Dong C., Yang D.D., Tournier C., Whitmarsh A.J., Xu J., Davis R. J., Flavell R.A. JNK is required for effector T-cell function but not for T-cell activation. Nature. 2000;405:91–94. doi: 10.1038/35011091. [DOI] [PubMed] [Google Scholar]
  19. Dumesic P.A., Scholl F.A., Barragan D.I., Khavari P.A. Erk1/2 MAP kinases are required for epidermal G2/M progression. J Cell Biol. 2009;185:409–422. doi: 10.1083/jcb.200804038. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Eferl R., Wagner E.F. AP-1: a double-edged sword in tumorigenesis. Nat Rev Cancer. 2003;3:859–868. doi: 10.1038/nrc1209. [DOI] [PubMed] [Google Scholar]
  21. Fuchs S.Y., Dolan L., Davis R.J., Ronai Z. Phosphorylation-dependent targeting of c-Jun ubiquitination by Jun N-kinase. Oncogene. 1996;13:1531–1535. [PubMed] [Google Scholar]
  22. Ge B., Gram H., Di Padova F., Huang B., New L., Ulevitch R.J., Luo Y., Han J. MAPKK-independent activation of p38alpha mediated by TAB1-dependent autophosphorylation of p38alpha. Science. 2002;295:1291–1294. doi: 10.1126/science.1067289. [DOI] [PubMed] [Google Scholar]
  23. Guerra C., Schuhmacher A.J., Canamero M., Grippo P.J., Verdaguer L., Perez-Gallego L., Dubus P., Sandgren E.P., Barbacid M. Chronic pancreatitis is essential for induction of pancreatic ductal adenocarcinoma by K-Ras oncogenes in adult mice. Cancer Cell. 2007;11:291–302. doi: 10.1016/j.ccr.2007.01.012. [DOI] [PubMed] [Google Scholar]
  24. Han J., Sun P. The pathways to tumor suppression via route p38. Trends Biochem Sci. 2007;32:364–371. doi: 10.1016/j.tibs.2007.06.007. [DOI] [PubMed] [Google Scholar]
  25. Hasselblatt P., Rath M., Komnenovic V., Zatloukal K., Wagner E.F. Hepatocyte survival in acute hepatitis is due to c-Jun/AP-1-dependent expression of inducible nitric oxide synthase. Proc Natl Acad Sci U S A. 2007;104:17105–17110. doi: 10.1073/pnas.0706272104. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Hatano N., Mori Y., Oh-hora M., Kosugi A., Fujikawa T., Nakai N., Niwa H., Miyazaki J., Hamaoka T., Ogata M. Essential role for ERK2 mitogen-activated protein kinase in placental development. Genes Cells. 2003;8:847–856. doi: 10.1046/j.1365-2443.2003.00680.x. [DOI] [PubMed] [Google Scholar]
  27. He S., Wang L., Miao L., Wang T., Du F., Zhao L., Wang X. Receptor interacting protein kinase-3 determines cellular necrotic response to TNF-alpha. Cell. 2009;137:1100–1111. doi: 10.1016/j.cell.2009.05.021. [DOI] [PubMed] [Google Scholar]
  28. Heinrichsdorff J., Luedde T., Perdiguero E., Nebreda A.R., Pasparakis M. p38 alpha MAPK inhibits JNK activation and collaborates with IkappaB kinase 2 to prevent endotoxin-induced liver failure. EMBO Rep. 2008;9:1048–1054. doi: 10.1038/embor.2008.149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Hotchkiss R.S., Strasser A., McDunn J.E., Swanson P.E. Cell death. N Engl J Med. 2009;361:1570–1583. doi: 10.1056/NEJMra0901217. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Hui L., Bakiri L., Mairhorfer A., Schweifer N., Haslinger C., Kenner L., Komnenovic V., Scheuch H., Beug H., Wagner E.F. p38alpha suppresses normal and cancer cell proliferation by antagonizing the JNK-c-Jun pathway. Nat Genet. 2007;39:741–749. doi: 10.1038/ng2033. [DOI] [PubMed] [Google Scholar]
  31. Hui L., Bakiri L., Stepniak E., Wagner E.F. p38alpha: a suppressor of cell proliferation and tumorigenesis. Cell Cycle. 2007;6:2429–2433. doi: 10.4161/cc.6.20.4774. [DOI] [PubMed] [Google Scholar]
  32. Hui L., Zatloukal K., Scheuch H., Stepniak E., Wagner E.F. Proliferation of human HCC cells and chemically induced mouse liver cancers requires JNK1-dependent p21 downregulation. J Clin Invest. 2008;118:3943–3953. doi: 10.1172/JCI37156. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Jaeschke A., Karasarides M., Ventura J.J., Ehrhardt A., Zhang C., Flavell R.A., Shokat K.M., Davis R.J. JNK2 is a positive regulator of the cJun transcription factor. Mol Cell. 2006;23:899–911. doi: 10.1016/j.molcel.2006.07.028. [DOI] [PubMed] [Google Scholar]
  34. Jeffrey K.L., Brummer T., Rolph M.S., Liu S.M., Callejas N.A., Grumont R.J., Gillieron C., Mackay F., Grey S., Camps M. Positive regulation of immune cell function and inflammatory responses by phosphatase PAC-1. Nat Immunol. 2006;7:274–283. doi: 10.1038/ni1310. [DOI] [PubMed] [Google Scholar]
  35. Kang Y.J., Chen J., Otsuka M., Mols J., Ren S., Wang Y., Han J. Macrophage deletion of p38alpha partially impairs lipopolysaccharide-induced cellular activation. J Immunol. 2008;180:5075–5082. doi: 10.4049/jimmunol.180.7.5075. [DOI] [PubMed] [Google Scholar]
  36. Keyse S.M. Dual-specificity MAP kinase phosphatases (MKPs) and cancer. Cancer Metastasis Rev. 2008;27:253–261. doi: 10.1007/s10555-008-9123-1. [DOI] [PubMed] [Google Scholar]
  37. Kim C., Sano Y., Todorova K., Carlson B.A., Arpa L., Celada A., Lawrence T., Otsu K., Brissette J.L., Arthur J.S. The kinase p38 alpha serves cell type-specific inflammatory functions in skin injury and coordinates pro- and anti-inflammatory gene expression. Nat Immunol. 2008;9:1019–1027. doi: 10.1038/ni.1640. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Kotlyarov A., Neininger A., Schubert C., Eckert R., Birchmeier C., Volk H.D., Gaestel M. MAPKAP kinase 2 is essential for LPS-induced TNF-alpha biosynthesis. Nat Cell Biol. 1999;1:94–97. doi: 10.1038/10061. [DOI] [PubMed] [Google Scholar]
  39. Kuan C.Y., Yang D.D., Samanta Roy D.R., Davis R.J., Rakic P., Flavell R.A. The Jnk1 and Jnk2 protein kinases are required for regional specific apoptosis during early brain development. Neuron. 1999;22:667–676. doi: 10.1016/S0896-6273(00)80727-8. [DOI] [PubMed] [Google Scholar]
  40. Lang R., Hammer M., Mages J. DUSP meet immunology: dual specificity MAPK phosphatases in control of the inflammatory response. J Immunol. 2006;177:7497–7504. doi: 10.4049/jimmunol.177.11.7497. [DOI] [PubMed] [Google Scholar]
  41. Lawler S., Fleming Y., Goedert M., Cohen P. Synergistic activation of SAPK1/JNK1 by two MAP kinase kinases in vitro. Curr Biol. 1998;8:1387–1390. doi: 10.1016/S0960-9822(98)00019-0. [DOI] [PubMed] [Google Scholar]
  42. Lei K., Nimnual A., Zong W.X., Kennedy N.J., Flavell R.A., Thompson C.B., Bar-Sagi D., Davis R.J. The Bax subfamily of Bcl2-related proteins is essential for apoptotic signal transduction by c-Jun NH(2)-terminal kinase. Mol Cell Biol. 2002;22:4929–4942. doi: 10.1128/MCB.22.13.4929-4942.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Maeda S., Chang L., Li Z.W., Luo J.L., Leffert H., Karin M. IKKbeta is required for prevention of apoptosis mediated by cell-bound but not by circulating TNFalpha. Immunity. 2003;19:725–737. doi: 10.1016/S1074-7613(03)00301-7. [DOI] [PubMed] [Google Scholar]
  44. Maeda S., Kamata H., Luo J.L., Leffert H., Karin M. IKKbeta couples hepatocyte death to cytokine-driven compensatory proliferation that promotes chemical hepatocarcinogenesis. Cell. 2005;121:977–990. doi: 10.1016/j.cell.2005.04.014. [DOI] [PubMed] [Google Scholar]
  45. Manning A.M., Davis R.J. Targeting JNK for therapeutic benefit: from junk to gold. Nat Rev Drug Discov. 2003;2:554–565. doi: 10.1038/nrd1132. [DOI] [PubMed] [Google Scholar]
  46. Mantovani A., Allavena P., Sica A., Balkwill F. Cancerrelated inflammation. Nature. 2008;454:436–444. doi: 10.1038/nature07205. [DOI] [PubMed] [Google Scholar]
  47. Mathew R., Karantza-Wadsworth V., White E. Role of autophagy in cancer. Nat Rev Cancer. 2007;7:961–967. doi: 10.1038/nrc2254. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Mazzucchelli C., Vantaggiato C., Ciamei A., Fasano S., Pakhotin P., Krezel W., Welzl H., Wolfer D.P., Pages G., Valverde O. Knockout of ERK1 MAP kinase enhances synaptic plasticity in the striatum and facilitates striatal-mediated learning and memory. Neuron. 2002;34:807–820. doi: 10.1016/S0896-6273(02)00716-X. [DOI] [PubMed] [Google Scholar]
  49. Mebratu Y., Tesfaigzi Y. How ERK1/2 activation controls cell proliferation and cell death: Is subcellular localization the answer. Cell Cycle. 2009;8:1168–1175. doi: 10.4161/cc.8.8.8147. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Mitsuyama K., Suzuki A., Tomiyasu N., Tsuruta O., Kitazaki S., Takeda T., Satoh Y., Bennett B.L., Toyonaga A., Sata M. Pro-inflammatory signaling by Jun-N-terminal kinase in inflammatory bowel disease. Int J Mol Med. 2006;17:449–455. [PubMed] [Google Scholar]
  51. Mudgett J.S., Ding J., Guh-Siesel L., Chartrain N.A., Yang L., Gopal S., Shen M.M. Essential role for p38alpha mitogen-activated protein kinase in placental angiogenesis. Proc Natl Acad Sci U S A. 2000;97:10454–10459. doi: 10.1073/pnas.180316397. [DOI] [PMC free article] [PubMed] [Google Scholar]
  52. Pages G., Guerin S., Grall D., Bonino F., Smith A., Anjuere F., Auberger P., Pouyssegur J. Defective thymocyte maturation in p44 MAP kinase (Erk 1) knockout mice. Science. 1999;286:1374–1377. doi: 10.1126/science.286.5443.1374. [DOI] [PubMed] [Google Scholar]
  53. Patterson K.I., Brummer T., O’Brien P.M., Daly R.J. Dual-specificity phosphatases: critical regulators with diverse cellular targets. Biochem J. 2009;418:475–489. doi: 10.1042/BJ20082234. [DOI] [PubMed] [Google Scholar]
  54. Pearson G., Robinson F., Beers Gibson T., Xu B.E., Karandikar M., Berman K., Cobb M.H. Mitogen-activated protein (MAP) kinase pathways: regulation and physiological functions. Endocr Rev. 2001;22:153–183. doi: 10.1210/edrv.22.2.0428. [DOI] [PubMed] [Google Scholar]
  55. Perdiguero E., Ruiz-Bonilla V., Gresh L., Hui L., Ballestar E., Sousa-Victor P., Baeza-Raja B., Jardi M., Bosch-Comas A., Esteller M. Genetic analysis of p38 MAP kinases in myogenesis: fundamental role of p38alpha in abrogating myoblast proliferation. EMBO J. 2007;26:1245–1256. doi: 10.1038/sj.emboj.7601587. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Pruitt K., Pruitt W.M., Bilter G.K., Westwick J.K., Der C.J. Raf-independent deregulation of p38 and JNK mitogen-activated protein kinases are critical for Ras transformation. J Biol Chem. 2002;277:31808–31817. doi: 10.1074/jbc.M203964200. [DOI] [PubMed] [Google Scholar]
  57. Pullikuth A.K., Catling A.D. Scaffold mediated regulation of MAPK signaling and cytoskeletal dynamics: a perspective. Cell Signal. 2007;19:1621–1632. doi: 10.1016/j.cellsig.2007.04.012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Rincon M., Davis R.J. Regulation of the immune response by stress-activated protein kinases. Immunol Rev. 2009;228:212–224. doi: 10.1111/j.1600-065X.2008.00744.x. [DOI] [PubMed] [Google Scholar]
  59. Roberts P.J., Der C.J. Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer. Oncogene. 2007;26:3291–3310. doi: 10.1038/sj.onc.1210422. [DOI] [PubMed] [Google Scholar]
  60. Saba-El-Leil M.K., Vella F.D., Vernay B., Voisin L., Chen L., Labrecque N., Ang S.L., Meloche S. An essential function of the mitogen-activated protein kinase Erk2 in mouse trophoblast development. EMBO Rep. 2003;4:964–968. doi: 10.1038/sj.embor.embor939. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. Sabapathy K., Hochedlinger K., Nam S.Y., Bauer A., Karin M., Wagner E.F. Distinct roles for JNK1 and JNK2 in regulating JNK activity and c-Jun-dependent cell proliferation. Mol Cell. 2004;15:713–725. doi: 10.1016/j.molcel.2004.08.028. [DOI] [PubMed] [Google Scholar]
  62. Sabapathy K., Jochum W., Hochedlinger K., Chang L., Karin M., Wagner E.F. Defective neural tube morphogenesis and altered apoptosis in the absence of both JNK1 and JNK2. Mech Dev. 1999;89:115–124. doi: 10.1016/S0925-4773(99)00213-0. [DOI] [PubMed] [Google Scholar]
  63. Sakurai T., He G., Matsuzawa A., Yu G.Y., Maeda S., Hardiman G., Karin M. Hepatocyte necrosis induced by oxidative stress and IL-1 alpha release mediate carcinogen-induced compensatory proliferation and liver tumorigenesis. Cancer Cell. 2008;14:156–165. doi: 10.1016/j.ccr.2008.06.016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Sancho R., Nateri A.S., de Vinuesa A.G., Aguilera C., Nye E., Spencer-Dene B., Behrens A. JNK signalling modulates intestinal homeostasis and tumourigenesis in mice. EMBO J. 2009;28:1843–1854. doi: 10.1038/emboj.2009.153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. She Q.B., Chen N., Bode A.M., Flavell R.A., Dong Z. Deficiency of c-Jun-NH(2)-terminal kinase-1 in mice enhances skin tumor development by 12-O-tetradecanoylphorbol-13-acetate. Cancer Res. 2002;62:1343–1348. [PubMed] [Google Scholar]
  66. Shen Y.H., Godlewski J., Zhu J., Sathyanarayana P., Leaner V., Birrer M.J., Rana A., Tzivion G. Cross-talk between JNK/SAPK and ERK/MAPK pathways: sustained activation of JNK blocks ERK activation by mitogenic factors. J Biol Chem. 2003;278:26715–26721. doi: 10.1074/jbc.M303264200. [DOI] [PubMed] [Google Scholar]
  67. Sparmann A., Bar-Sagi D. Ras-induced interleukin-8 expression plays a critical role in tumor growth and angiogenesis. Cancer Cell. 2004;6:447–458. doi: 10.1016/j.ccr.2004.09.028. [DOI] [PubMed] [Google Scholar]
  68. Streetz K., Fregien B., Plumpe J., Korber K., Kubicka S., Sass G., Bischoff S.C., Manns M.P., Tiegs G., Trautwein C. Dissection of the intracellular pathways in hepatocytes suggests a role for Jun kinase and IFN regulatory factor-1 in Con A-induced liver failure. J Immunol. 2001;167:514–523. doi: 10.4049/jimmunol.167.1.514. [DOI] [PubMed] [Google Scholar]
  69. Sumara G., Formentini I., Collins S., Sumara I., Windak R., Bodenmiller B., Ramracheya R., Caille D., Jiang H., Platt K.A. Regulation of PKD by the MAPK p38delta in insulin secretion and glucose homeostasis. Cell. 2009;136:235–248. doi: 10.1016/j.cell.2008.11.018. [DOI] [PMC free article] [PubMed] [Google Scholar]
  70. Sumimoto H., Imabayashi F., Iwata T., Kawakami Y. The BRAF-MAPK signaling pathway is essential for cancer-immune evasion in human melanoma cells. J Exp Med. 2006;203:1651–1656. doi: 10.1084/jem.20051848. [DOI] [PMC free article] [PubMed] [Google Scholar]
  71. Sun P., Yoshizuka N., New L., Moser B.A., Li Y., Liao R., Xie C., Chen J., Deng Q., Yamout M. PRAK is essential for ras-induced senescence and tumor suppression. Cell. 2007;128:295–308. doi: 10.1016/j.cell.2006.11.050. [DOI] [PubMed] [Google Scholar]
  72. Tamura K., Sudo T., Senftleben U., Dadak A.M., Johnson R., Karin M. Requirement for p38alpha in erythropoietin expression: a role for stress kinases in erythropoiesis. Cell. 2000;102:221–231. doi: 10.1016/S0092-8674(00)00027-1. [DOI] [PubMed] [Google Scholar]
  73. Tong C., Yin Z., Song Z., Dockendorff A., Huang C., Mariadason J., Flavell R.A., Davis R.J., Augenlicht L.H., Yang W. c-Jun NH2-terminal kinase 1 plays a critical role in intestinal homeostasis and tumor suppression. Am J Pathol. 2007;171:297–303. doi: 10.2353/ajpath.2007.061036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  74. Tournier C., Dong C., Turner T.K., Jones S.N., Flavell R.A., Davis R.J. MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines. Genes Dev. 2001;15:1419–1426. doi: 10.1101/gad.888501. [DOI] [PMC free article] [PubMed] [Google Scholar]
  75. Tournier C., Hess P., Yang D.D., Xu J., Turner T.K., Nimnual A., Bar-Sagi D., Jones S.N., Flavell R.A., Davis R.J. Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science. 2000;288:870–874. doi: 10.1126/science.288.5467.870. [DOI] [PubMed] [Google Scholar]
  76. Ventura J.J., Hubner A., Zhang C., Flavell R.A., Shokat K.M., Davis R.J. Chemical genetic analysis of the time course of signal transduction by JNK. Mol Cell. 2006;21:701–710. doi: 10.1016/j.molcel.2006.01.018. [DOI] [PubMed] [Google Scholar]
  77. Ventura J.J., Tenbaum S., Perdiguero E., Huth M., Guerra C., Barbacid M., Pasparakis M., Nebreda A.R. p38alpha MAP kinase is essential in lung stem and progenitor cell proliferation and differentiation. Nat Genet. 2007;39:750–758. doi: 10.1038/ng2037. [DOI] [PubMed] [Google Scholar]
  78. Virgin H.W., Levine B. Autophagy genes in immunity. Nat Immunol. 2009;10:461–470. doi: 10.1038/ni.1726. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Vivanco I., Palaskas N., Tran C., Finn S.P., Getz G., Kennedy N. J., Jiao J., Rose J., Xie W., Loda M. Identification of the JNK signaling pathway as a functional target of the tumor suppressor PTEN. Cancer Cell. 2007;11:555–569. doi: 10.1016/j.ccr.2007.04.021. [DOI] [PubMed] [Google Scholar]
  80. Wada T., Joza N., Cheng H.Y., Sasaki T., Kozieradzki I., Bachmaier K., Katada T., Schreiber M., Wagner E.F., Nishina H. MKK7 couples stress signalling to G2/M cell-cycle progression and cellular senescence. Nat Cell Biol. 2004;6:215–226. doi: 10.1038/ncb1098. [DOI] [PubMed] [Google Scholar]
  81. Wagner E.F., Nebreda A.R. Signal integration by JNK and p38 MAPK pathways in cancer development. Nat Rev Cancer. 2009;9:537–549. doi: 10.1038/nrc2694. [DOI] [PubMed] [Google Scholar]
  82. Weston C.R., Davis R.J. The JNK signal transduction pathway. Curr Opin Cell Biol. 2007;19:142–149. doi: 10.1016/j.ceb.2007.02.001. [DOI] [PubMed] [Google Scholar]
  83. Yao Y., Li W., Wu J., Germann U.A., Su M.S., Kuida K., Boucher D.M. Extracellular signal-regulated kinase 2 is necessary for mesoderm differentiation. Proc Natl Acad Sci U S A. 2003;100:12759–12764. doi: 10.1073/pnas.2134254100. [DOI] [PMC free article] [PubMed] [Google Scholar]
  84. Zarubin T., Han J. Activation and signaling of the p38 MAP kinase pathway. Cell Res. 2005;15:11–18. doi: 10.1038/sj.cr.7290257. [DOI] [PubMed] [Google Scholar]
  85. Zhang D.W., Shao J., Lin J., Zhang N., Lu B.J., Lin S.C., Dong M. Q., Han J. RIP3, an energy metabolism regulator that switches TNF-induced cell death from apoptosis to necrosis. Science. 2009;325:332–336. doi: 10.1126/science.1172308. [DOI] [PubMed] [Google Scholar]

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