Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival

FASEB Journal

Volumn 22, Issue 4, 2008, Pages 954-965

  Junttila, Melissa R ^a   Li, Song Ping ^b   Westermarck, Jukka ^a,c  

^a UNIVERSITY OF TURKU   (Finland)

^b UNIVERSITY OF HELSINKI   (Finland)

^c UNIVERSITY OF TAMPERE   (Finland)

Author keywords

Cancer; ERK; MKK; p38; Protein phosphatase; Transformation

Indexed keywords

MITOGEN ACTIVATED PROTEIN KINASE 1; MITOGEN ACTIVATED PROTEIN KINASE 3; MITOGEN ACTIVATED PROTEIN KINASE P38; PHOSPHATASE; PHOSPHOPROTEIN PHOSPHATASE 2A; STRESS ACTIVATED PROTEIN KINASE;

APOPTOSIS; CELL SURVIVAL; ENZYME INHIBITION; ENZYME REGULATION; HUMAN; NONHUMAN; PRIORITY JOURNAL; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; CELL SURVIVAL; HUMANS; MAP KINASE SIGNALING SYSTEM; MITOGEN-ACTIVATED PROTEIN KINASES; MODELS, BIOLOGICAL; PHOSPHOPROTEIN PHOSPHATASES;

EID: 41549160315     PISSN: 08926638     EISSN: None     Source Type: Journal    
DOI: 10.1096/fj.06-7859rev     Document Type: Review

References (134)

1. Pearson, G., Robinson, F., Beers Gibson, T., Xu, B. E., Karandikar, M., Berman, K., and Cobb, M. H. (2001) Mitogenactivated protein (MAP) kinase pathways: regulation and physiological functions. Endocr. Rev. 22, 153-183
2. Davis, R. (2000) Signal transduction by the JNK group of MAP kinases. Cell 103, 239-252
3. Raman, M., Chen, W., and Cobb, M. H. (2007) Differential regulation and properties of MAPKs. Oncogene 26, 3100-3112
4. Roux, P. P., and Blenis, J. (2004) ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol. Mol. Biol. Rev. 68, 320-344
5. Weston, C. R., and Davis, R. J. (2007) The JNK signal transduction pathway. Curr. Opin. Cell Biol. 19, 142-149
6. Hayashi, M., and Lee, J. D. (2004) Role of the BMK1/ERK5 signaling pathway: lessons from knockout mice. J. Mol. Med. 82, 800-808
7. Ballif, B. A., and Blenis, J. (2001) Molecular mechanisms mediating mammalian mitogen-activated protein kinase (MAPK) kinase (MEK)-MAPK cell survival signals. Cell Growth Differ. 12, 397-408
8. Rubinfeld, H., and Seger, R. (2005) The ERK cascade: a prototype of MAPK signaling. Mol. Biotechnol. 31, 151-174
9. Meloche, S., and Pouyssegur, J. (2007) The ERK1/2 mitogen-activated protein kinase pathway as a master regulator of the G1- to S-phase transition. Oncogene 26, 3227-3239
10. McKay, M. M., and Morrison, D. K. (2007) Integrating signals from RTKs to ERK/MAPK. Oncogene 26, 3113-3121
11. Wellbrock, C., Karasarides, M., and Marais, R. (2004) The RAF proteins take centre stage. Nat. Rev. Mol. Cell. Biol. 5, 875-885
12. Blank, J. L., Gerwins, P., Elliott, E. M., Sather, S., and Johnson, G. L. (1996) Molecular cloning of mitogen-activated protein/ERK kinase kinases (MEKK) 2 and 3. Regulation of sequential phosphorylation pathways involving mitogen-activated protein kinase and c-Jun kinase. J. Biol. Chem. 271, 5361-5368
13. Park, E. R., Eblen, S. T., and Catling, A. D. (2007) MEK1 activation by PAK: a novel mechanism. Cell. Signal. 19, 1488-1496
14. Slack-Davis, J. K., Eblen, S. T., Zecevic, M., Boerner, S. A., Tarcsafalvi, A., Diaz, H. B., Marshall, M. S., Weber, M. J., Parsons, J. T., and Catling, A. D. (2003) PAK1 phosphorylation of MEK1 regulates fibronectin-stimulated MAPK activation. J. Cell Biol. 162, 281-291
15. Karandikar, M., Xu, S., and Cobb, M. H. (2000) MEKK1 binds raf-1 and the ERK2 cascade components. J. Biol. Chem. 275, 40120-40127
16. Waetzig, V., and Herdegen, T. (2005) MEKK1 controls neurite regrowth after experimental injury by balancing ERK1/2 and JNK2 signaling. Mol. Cell. Neurosci. 30, 67-78
17. Zebisch, A., Czernilofsky, A. P., Keri, G., Smigelskaite, J., Sill, H., and Troppmair, J. (2007) Signaling through RAS-RAF-MEK-ERK: from basics to bedside. Curr. Med. Chem. 14, 601-623
18. Troppmair, J., Bruder, J. T., Munoz, H., Lloyd, P. A., Kyriakis, J., Banerjee, P., Avruch, J., and Rapp, U. R. (1994) Mitogen-activated protein kinase/extracellular signal-regulated protein kinase activation by oncogenes, serum, and 12-O-tetradecanoylphorbol-13-acetate requires Raf and is necessary for transformation. J. Biol. Chem. 269, 7030-7035
19. Rangarajan, A., Hong, S. J., Gifford, A., and Weinberg, R. A. (2004) Species- and cell type-specific requirements for cellular transformation. Cancer Cell 6, 171-183
20. Davies, H., Bignell, G. R., Cox, C., Stephens, P., Edkins, S., Clegg, S., Teague, J., Woffendin, H., Garnett, M. J., Bottomley, W., Davis, N., Dicks, E., Ewing, R., Floyd, Y., Gray, K., Hall, S., Hawes, R., Hughes, J., Kosmidou, V., Menzies, A., Mould, C., Parker, A., Stevens, C., Watt, S., Hooper, S., Wilson, R., Jayatilake, H., Gusterson, B. A., Cooper, C., Shipley, J., Hargrave, D., Pritchard-Jones, K., Maitland, N., Chenevix-Trench, G., Riggins, G. J., Bigner, D. D., Palmieri, G., Cossu, A., Flanagan, A., Nicholson, A., Ho, J. W., Leung, S. Y., Yuen, S. T., Weber, B. L., Seigler, H. F., Darrow, T. L., Paterson, H., Marais, R., Marshall, C. J., Wooster, R., Stratton, M. R., and Futreal, P. A. (2002) Mutations of the BRAF gene in human cancer. Nature 417, 949-954
21. Gray-Schopfer, V., Wellbrock, C., and Marais, R. (2007) Melanoma biology and new targeted therapy. Nature 445, 851-857
22. Bonni, A., Brunet, A., West, A. E., Datta, S. R., Takasu, M. A., and Greenberg, M. E. (1999) Cell survival promoted by the Ras-MAPK signaling pathway by transcription-dependent and -independent mechanisms. Science 286, 1358-1362
23. Holmström, T. H., Schmitz, I., Soderstrom, T. S., Poukkula, M., Johnson, V. L., Chow, S. C., Krammer, P. H., and Eriksson, J. E. (2000) MAPK/ERK signaling in activated T cells inhibits CD95/Fas-mediated apoptosis downstream of DISC assembly. EMBO J. 19, 5418-5428
24. Sebolt-Leopold, J. S., Dudley, D. T., Herrera, R., Van Becelaere, K., Wiland, A., Gowan, R. C., Tecle, H., Barrett, S. D., Bridges, A., Przybranowski, S., Leopold, W. R., and Saltiel, A. R. (1999) Blockade of the MAP kinase pathway suppresses growth of colon tumors in vivo. Nat. Med. 5, 810-816
25. Roberts, P. J., and Der, C. J. (2007) Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer Oncogene 26, 3291-3310
26. Grbovic, O. M., Basso, A. D., Sawai, A., Ye, Q., Friedlander, P., Solit, D., and Rosen, N. (2006) V600E B-Raf requires the Hsp90 chaperone for stability and is degraded in response to Hsp90 inhibitors. Proc. Natl. Acad. Sci. U. S. A. 103, 57-62
27. Dong, C., Yang, D. D., Tournier, C., Whitmarsh, A. J., Xu, J., Davis, R. J., and Flavell, R. A. (2000) JNK is required for effector T-cell function but not for T-cell activation. Nature 405, 91-94
28. Tournier, C., Dong, C., Turner, T. K., Jones, S. N., Flavell, R. A., and Davis, R. J. (2001) MKK7 is an essential component of the JNK signal transduction pathway activated by proinflammatory cytokines. Genes Dev. 15, 1419-1426
29. Kamata, H., Honda, S., Maeda, S., Chang, L., Hirata, H., and Karin, M. (2005) Reactive oxygen species promote TNFα-induced death and sustained JNK activation by inhibiting MAP kinase phosphatases. Cell 120, 649-661
30. Sabapathy, K., Kallunki, T., David, J. P., Graef, I., Karin, M., and Wagner, E. F. (2001) c-Jun NH2-terminal kinase (JNK)1 and JNK2 have similar and stage-dependent roles in regulating T cell apoptosis and proliferation. J. Exp. Med. 193, 317-328
31. Tournier, C., Hess, P., Yang, D. D., Xu, J., Turner, T. K., Nimnual, A., Bar-Sagi, D., Jones, S. N., Flavell, R. A., and Davis, R. J. (2000) Requirement of JNK for stress-induced activation of the cytochrome c-mediated death pathway. Science 288, 870-874
32. Yang, D. D., Kuan, C. Y., Whitmarsh, A. J., Rincon, M., Zheng, T. S., Davis, R. J., Rakic, P., and Flavell, R. A. (1997) Absence of excitotoxicity-induced apoptosis in the hippocampus of mice lacking the Jnk3 gene. Nature 389, 865-870
33. Shaulian, E., and Karin, M. (2002) AP-1 as a regulator of cell life and death. Nat. Cell Biol. 4, E131-136
34. Yamamoto, K., Ichijo, H., and Korsmeyer, S. J. (1999) BCL-2 is phosphorylated and inactivated by an ASK1/Jun N-terminal protein kinase pathway normally activated at G(2)/M. Mol. Cell. Biol. 19, 8469-8478
35. Ashwell, J. D. (2006) The many paths to p38 mitogen-activated protein kinase activation in the immune system. Nat. Rev. 6, 532-540
36. Lu, H. T., Yang, D. D., Wysk, M., Gatti, E., Mellman, I., Davis, R. J., and Flavell, R. A. (1999) Defective IL-12 production in mitogen-activated protein (MAP) kinase kinase 3 (Mkk3)-deficient mice. EMBO J. 18, 1845-1857
37. Wysk, M., Yang, D. D., Lu, H. T., Flavell, R. A., and Davis, R. J. (1999) Requirement of mitogen-activated protein kinase kinase 3 (MKK3) for tumor necrosis factor-induced cytokine expression. Proc. Natl. Acad. Sci. U. S. A. 96, 3763-3768
38. Li, S.-P., Junttila, M. R., Han, J., Kähäri, V.-M., and Westermarck, J. (2003) p38 Mitogen-activated protein kinase pathway suppresses cell survival by inducing dephosphorylation of mitogen-activated protein/extracellular signal-regulated kinase kinase1,2. Cancer Res. 63, 3473-3477
39. Tanaka, N., Kamanaka, M., Enslen, H., Dong, C., Wysk, M., Davis, R. J., and Flavell, R. A. (2002) Differential involvement of p38 mitogen-activated protein kinase kinases MKK3 and MKK6 in T-cell apoptosis. EMBO Rep. 3, 785-791
40. Jiang, Y., Li, Z., Schwarz, E. M., Lin, A., Guan, K., Ulevitch, R. J., and Han, J. (1997) Structure-function studies of p38 mitogen-activated protein kinase. Loop 12 influences substrate specificity and autophosphorylation, but not upstream kinase selection. J. Biol. Chem. 272, 11096-11102
41. Ganiatsas, S., Kwee, L., Fujiwara, Y., Perkins, A., Ikeda, T., Labow, M., and Zon, L. (1998) SEK1 deficiency reveals mitogen-activated protein kinase cascade crossregulation and leads to abnormal hepatogenesis. Proc. Natl. Acad. Sci. U. S. A. 95, 6881-6886
42. Brancho, D., Tanaka, N., Jaeschke, A., Ventura, J. J., Kelkar, N., Tanaka, Y., Kyuuma, M., Takeshita, T., Flavell, R. A., and Davis, R. J. (2003) Mechanism of p38 MAP kinase activation in vivo. Genes Dev. 17, 1969-1978
43. Raingeaud, J., Gupta, S., Rogers, J. S., Dickens, M., Han, J., Ulevitch, R. J., and Davis, R. J. (1995) Pro-inflammatory cytokines and environmental stress cause p38 mitogen-activated protein kinase activation by dual phosphorylation on tyrosine and threonine. J. Biol. Chem. 270, 7420-7426
44. Tobiume, K., Matsuzawa, A., Takahashi, T., Nishitoh, H., Morita, K., Takeda, K., Minowa, O., Miyazono, K., Noda, T., and Ichijo, H. (2001) ASK1 is required for sustained activations of JNK/p38 MAP kinases and apoptosis. EMBO. Rep. 2, 222-228
45. Porras, A., Zuluaga, S., Black, E., Valladares, A., Alvarez, A. M., Ambrosino, C., Benito, M., and Nebreda, A. R. (2004) P38 alpha mitogen-activated protein kinase sensitizes cells to apoptosis induced by different stimuli. Mol. Biol. Cell 15, 922-933
46. Xia, Z., Dickens, M., Raingeaud, J., Davis, R. J., and Greenberg, M. E. (1995) Opposing effects of ERK and JNK-p38 MAP kinases on apoptosis. Science 270, 1326-1331
47. Grethe, S., and Porn-Ares, M. I. (2006) p38 MAPK regulates phosphorylation of Bad via PP2A-dependent suppression of the MEK1/2-ERK1/2 survival pathway in TNF-alpha induced endothelial apoptosis. Cell. Signal. 18, 531-540
48. Efimova, T., Broome, A. M., and Eckert, R. L. (2004) Protein kinase Cdelta regulates keratinocyte death and survival by regulating activity and subcellular localization of a p38delta-extracellular signal-regulated kinase 1/2 complex. Mol. Cell. Biol. 24, 8167-8183
49. Bulavin, D. V., Higashimoto, Y., Popoff, I. J., Gaarde, W. A., Basrur, V., Potapova, O., Appella, E., and Fornace, A. J., Jr. (2001) Initiation of a G2/M checkpoint after ultraviolet radiation requires p38 kinase. Nature 411, 102-107
50. Bulavin, D. V., and Fornace, A. J., Jr. (2004) p38 MAP kinase's emerging role as a tumor suppressor. Adv. Cancer Res. 92, 95-118
51. Gauthier, M. L., Pickering, C. R., Miller, C. J., Fordyce, C. A., Chew, K. L., Berman, H. K., and Tlsty, T. D. (2005) p38 regulates cyclooxygenase-2 in human mammary epithelial cells and is activated in premalignant tissue. Cancer Res. 65, 1792-1799
52. Greenberg, A. K., Basu, S., Hu, J., Yie, T. A., Tchou-Wong, K. M., Rom, W. N., and Lee, T. C. (2002) Selective p38 activation in human non-small cell lung cancer Am. J. Respir. Cell Mol. Biol. 26, 558-564
53. Junttila, M. R., Ala-Aho, R., Jokilehto, T., Peltonen, J., Kallajoki, M., Grenman, R., Jaakkola, P., Westermarck, J., and Kähäri, V. M. (2007) p38alpha and p38delta mitogen-activated protein kinase isoforms regulate invasion and growth of head and neck squamous carcinoma cells. Oncogene 26, 5267-5279
54. Johansson, N., Ala-aho, R., Uitto, V., Grenman, R., Fusenig, N. E., Lopez-Otin, C., and Kähäri, V. M. (2000) Expression of collagenase-3 (MMP-13) and collagenase-1 (MMP-1) by transformed keratinocytes is dependent on the activity of p38 mitogen- activated protein kinase. J. Cell Sci. 113(Pt 2), 227-235
55. Efimova, T., Broome, A. M., and Eckert, R. L. (2003) A regulatory role for p38 delta MAPK in keratinocyte differentiation. Evidence for p38 delta-ERK1/2 complex formation. J. Biol. Chem. 278, 34277-34285
56. Biondi, R. M., and Nebreda, A. R. (2003) Signalling specificity of Ser/Thr protein kinases through docking-site-mediated interactions. Biochem. J. 372, 1-13
57. Remenyi, A., Good, M. C., Bhattacharyya, R. P., and Lim, W. A. (2005) The role of docking interactions in mediating signaling input, output, and discrimination in the yeast MAPK network. Mol. Cell 20, 951-962
58. Jacobs, D., Glossip, D., Xing, H., Muslin, A. J., and Kornfeld, K. (1999) Multiple docking sites on substrate proteins form a modular system that mediates recognition by ERK MAP kinase. Genes Dev. 13, 163-175
59. Kolch, W. (2005) Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat. Rev. Mol. Cell. Biol. 6, 827-837
60. Dhanasekaran, D. N., Kashef, K., Lee, C. M., Xu, H., and Reddy, E. P. (2007) Scaffold proteins of MAP-kinase modules. Oncogene 26, 3185-3202
61. Schaeffer, H. J., Catling, A. D., Eblen, S. T., Collier, L. S., Krauss, A., and Weber, M. J. (1998) MP1: a MEK binding partner that enhances enzymatic activation of the MAP kinase cascade. Science 281, 1668-1671
62. Whitmarsh, A. J., Cavanagh, J., Tournier, C., Yasuda, J., and Davis, R. J. (1998) A mammalian scaffold complex that selectively mediates MAP kinase activation. Science 281, 1671-1674
63. Roy, M., Li, Z., and Sacks, D. B. (2005) IQGAP1 is a scaffold for mitogen-activated protein kinase signaling. Mol. Cell. Biol. 25, 7940-7952
64. Noselli, S., and Perrimon, N. (2000) Are there close encounters between signaling pathways? Science 290, 68-69
65. Hunter, T. (1995) Protein kinases and phosphatases: the yin and yang of protein phosphorylation and signaling. Cell. 80, 225-236
66. Hornberg, J. J., Binder, B., Bruggeman, F. J., Schoeberl, B., Heinrich, R., and Westerhoff, H. V. (2005) Control of MAPK signalling: from complexity to what really matters. Oncogene 24, 5533-5542
67. Hornberg, J. J., Bruggeman, F. J., Binder, B., Geest, C. R., de Vaate, A. J., Lankelma, J., Heinrich, R., and Westerhoff, H. V. (2005) Principles behind the multifarious control of signal transduction. ERK phosphorylation and kinase/phosphatase control. FEBS J. 272, 244-258
68. Janssens, V., and Goris, J. (2001) Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem. J. 353, 417- 439
69. Alonso, A., Sasin, J., Bottini, N., Friedberg, I., Friedberg, I., Osterman, A., Godzik, A., Hunter, T., Dixon, J., and Mustelin, T. (2004) Protein tyrosine phosphatases in the human genome. Cell 117, 699-711
70. Owens, D. M., and Keyse, S. M. (2007) Differential regulation of MAP kinase signalling by dual-specificity protein phosphatases. Oncogene 26, 3203-3213
71. Wang, P. Y., Liu, P., Weng, J., Sontag, E., and Anderson, R. G. (2003) A cholesterol-regulated PP2A/HePTP complex with dual specificity ERK1/2 phosphatase activity. EMBO J. 22, 2658-2667
72. Mattila, E., Pellinen, T., Nevo, J., Vuoriluoto, K., Arjonen, A., and Ivaska, J. (2005) Negative regulation of EGFR signalling through integrin-alpha1beta1-mediated activation of protein tyrosine phosphatase TCPTP. Nat. Cell Biol. 7, 78-85
73. Haj, F. G., Markova, B., Klaman, L. D., Bohmer, F. D., and Neel, B. G. (2003) Regulation of receptor tyrosine kinase signaling by protein tyrosine phosphatase-1B. J. Biol. Chem. 278, 739-744
74. Zhang, S. Q., Yang, W., Kontaridis, M. I., Bivona, T. G., Wen, G., Araki, T., Luo, J., Thompson, J. A., Schraven, B. L., Philips, M. R., and Neel, B. G. (2004) Shp2 regulates SRC family kinase activity and Ras/Erk activation by controlling Csk recruitment. Mol. Cell 13, 341-355
75. Saxena, M., Williams, S., Tasken, K., and Mustelin, T. (1999) Crosstalk between cAMP-dependent kinase and MAP kinase through a protein tyrosine phosphatase. Nat. Cell Biol. 1, 305-311
76. Paul, S., Nairn, A. C., Wang, P., and Lombroso, P. J. (2003) NMDA-mediated activation of the tyrosine phosphatase STEP regulates the duration of ERK signaling. Nat. Neurosci. 6, 34-42
77. Toledano-Katchalski, H., Kraut, J., Sines, T., Granot-Attas, S., Shohat, G., Gil-Henn, H., Yung, Y., and Elson, A. (2003) Protein tyrosine phosphatase epsilon inhibits signaling by mitogen-activated protein kinases. Mol. Cancer Res. 1, 541-550
78. MAPK cascade. J. Biol. Chem. 272, 1368-1376
79. Brondello, J. M., Pouyssegur, J., and McKenzie, F. R. (1999) Reduced MAP kinase phosphatase-1 degradation after p42/p44MAPK-dependent phosphorylation. Science 286, 2514-2517
80. Dowd, S., Sneddon, A. A., and Keyse, S. M. (1998) Isolation of the human genes encoding the pyst1 and Pyst2 phosphatases: characterisation of Pyst2 as a cytosolic dual-specificity MAP kinase phosphatase and its catalytic activation by both MAP and SAP kinases. J. Cell Sci. 111(Pt 22), 3389-3399
81. Breitwieser, W., Lyons, S., Flenniken, A. M., Ashton, G., Bruder, G., Willington, M., Lacaud, G., Kouskoff, V., and Jones, N. (2007) Feedback regulation of p38 activity via ATF2 is essential for survival of embryonic liver cells. Genes Dev. 21, 2069-2082
82. Janssens, V., Goris, J., and Van Hoof, C. (2005) PP2A: the expected tumor suppressor. Curr. Opin. Genet. Dev. 15, 34-41
83. Cho, U. S., and Xu, W. (2007) Crystal structure of a protein phosphatase 2A heterotrimeric holoenzyme. Nature 445, 53-57
84. Xu, Y., Xing, Y., Chen, Y., Chao, Y., Lin, Z., Fan, E., Yu, J. W., Strack, S., Jeffrey, P. D., and Shi, Y. (2006) Structure of the protein phosphatase 2A holoenzyme. Cell 127, 1239-1251
85. Ikehara, T., Ikehara, S., Imamura, S., Shinjo, F., and Yasumoto, T. (2007) Methylation of the C-terminal leucine residue of the PP2A catalytic subunit is unnecessary for the catalytic activity and the binding of regulatory subunit (PR55/B). Biochem. Biophys. Res. Commun. 354, 1052-1057
86. Longin, S., Zwaenepoel, K., Louis, J. V., Dilworth, S., Goris, J., and Janssens, V. (2007) Selection of protein phosphatase 2A regulatory subunits is mediated by the C-terminus of the catalytic subunit. J. Biol. Chem. 282, 26971-26980
87. Arroyo, J. D., and Hahn, H. (2005) Involvement of PP2A in viral and cellular transformation. Oncogene 24, 7746-7755
88. Prickett, T. D., and Brautigan, D. L. (2007) Cytokine activation of p38 mitogen-activated protein kinase and apoptosis is opposed by alpha-4 targeting of protein phosphatase 2A for site-specific dephosphorylation of MEK3. Mol. Cell. Biol. 27, 4217-4227
89. Sontag, E., Fedorov, S., Kamibayashi, C., Robbins, D., Cobb, M., and Mumby, M. (1993) The interaction of SV40 small tumor antigen with protein phosphatase 2A stimulates the map kinase pathway and induces cell proliferation. Cell 75, 887-897
90. Westermarck, J., Holmstrom, T., Ahonen, M., Eriksson, J. E., and Kähäri, V. M. (1998) Enhancement of fibroblast collagenase-1 (MMP-1) gene expression by tumor promoter okadaic acid is mediated by stress-activated protein kinases Jun N-terminal kinase and p38. Matrix Biol. 17, 547-557
91. Kins, S., Kurosinski, P., Nitsch, R. M., and Gotz, J. (2003) Activation of the ERK and JNK signaling pathways caused by neuron-specific inhibition of PP2A in transgenic mice. Am. J. Pathol. 163, 833-843
92. Silverstein, A. M., Barrow, C. A., Davis, A. J., and Mumby, M. C. (2002) Actions of PP2A on the MAP kinase pathway and apoptosis are mediated by distinct regulatory subunits. Proc. Natl. Acad. Sci. U. S. A. 99, 4221-4226
93. Strack, S. (2002) Overexpression of the protein phosphatase 2A regulatory subunit Bgamma promotes neuronal differentiation by activating the MAP kinase (MAPK) cascade. J. Biol. Chem. 277, 41525-41532
94. Van Kanegan, M. J., Adams, D. G., Wadzinski, B. E., and Strack, S. (2005) Distinct protein phosphatase 2A heterotrimers modulate growth factor signaling to extracellular signal-regulated kinases and Akt. J. Biol. Chem. 280, 36029-36036
95. Letourneux, C., Rocher, G., and Porteu, F. (2006) B56-containing PP2A dephosphorylate ERK and their activity is controlled by the early gene IEX-1 and ERK. EMBO J. 25, 727-738
96. Takahashi, K., Nakajima, E., and Suzuki, K. (2006) Involvement of protein phosphatase 2A in the maintenance of E-cadherin-mediated cell-cell adhesion through recruitment of IQGAP1. J. Cell. Physiol. 206, 814-820
97. Ugi, S., Imamura, T., Ricketts, W., and Olefsky, J. M. (2002) Protein phosphatase 2A forms a molecular complex with Shc and regulates Shc tyrosine phosphorylation and downstream mitogenic signaling. Mol. Cell. Biol. 22, 2375-2387
98. Wassarman, D. A., Solomon, N. M., Chang, H. C., Karim, F. D., Therrien, M., and Rubin, G. M. (1996) Protein phosphatase 2A positively and negatively regulates Ras1-mediated photoreceptor development in Drosophila. Genes Dev. 10, 272-278
99. Abraham, D., Podar, K., Pacher, M., Kubicek, M., Welzel, N., Hemmings, B. A., Dilworth, S. M., Mischak, H., Kolch, W., and Baccarini, M. (2000) Raf-1-associated PP2A as a positive regulator of kinase activation. J. Biol. Chem. 275, 22300-22304
100. Ory, S., Zhou, M., Conrads, T. P., Veenstra, T. D., and Morrison, D. K. (2003) Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites. Curr. Biol. 13, 1356-1364
101. Dougherty, M. K., Muller, J., Ritt, D. A., Zhou, M., Zhou, X. Z., Copeland, T. D., Conrads, T. P., Veenstra, T. D., Lu, K. P., and Morrison, D. K. (2005) Regulation of Raf-1 by direct feedback phosphorylation. Mol. Cell 17, 215-224
102. Hashigasako, A., Machide, M., Nakamura, T., Matsumoto, K., and Nakamura, T. (2004) Bi-directional regulation of Ser-985 phosphorylation of c-Met via protein kinase C and protein phosphatase 2A involves c-Met activation and cellular responsiveness to hepatocyte growth factor. J. Biol. Chem. 279, 26445-26452
103. Friedman, A., and Perrimon, N. (2006) A functional RNAi screen for regulators of receptor tyrosine kinase and ERK signalling. Nature 444, 230-234
104. Hanada, M., Ninomiya-Tsuji, J., Komaki, K., Ohnishi, M., Katsura, K., Kanamaru, R., Matsumoto, K., and Tamura, S. (2001) Regulation of the TAK1 signaling pathway by protein phosphatase 2C. J. Biol. Chem. 276, 5753-5759
105. Heriche, J. K., Lebrin, F., Rabilloud, T., Leroy, D., Chambaz, E. M., and Goldberg, Y. (1997) Regulation of protein phosphatase 2A by direct interaction with casein kinase 2alpha. Science 276, 952-955
106. Westermarck, J., Li, S., Kallunki, T., Han, J., and Kähäri, V.-M. (2001) p38 MAPK dependent activation of protein phosphatase-1 and 2A inhibits MEK1,2 activity and collagenase-1 (MMP-1) gene expression. Mol. Cell. Biol. 21, 2373-2383
107. Liu, Q., and Hofmann, P. A. (2004) Protein phosphatase 2A-mediated cross-talk between p38 MAPK and ERK in apoptosis of cardiac myocytes. Am. J. Physiol. Heart Circ. Physiol. 286, H2204-2212
108. Liu, Q., and Hofmann, P. A. (2003) Modulation of protein phosphatase 2a by adenosine A1 receptors in cardiomyocytes: role for p38 MAPK. Am. J. Physiol. Heart Circ. Physiol. 285, H97-103
109. Lee, J., Hong, F., Kwon, S., Kim, S. S., Kim, D. O., Kang, H. S., Lee, S. J., Ha, J., and Kim, S. S. (2002) Activation of p38 MAPK induces cell cycle arrest via inhibition of Raf/ERK pathway during muscle differentiation. Biochem. Biophys. Res. Commun. 298, 765-771
110. Kogkopoulou, O., Tzakos, E., Mavrothalassitis, G., Baldari, C. T., Paliogianni, F., Young, H. A., and Thyphronitis, G. (2006) Conditional up-regulation of IL-2 production by p38 MAPK inactivation is mediated by increased Erk1/2 activity. J. Leukocyte Biol. 79, 1052-1060
111. Ossum, C. G., Wulff, T., and Hoffmann, E. K. (2006) Regulation of the mitogen-activated protein kinase p44 ERK activity during anoxia/recovery in rainbow trout hypodermal fibroblasts. J. Exp. Biol. 209, 1765-1776
112. Sayed, M., Kim, S. O., Salh, B. S., Issinger, O. G., and Pelech, S. L. (2000) Stress-induced activation of protein kinase CK2 by direct interaction with p38 mitogen-activated protein kinase. J. Biol. Chem. 275, 16569-16573
113. Zhang, H., Shi, X., Hampong, M., Blanis, L., and Pelech, S. (2001) Stress-induced inhibition of ERK1 and ERK2 by direct interaction with p38 MAP kinase. J. Biol. Chem. 276, 6905-6908
114. Nyati, M. K., Feng, F. Y., Maheshwari, D., Varambally, S., Zielske, S. P., Ahsan, A., Chun, P. Y., Arora, V. A., Davis, M. A., Jung, M., Ljungman, M., Canman, C. E., Chinnaiyan, A. M., and Lawrence, T. S. (2006) Ataxia telangiectasia mutated down-regulates phospho-extracellular signal-regulated kinase 1/2 via activation of MKP-1 in response to radiation. Cancer Res. 66, 11554-11559
115. Kool, J., Hamdi, M., Cornelissen-Steijger, P., van der Eb, A. J., Terleth, C., and van Dam, H. (2003) Induction of ATF3 by ionizing radiation is mediated via a signaling pathway that includes ATM, Nibrin1, stress-induced MAPkinases and ATF-2. Oncogene 22, 4235-4242
116. Dong, Z., and Bode, A. M. (2003) Dialogue between ERKs and JNKs: friendly or antagonistic? Mol. Interv. 3, 306-308
117. Black, E. J., Walker, M., Clark, W., MacLaren, A., and Gillespie, D. A. (2002) Cell transformation by v-Jun deactivates ERK MAP kinase signalling. Oncogene 21, 6540-6548
118. Shen, Y. H., Godlewski, J., Zhu, J., Sathyanarayana, P., Leaner, V., Birrer, M. J., Rana, A., and Tzivion, G. (2003) Cross-talk between JNK/SAPK and ERK/MAPK pathways: sustained activation of JNK blocks ERK activation by mitogenic factors. J. Biol. Chem. 278, 26715-26721
119. Leppä, S., and Bohmann, D. (1999) Diverse functions of JNK signaling and c-Jun in stress response and apoptosis. Oncogene 18, 6158-6162
120. Hahn, W. C., Dessain, S. K., Brooks, M. W., King, J. E., Elenbaas, B., Sabatini, D. M., DeCaprio, J. A., and Weinberg, R. A. (2002) Enumeration of the simian virus 40 early region elements necessary for human cell transformation. Mol. Cell. Biol. 22, 2111-2123
121. Mumby, M. (2007) PP2A: unveiling a reluctant tumor suppressor. Cell 130, 21-24
122. Boehm, J. S., Zhao, J. J., Yao, J., Kim, S. Y., Firestein, R., Dunn, I. F., Sjostrom, S. K., Garraway, L. A., Weremowicz, S., Richardson, A. L., Greulich, H., Stewart, C. J., Mulvey, L. A., Shen, R. R., Ambrogio, L., Hirozane-Kishikawa, T., Hill, D. E., Vidal, M., Meyerson, M., Grenier, J. K., Hinkle, G., Root, D. E., Roberts, T. M., Lander, E. S., Polyak, K., and Hahn, W. C. (2007) Integrative genomic approaches identify IKBKE as a breast cancer oncogene. Cell 129, 1065-1079
123. Pruitt, K., Pruitt, W. M., Bilter, G. K., Westwick, J. K., and Der, C. J. (2002) Raf-independent deregulation of p38 and JNK mitogen-activated protein kinases are critical for Ras transformation. J. Biol. Chem. 277, 31808-31817
124. Dolado, I., Swat, A., Ajenjo, N., De Vita, G., Cuadrado, A., and Nebreda, A. R. (2007) p38alpha MAP kinase as a sensor of reactive oxygen species in tumorigenesis. Cancer Cell 11, 191-205
125. Ambrosino, C., Iwata, T., Scafoglio, C., Mallardo, M., Klein, R., and Nebreda, A. R. (2006) TEF-1 and C/EBPbeta are major p38alpha MAPK-regulated transcription factors in proliferating cardiomyocytes. Biochem. J. 396, 163-172
126. Lu, Z., Xu, S., Joazeiro, C., Cobb, M., and Hunter, T. (2002) The PHD Domain of MEKK1 acts as an E3 ubiquitin ligase and mediates ubiquitination and degradation of ERK1/2. Mol. Cell 9, 945-956
127. McGuire, T. F., Trump, D. L., and Johnson, C. S. (2001) Vitamin D3-induced apoptosis of murine squamous cell carcinoma cells. Selective induction of caspase-dependent MEK cleavage and up-regulation of MEKK-1. J. Biol. Chem. 276, 26365-26373
128. Suzuki, K., Hasegawa, T., Sakamoto, C., Zhou, Y. M., Hato, F., Hino, M., Tatsumi, N., and Kitagawa, S. (2001) Cleavage of mitogen-activated protein kinases in human neutrophils undergoing apoptosis: role in decreased responsiveness to inflammatory cytokines. J. Immunol. 166, 1185-1192
129. Widmann, C., Gibson, S., and Johnson, G. L. (1998) Caspase-dependent cleavage of signaling protein during apoptosis. J. Biol. Chem. 273, 7141-7147
130. Hood, J. D., Bednarski, M., Frausto, R., Guccione, S., Reisfeld, R. A., Xiang, R., and Cheresh, D. A. (2002) Tumor regression by targeted gene delivery to the neovasculature. Science 296, 2404-2407
131. Wojnowski, L., Zimmer, A. M., Beck, T. W., Hahn, H., Bernal, R., Rapp, U. R., and Zimmer, A. (1997) Endothelial apoptosis in Braf-deficient mice. Nat. Genet. 16, 293-297
132. Alberola-Ila, J., Forbush, K. A., Seger, R., Krebs, E. G., and Perlmutter, R. M. (1995) Selective requirement for MAP kinase activation in thymocyte differentiation. Nature 373, 620-623
133. McNeil, L. K., Starr, T. K., and Hogquist, K. A. (2005) A requirement for sustained ERK signaling during thymocyte positive selection in vivo. Proc. Natl. Acad. Sci. U. S. A. 102, 13574-13579
134. Sharma, S. V., Gajowniczek, P., Way, I. P., Lee, D. Y., Jiang, J., Yuza, Y., Classon, M., Haber, D. A., and Settleman, J. (2006) A common signaling cascade may underlie "addiction" to the Src, BCR-ABL, and EGF receptor oncogenes. Cancer Cell 10, 425-435