This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Chiariello, M.
Right arrow Articles by Gutkind, J. S.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chiariello, M.
Right arrow Articles by Gutkind, J. S.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, March 2000, p. 1747-1758, Vol. 20, No. 5
0270-7306/00/$04.00+0

Multiple Mitogen-Activated Protein Kinase Signaling Pathways Connect the Cot Oncoprotein to the c-jun Promoter and to Cellular Transformation

Mario Chiariello, Maria Julia Marinissen, and J. Silvio Gutkind*

Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland 20892-4330

Received 23 August 1999/Returned for modification 20 September 1999/Accepted 16 November 1999

The serine/threonine kinase Cot is a member of the mitogen-activated protein kinase (MAPK) kinase kinase family implicated in cellular transformation. Enhanced expression of this protein has been shown to activate both the MAPK and the c-Jun N-terminal kinase (JNK) pathways and to stimulate the nuclear factor of activated T cells and NF-kappa B-dependent transcription. However, the nature of the normal functions of the Cot protein and the molecular mechanisms responsible for its oncogenic potential are still largely unknown. Here, we show that overexpression of the cot proto-oncogene is sufficient to stimulate the expression of c-jun and that, in turn, the activity of c-Jun is required for Cot-induced transformation. These observations prompted us to explore the molecular events by which Cot regulates c-jun expression. We found that Cot potently stimulates the activity of the c-jun promoter utilizing JNK-dependent and -independent pathways, the latter involving two novel members of the MAPK family, p38gamma (ERK6) and ERK5. Molecularly, this activity was found to be dependent on the ability of Cot to activate, in vivo, members of each class of the MAPK kinase superfamily, including MEK, SEK, MKK6, and MEK5. Furthermore, the use of dominant interfering molecules revealed that Cot requires JNK, p38s, and ERK5 to stimulate the c-jun promoter fully and to induce neoplastic transformation. These findings indicate that Cot represents the first example of a serine/threonine kinase acting simultaneously on all known MAPK cascades. Moreover, these observations strongly suggest that the transforming ability of Cot results from the coordinated activation of these pathways, which ultimately converge on the regulation of the expression and activity of the product of the c-jun proto-oncogene.

* Corresponding author. Mailing address: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, 9000 Rockville Pike, Building 30, Room 211, Bethesda, MD 20892-4330. Phone: (301) 496-6259. Fax: (301) 402-0823. E-mail: gutkind{at}nih.gov.

Molecular and Cellular Biology, March 2000, p. 1747-1758, Vol. 20, No. 5
0270-7306/00/$04.00+0


This article has been cited by other articles:

  • Khanal, P., Lee, K.-Y., Kang, K.-W., Kang, B. S., Choi, H. S. (2009). Tpl-2 kinase downregulates the activity of p53 and enhances signaling pathways leading to activation of activator protein 1 induced by EGF. Carcinogenesis 30: 682-689 [Abstract] [Full Text]  
  • Young, J. E., Garden, G. A., Martinez, R. A., Tanaka, F., Miguel Sandoval, C., Smith, A. C., Sopher, B. L., Lin, A., Fischbeck, K. H., Ellerby, L. M., Morrison, R. S., Taylor, J. P., La Spada, A. R. (2009). Polyglutamine-Expanded Androgen Receptor Truncation Fragments Activate a Bax-Dependent Apoptotic Cascade Mediated by DP5/Hrk. J. Neurosci. 29: 1987-1997 [Abstract] [Full Text]  
  • Watford, W. T., Hissong, B. D., Durant, L. R., Yamane, H., Muul, L. M., Kanno, Y., Tato, C. M., Ramos, H. L., Berger, A. E., Mielke, L., Pesu, M., Solomon, B., Frucht, D. M., Paul, W. E., Sher, A., Jankovic, D., Tsichlis, P. N., O'Shea, J. J. (2008). Tpl2 kinase regulates T cell interferon-{gamma} production and host resistance to Toxoplasma gondii. JEM 205: 2803-2812 [Abstract] [Full Text]  
  • Choi, H. S., Kang, B. S., Shim, J.-H., Cho, Y.-Y., Choi, B. Y., Bode, A. M., Dong, Z. (2008). Cot, a novel kinase of histone H3, induces cellular transformation through up-regulation of c-fos transcriptional activity. FASEB J. 22: 113-126 [Abstract] [Full Text]  
  • Robinson, M. J., Beinke, S., Kouroumalis, A., Tsichlis, P. N., Ley, S. C. (2007). Phosphorylation of TPL-2 on Serine 400 Is Essential for Lipopolysaccharide Activation of Extracellular Signal-Regulated Kinase in Macrophages. Mol. Cell. Biol. 27: 7355-7364 [Abstract] [Full Text]  
  • Wang, Y., Su, B., Xia, Z. (2006). Brain-derived Neurotrophic Factor Activates ERK5 in Cortical Neurons via a Rap1-MEKK2 Signaling Cascade. J. Biol. Chem. 281: 35965-35974 [Abstract] [Full Text]  
  • Madson, J. G., Lynch, D. T., Tinkum, K. L., Putta, S. K., Hansen, L. A. (2006). Erbb2 Regulates Inflammation and Proliferation in the Skin after Ultraviolet Irradiation. Am. J. Pathol. 169: 1402-1414 [Abstract] [Full Text]  
  • Knoechel, B., Lohr, J., Zhu, S., Wong, L., Hu, D., Ausubel, L., Abbas, A. K. (2006). Functional and Molecular Comparison of Anergic and Regulatory T Lymphocytes.. J. Immunol. 176: 6473-6483 [Abstract] [Full Text]  
  • Iavarone, C., Acunzo, M., Carlomagno, F., Catania, A., Melillo, R. M., Carlomagno, S. M., Santoro, M., Chiariello, M. (2006). Activation of the Erk8 Mitogen-activated Protein (MAP) Kinase by RET/PTC3, a Constitutively Active Form of the RET Proto-oncogene. J. Biol. Chem. 281: 10567-10576 [Abstract] [Full Text]  
  • Banerjee, A., Gugasyan, R., McMahon, M., Gerondakis, S. (2006). Diverse Toll-like receptors utilize Tpl2 to activate extracellular signal-regulated kinase (ERK) in hemopoietic cells. Proc. Natl. Acad. Sci. USA 103: 3274-3279 [Abstract] [Full Text]  
  • Monje, P., Hernandez-Losa, J., Lyons, R. J., Castellone, M. D., Gutkind, J. S. (2005). Regulation of the Transcriptional Activity of c-Fos by ERK: A NOVEL ROLE FOR THE PROLYL ISOMERASE PIN1. J. Biol. Chem. 280: 35081-35084 [Abstract] [Full Text]  
  • Das, S., Cho, J., Lambertz, I., Kelliher, M. A., Eliopoulos, A. G., Du, K., Tsichlis, P. N. (2005). Tpl2/Cot Signals Activate ERK, JNK, and NF-{kappa}B in a Cell-type and Stimulus-specific Manner. J. Biol. Chem. 280: 23748-23757 [Abstract] [Full Text]  
  • Carvajal-Vergara, X., Tabera, S., Montero, J. C., Esparis-Ogando, A., Lopez-Perez, R., Mateo, G., Gutierrez, N., Parmo-Cabanas, M., Teixido, J., San Miguel, J. F., Pandiella, A. (2005). Multifunctional role of Erk5 in multiple myeloma. Blood 105: 4492-4499 [Abstract] [Full Text]  
  • Cho, J., Melnick, M., Solidakis, G. P., Tsichlis, P. N. (2005). Tpl2 (Tumor Progression Locus 2) Phosphorylation at Thr290 Is Induced by Lipopolysaccharide via an I{kappa}-B Kinase-{beta}-dependent Pathway and Is Required for Tpl2 Activation by External Signals. J. Biol. Chem. 280: 20442-20448 [Abstract] [Full Text]  
  • Tanos, T., Marinissen, M. J., Leskow, F. C., Hochbaum, D., Martinetto, H., Gutkind, J. S., Coso, O. A. (2005). Phosphorylation of c-Fos by Members of the p38 MAPK Family: ROLE IN THE AP-1 RESPONSE TO UV LIGHT. J. Biol. Chem. 280: 18842-18852 [Abstract] [Full Text]  
  • Beloueche-Babari, M., Jackson, L. E., Al-Saffar, N. M.S., Workman, P., Leach, M. O., Ronen, S. M. (2005). Magnetic Resonance Spectroscopy Monitoring of Mitogen-Activated Protein Kinase Signaling Inhibition. Cancer Res. 65: 3356-3363 [Abstract] [Full Text]  
  • Barros, J. C., Marshall, C. J. (2005). Activation of either ERK1/2 or ERK5 MAP kinase pathways can lead to disruption of the actin cytoskeleton. J. Cell Sci. 118: 1663-1671 [Abstract] [Full Text]  
  • Cho, J., Tsichlis, P. N. (2005). Phosphorylation at Thr-290 regulates Tpl2 binding to NF-{kappa}B1/p105 and Tpl2 activation and degradation by lipopolysaccharide. Proc. Natl. Acad. Sci. USA 102: 2350-2355 [Abstract] [Full Text]  
  • Luciano, B. S., Hsu, S., Channavajhala, P. L., Lin, L.-L., Cuozzo, J. W. (2004). Phosphorylation of Threonine 290 in the Activation Loop of Tpl2/Cot Is Necessary but Not Sufficient for Kinase Activity. J. Biol. Chem. 279: 52117-52123 [Abstract] [Full Text]  
  • Bieche, I., Lerebours, F., Tozlu, S., Espie, M., Marty, M., Lidereau, R. (2004). Molecular Profiling of Inflammatory Breast Cancer: Identification of a Poor-Prognosis Gene Expression Signature. Clin. Cancer Res. 10: 6789-6795 [Abstract] [Full Text]  
  • Silva, A. M., Whitmore, M., Xu, Z., Jiang, Z., Li, X., Williams, B. R. G. (2004). Protein Kinase R (PKR) Interacts with and Activates Mitogen-activated Protein Kinase Kinase 6 (MKK6) in Response to Double-stranded RNA Stimulation. J. Biol. Chem. 279: 37670-37676 [Abstract] [Full Text]  
  • Raviv, Z., Kalie, E., Seger, R. (2004). MEK5 and ERK5 are localized in the nuclei of resting as well as stimulated cells, while MEKK2 translocates from the cytosol to the nucleus upon stimulation. J. Cell Sci. 117: 1773-1784 [Abstract] [Full Text]  
  • Pi, X., Yan, C., Berk, B. C. (2004). Big Mitogen-Activated Protein Kinase (BMK1)/ERK5 Protects Endothelial Cells From Apoptosis. Circ. Res. 94: 362-369 [Abstract] [Full Text]  
  • Sancho, R., Macho, A., de La Vega, L., Calzado, M. A., Fiebich, B. L., Appendino, G., Munoz, E. (2004). Immunosuppressive Activity of Endovanilloids: N-Arachidonoyl-Dopamine Inhibits Activation of the NF-{kappa}B, NFAT, and Activator Protein 1 Signaling Pathways. J. Immunol. 172: 2341-2351 [Abstract] [Full Text]  
  • Caivano, M., Rodriguez, C., Cohen, P., Alemany, S. (2003). 15-Deoxy-{Delta}12,14-prostaglandin J2 Regulates Endogenous Cot MAPK Kinase Kinase 1 Activity Induced by Lipopolysaccharide. J. Biol. Chem. 278: 52124-52130 [Abstract] [Full Text]  
  • Iavarone, C., Catania, A., Marinissen, M. J., Visconti, R., Acunzo, M., Tarantino, C., Carlomagno, M. S., Bruni, C. B., Gutkind, J. S., Chiariello, M. (2003). The Platelet-derived Growth Factor Controls c-myc Expression through a JNK- and AP-1-dependent Signaling Pathway. J. Biol. Chem. 278: 50024-50030 [Abstract] [Full Text]  
  • Marinissen, M. J., Servitja, J.-M., Offermanns, S., Simon, M. I., Gutkind, J. S. (2003). Thrombin Protease-activated Receptor-1 Signals through Gq- and G13-initiated MAPK Cascades Regulating c-Jun Expression to Induce Cell Transformation. J. Biol. Chem. 278: 46814-46825 [Abstract] [Full Text]  
  • Channavajhala, P. L., Wu, L., Cuozzo, J. W., Hall, J. P., Liu, W., Lin, L.-L., Zhang, Y. (2003). 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 [Abstract] [Full Text]  
  • Gandara, M. L., Lopez, P., Hernando, R., Castano, J. G., Alemany, S. (2003). The COOH-Terminal Domain of Wild-Type Cot Regulates Its Stability and Kinase Specific Activity. Mol. Cell. Biol. 23: 7377-7390 [Abstract] [Full Text]  
  • Monje, P., Marinissen, M. J., Gutkind, J. S. (2003). Phosphorylation of the Carboxyl-Terminal Transactivation Domain of c-Fos by Extracellular Signal-Regulated Kinase Mediates the Transcriptional Activation of AP-1 and Cellular Transformation Induced by Platelet-Derived Growth Factor. Mol. Cell. Biol. 23: 7030-7043 [Abstract] [Full Text]  
  • Brancho, D., Tanaka, N., Jaeschke, A., Ventura, J.-J., Kelkar, N., Tanaka, Y., Kyuuma, M., Takeshita, T., Flavell, R. A., Davis, R. J. (2003). Mechanism of p38 MAP kinase activation in vivo. Genes Dev. 17: 1969-1978 [Abstract] [Full Text]  
  • Beinke, S., Deka, J., Lang, V., Belich, M. P., Walker, P. A., Howell, S., Smerdon, S. J., Gamblin, S. J., Ley, S. C. (2003). NF-{kappa}B1 p105 Negatively Regulates TPL-2 MEK Kinase Activity. Mol. Cell. Biol. 23: 4739-4752 [Abstract] [Full Text]  
  • Kikuchi, T., Yoshikai, Y., Miyoshi, J., Katsuki, M., Musikacharoen, T., Mitani, A., Tanaka, S., Noguchi, T., Matsuguchi, T. (2003). Cot/Tpl2 is Essential for RANKL Induction by Lipid A in Osteoblasts. JDR 82: 546-550 [Abstract] [Full Text]  
  • Bae, D.-S., Handa, R. J., Yang, R. S. H., Campain, J. A. (2003). Gene Expression Patterns as Potential Molecular Biomarkers for Malignant Transformation in Human Keratinocytes Treated with MNNG, Arsenic, or a Metal Mixture. Toxicol Sci 74: 32-42 [Abstract] [Full Text]  
  • Pramanik, R., Qi, X., Borowicz, S., Choubey, D., Schultz, R. M., Han, J., Chen, G. (2003). p38 Isoforms Have Opposite Effects on AP-1-dependent Transcription through Regulation of c-Jun. THE DETERMINANT ROLE OF THE ISOFORMS IN THE p38 MAPK SIGNAL SPECIFICITY. J. Biol. Chem. 278: 4831-4839 [Abstract] [Full Text]  
  • Dwivedi, P. P., Hii, C. S. T., Ferrante, A., Tan, J., Der, C. J., Omdahl, J. L., Morris, H. A., May, B. K. (2002). Role of MAP Kinases in the 1,25-Dihydroxyvitamin D3-induced Transactivation of the Rat Cytochrome P450C24 (CYP24) Promoter. SPECIFIC FUNCTIONS FOR ERK1/ERK2 AND ERK5. J. Biol. Chem. 277: 29643-29653 [Abstract] [Full Text]  
  • Reddy, S. P. M., Adiseshaiah, P., Shapiro, P., Vuong, H. (2002). BMK1 (ERK5) Regulates Squamous Differentiation Marker SPRR1B Transcription in Clara-like H441 Cells. Am. J. Respir. Cell Mol. Bio. 27: 64-70 [Abstract] [Full Text]  
  • Laderoute, K. R., Calaoagan, J. M., Gustafson-Brown, C., Knapp, A. M., Li, G.-C., Mendonca, H. L., Ryan, H. E., Wang, Z., Johnson, R. S. (2002). The Response of c-Jun/AP-1 to Chronic Hypoxia Is Hypoxia-Inducible Factor 1{alpha} Dependent. Mol. Cell. Biol. 22: 2515-2523 [Abstract] [Full Text]  
  • Suzaki, Y., Yoshizumi, M., Kagami, S., Koyama, A. H., Taketani, Y., Houchi, H., Tsuchiya, K., Takeda, E., Tamaki, T. (2002). Hydrogen Peroxide Stimulates c-Src-mediated Big Mitogen-activated Protein Kinase 1 (BMK1) and the MEF2C Signaling Pathway in PC12 Cells. POTENTIAL ROLE IN CELL SURVIVAL FOLLOWING OXIDATIVE INSULTS. J. Biol. Chem. 277: 9614-9621 [Abstract] [Full Text]  
  • Esparis-Ogando, A., Diaz-Rodriguez, E., Montero, J. C., Yuste, L., Crespo, P., Pandiella, A. (2002). Erk5 Participates in Neuregulin Signal Transduction and Is Constitutively Active in Breast Cancer Cells Overexpressing ErbB2. Mol. Cell. Biol. 22: 270-285 [Abstract] [Full Text]  
  • Benkhelifa, S., Provot, S., Nabais, E., Eychene, A., Calothy, G., Felder-Schmittbuhl, M.-p. (2001). Phosphorylation of MafA Is Essential for Its Transcriptional and Biological Properties. Mol. Cell. Biol. 21: 4441-4452 [Abstract] [Full Text]  
  • Velasco-Sampayo, A., Alemany, S. (2001). p27kif Protein Levels and E2F Activity Are Targets of Cot Kinase During G1 Phase Progression in T Cells. J. Immunol. 166: 6084-6090 [Abstract] [Full Text]  
  • Chiou, C-C, Chan, C-C, Sheu, D-L, Chen, K-T, Li, Y-S, Chan, E-C (2001). Helicobacter pylori infection induced alteration of gene expression in human gastric cells. Gut 48: 598-604 [Abstract] [Full Text]  
  • Pearson, G., Robinson, F., Beers Gibson, T., Xu, B.-e, Karandikar, M., Berman, K., Cobb, M. H. (2001). Mitogen-Activated Protein (MAP) Kinase Pathways: Regulation and Physiological Functions. Endocr. Rev. 22: 153-183 [Abstract] [Full Text]  
  • Kyriakis, J. M., Avruch, J. (2001). Mammalian Mitogen-Activated Protein Kinase Signal Transduction Pathways Activated by Stress and Inflammation. Physiol. Rev. 81: 807-869 [Abstract] [Full Text]  
  • Chayama, K., Papst, P. J., Garrington, T. P., Pratt, J. C., Ishizuka, T., Webb, S., Ganiatsas, S., Zon, L. I., Sun, W., Johnson, G. L., Gelfand, E. W. (2001). Role of MEKK2-MEK5 in the regulation of TNF-alpha gene expression and MEKK2-MKK7 in the activation of c-Jun N-terminal kinase in mast cells. Proc. Natl. Acad. Sci. USA 10.1073/pnas.081021898v1 [Abstract] [Full Text]  
  • Janulis, M., Trakul, N., Greene, G., Schaefer, E. M., Lee, J. D., Rosner, M. R. (2001). A Novel Mitogen-Activated Protein Kinase Is Responsive to Raf and Mediates Growth Factor Specificity. Mol. Cell. Biol. 21: 2235-2247 [Abstract] [Full Text]  
  • Marinissen, M. J., Chiariello, M., Gutkind, J. S. (2001). Regulation of gene expression by the small GTPase Rho through the ERK6 (p38{gamma}) MAP kinase pathway. Genes Dev. 15: 535-553 [Abstract] [Full Text]  
  • Cavanaugh, J. E., Ham, J., Hetman, M., Poser, S., Yan, C., Xia, Z. (2001). Differential Regulation of Mitogen-Activated Protein Kinases ERK1/2 and ERK5 by Neurotrophins, Neuronal Activity, and cAMP in Neurons. J. Neurosci. 21: 434-443 [Abstract] [Full Text]  
  • Visconti, R., Gadina, M., Chiariello, M., Chen, E. H., Stancato, L. F., Gutkind, J. S., O'Shea, J. J. (2000). Importance of the MKK6/p38 pathway for interleukin-12-induced STAT4 serine phosphorylation and transcriptional activity. Blood 96: 1844-1852 [Abstract] [Full Text]  
  • Gotoh, I., Adachi, M., Nishida, E. (2001). Identification and Characterization of a Novel MAP Kinase Kinase Kinase, MLTK. J. Biol. Chem. 276: 4276-4286 [Abstract] [Full Text]  
  • Dong, F., Gutkind, J. S., Larner, A. C. (2001). Granulocyte Colony-stimulating Factor Induces Erk5 Activation, Which Is Differentially Regulated by Protein-tyrosine Kinases and Protein Kinase C. REGULATION OF CELL PROLIFERATION AND SURVIVAL. J. Biol. Chem. 276: 10811-10816 [Abstract] [Full Text]  
  • Pearson, G., English, J. M., White, M. A., Cobb, M. H. (2001). ERK5 and ERK2 Cooperate to Regulate NF-kappa B and Cell Transformation. J. Biol. Chem. 276: 7927-7931 [Abstract] [Full Text]  
  • de Gregorio, R., Iniguez, M. A., Fresno, M., Alemany, S. (2001). Cot Kinase Induces Cyclooxygenase-2 Expression in T Cells through Activation of the Nuclear Factor of Activated T Cells. J. Biol. Chem. 276: 27003-27009 [Abstract] [Full Text]  
  • Chayama, K., Papst, P. J., Garrington, T. P., Pratt, J. C., Ishizuka, T., Webb, S., Ganiatsas, S., Zon, L. I., Sun, W., Johnson, G. L., Gelfand, E. W. (2001). Role of MEKK2-MEK5 in the regulation of TNF-alpha gene expression and MEKK2-MKK7 in the activation of c-Jun N-terminal kinase in mast cells. Proc. Natl. Acad. Sci. USA 98: 4599-4604 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»