J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/09/941/13 $2.00
Volume 186, Number 6, September 15, 1997 941-953

Impaired CD28-mediated Interleukin 2 Production and Proliferation in Stress Kinase SAPK/ERK1 Kinase (SEK1)/Mitogen-activated Protein Kinase Kinase 4 (MKK4)-deficient T Lymphocytes

By Hiroshi Nishina,^* Martin Bachmann, Antonio J. Oliveira-dos-Santos,^* Ivona Kozieradzki,^* Klaus D. Fischer,^§ Bernhard Odermatt,^¶ Andrew Wakeham,^* Arda Shahinian,^* Hiroaki Takimoto,^* Alan Bernstein, Tak W. Mak,^* James R. Woodgett, Pamela S. Ohashi, and Josef M. Penninger^*

From the ^* Amgen Institute and Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, M5G 2C1 Toronto, Ontario, Canada;  Ontario Cancer Institute, Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada; ^§ Institute for Radiation and Cell Research, University of Wuerzburg, D-97078 Wuerzburg, Germany;  Samuel Lunenfeld Research Institute and Department of Medical Genetics, University of Toronto, Mount Sinai Hospital, Toronto, Ontario, Canada; and ^¶ Institute for Experimental Immunology, University of Zürich, 8091, Zürich, Switzerland

The dual specific kinase SAPK/ERK1 kinase (SEK1; mitogen-activated protein kinase kinase 4/Jun NH₂ terminal kinase [ JNK] kinase) is a direct activator of stress-activated protein kinases ([SAPKs]/JNKs) in response to CD28 costimulation, CD40 signaling, or activation of the germinal center kinase. Here we show that SEK1^/ recombination-activating gene (RAG)2^/ chimeric mice have a partial block in B cell maturation. However, peripheral B cells displayed normal responses to IL-4, IgM, and CD40 cross-linking. SEK1^/ peripheral T cells showed decreased proliferation and IL-2 production after CD28 costimulation and PMA/Ca²⁺ ionophore activation. Although CD28 expression was absolutely crucial to generate vesicular stomatitis virus (VSV)-specific germinal centers, SEK1^/RAG2^/ chimeras mounted a protective antiviral B cell response, exhibited normal IgG class switching, and made germinal centers in response to VSV. Interestingly, PMA/Ca²⁺ ionophore stimulation, which mimics TCR-CD3 and CD28-mediated signal transduction, induced SAPK/JNK activation in peripheral T cells, but not in thymocytes, from SEK1^/ mice. These results show that signaling pathways for SAPK activation are developmentally regulated in T cells. Although SEK1^/ thymocytes failed to induce SAPK/JNK in response to PMA/Ca²⁺ ionophore, SEK1^/RAG2^/ thymocytes proliferated and made IL-2 after PMA/Ca²⁺ ionophore and CD3/CD28 stimulation, albeit at significantly lower levels compared to SEK1^+/+RAG2^/ thymocytes, implying that CD28 costimulation and PMA/Ca²⁺ ionophore-triggered signaling pathways exist that can mediate proliferation and IL-2 production independently of SAPK activation. Our data provide the first genetic evidence that SEK1 is an important effector molecule that relays CD28 signaling to IL-2 production and T cell proliferation.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

• Yoshizawa, T., Hammaker, D., Sweeney, S. E., Boyle, D. L., Firestein, G. S. (2008). Synoviocyte Innate Immune Responses: I. Differential Regulation of Interferon Responses and the JNK Pathway by MAPK Kinases. J. Immunol. 181: 3252-3258 [Abstract] [Full Text]  
• Robinson, V. L., Shalhav, O., Otto, K., Kawai, T., Gorospe, M., Rinker-Schaeffer, C. W. (2008). Mitogen-Activated Protein Kinase Kinase 4/c-Jun NH2-Terminal Kinase Kinase 1 Protein Expression Is Subject to Translational Regulation in Prostate Cancer Cell Lines. Mol Cancer Res 6: 501-508 [Abstract] [Full Text]  
• Sethi, G., Ahn, K. S., Xia, D., Kurie, J. M., Aggarwal, B. B. (2007). Targeted Deletion of MKK4 Gene Potentiates TNF-Induced Apoptosis through the Down-Regulation of NF-{kappa}B Activation and NF-{kappa}B-Regulated Antiapoptotic Gene Products. J. Immunol. 179: 1926-1933 [Abstract] [Full Text]  
• Krawczyk, C. M., Jones, R. G., Atfield, A., Bachmaier, K., Arya, S., Odermatt, B., Ohashi, P. S., Penninger, J. M. (2005). Differential Control of CD28-Regulated In Vivo Immunity by the E3 Ligase Cbl-b. J. Immunol. 174: 1472-1478 [Abstract] [Full Text]  
• Liu, J. O. (2005). The Yins of T Cell Activation. Sci Signal 2005: re1-re1 [Abstract] [Full Text]  
• Kuida, K., Boucher, D. M. (2004). Functions of MAP Kinases: Insights from Gene-Targeting Studies. J Biochem 135: 653-656 [Abstract] [Full Text]  
• Berg-Brown, N. N., Gronski, M. A., Jones, R. G., Elford, A. R., Deenick, E. K., Odermatt, B., Littman, D. R., Ohashi, P. S. (2004). PKC{theta} Signals Activation versus Tolerance In Vivo. JEM 199: 743-752 [Abstract] [Full Text]  
• Nishitai, G., Shimizu, N., Negishi, T., Kishimoto, H., Nakagawa, K., Kitagawa, D., Watanabe, T., Momose, H., Ohata, S., Tanemura, S., Asaka, S., Kubota, J., Saito, R., Yoshida, H., Mak, T. W., Wada, T., Penninger, J. M., Azuma, N., Nishina, H., Katada, T. (2004). Stress Induces Mitochondria-mediated Apoptosis Independent of SAPK/JNK Activation in Embryonic Stem Cells. J. Biol. Chem. 279: 1621-1626 [Abstract] [Full Text]  
• Parry, R. V., Rumbley, C. A., Vandenberghe, L. H., June, C. H., Riley, J. L. (2003). CD28 and Inducible Costimulatory Protein Src Homology 2 Binding Domains Show Distinct Regulation of Phosphatidylinositol 3-Kinase, Bcl-xL, and IL-2 Expression in Primary Human CD4 T Lymphocytes. J. Immunol. 171: 166-174 [Abstract] [Full Text]  
• Kishimoto, H., Nakagawa, K., Watanabe, T., Kitagawa, D., Momose, H., Seo, J., Nishitai, G., Shimizu, N., Ohata, S., Tanemura, S., Asaka, S., Goto, T., Fukushi, H., Yoshida, H., Suzuki, A., Sasaki, T., Wada, T., Penninger, J. M., Nishina, H., Katada, T. (2003). Different Properties of SEK1 and MKK7 in Dual Phosphorylation of Stress-induced Activated Protein Kinase SAPK/JNK in Embryonic Stem Cells. J. Biol. Chem. 278: 16595-16601 [Abstract] [Full Text]  
• Freywald, A., Sharfe, N., Rashotte, C., Grunberger, T., Roifman, C. M. (2003). The EphB6 Receptor Inhibits JNK Activation in T Lymphocytes and Modulates T Cell Receptor-mediated Responses. J. Biol. Chem. 278: 10150-10156 [Abstract] [Full Text]  
• Sakakibara, A., Hattori, S., Nakamura, S., Katagiri, T. (2003). A Novel Hematopoietic Adaptor Protein, Chat-H, Positively Regulates T Cell Receptor-mediated Interleukin-2 Production by Jurkat Cells. J. Biol. Chem. 278: 6012-6017 [Abstract] [Full Text]  
• Masuda, A., Yoshikai, Y., Aiba, K., Matsuguchi, T. (2002). Th2 Cytokine Production from Mast Cells Is Directly Induced by Lipopolysaccharide and Distinctly Regulated by c-Jun N-Terminal Kinase and p38 Pathways. J. Immunol. 169: 3801-3810 [Abstract] [Full Text]  
• Gringhuis, S. I., Papendrecht-van der Voort, E. A. M., Leow, A., Levarht, E. W. N., Breedveld, F. C., Verweij, C. L. (2002). Effect of Redox Balance Alterations on Cellular Localization of LAT and Downstream T-Cell Receptor Signaling Pathways. Mol. Cell. Biol. 22: 400-411 [Abstract] [Full Text]  
• Kitagawa, D., Tanemura, S., Ohata, S., Shimizu, N., Seo, J., Nishitai, G., Watanabe, T., Nakagawa, K., Kishimoto, H., Wada, T., Tezuka, T., Yamamoto, T., Nishina, H., Katada, T. (2002). Activation of Extracellular Signal-regulated Kinase by Ultraviolet Is Mediated through Src-dependent Epidermal Growth Factor Receptor Phosphorylation. ITS IMPLICATION IN AN ANTI-APOPTOTIC FUNCTION. J. Biol. Chem. 277: 366-371 [Abstract] [Full Text]  
• Sasaki, T., Wada, T., Kishimoto, H., Irie-Sasaki, J., Matsumoto, G., Goto, T., Yao, Z., Wakeham, A., Mak, T. W., Suzuki, A., Cho, S. K., Zuniga-Pflucker, J. C., Oliveira-dos-Santos, A. J., Katada, T., Nishina, H., Penninger, J. M. (2001). The Stress Kinase Mitogen-activated Protein Kinase Kinase (MKK)7 Is a Negative Regulator of Antigen Receptor and Growth Factor Receptor-induced Proliferation in Hematopoietic Cells. JEM 194: 757-768 [Abstract] [Full Text]  
• Rivas, F. V., O'Herrin, S., Gajewski, T. F. (2001). CD28 Is Not Required for c-Jun N-Terminal Kinase Activation in T Cells. J. Immunol. 167: 3123-3128 [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]  
• Sabapathy, K., Kallunki, T., David, J.-P., Graef, I., Karin, M., 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. JEM 193: 317-328 [Abstract] [Full Text]  
• Marti, F., Krause, A., Post, N. H., Lyddane, C., Dupont, B., Sadelain, M., King, P. D. (2001). Negative-Feedback Regulation of CD28 Costimulation by a Novel Mitogen-Activated Protein Kinase Phosphatase, MKP6. J. Immunol. 166: 197-206 [Abstract] [Full Text]  
• Almeida, E. A.C., Ili, D., Han, Q., Hauck, C. R., Jin, F., Kawakatsu, H., Schlaepfer, D. D., Damsky, C. H. (2000). Matrix Survival Signaling: From Fibronectin via Focal Adhesion Kinase to c-Jun NH2-terminal Kinase. JCB 149: 741-754 [Abstract] [Full Text]  
• Weiss, L., Whitmarsh, A. J., Yang, D. D., Rincon, M., Davis, R. J., Flavell, R. A. (2000). Regulation of c-Jun NH2-terminal Kinase ( Jnk) Gene Expression during T Cell Activation. JEM 191: 139-146 [Abstract] [Full Text]  
• Bachmann, M. F., Nitschke, L., Krawczyk, C., Tedford, K., Ohashi, P. S., Fischer, K. D., Penninger, J. M. (1999). The Guanine-Nucleotide Exchange Factor Vav Is a Crucial Regulator of B Cell Receptor Activation and B Cell Responses to Nonrepetitive Antigens. J. Immunol. 163: 137-142 [Abstract] [Full Text]  
• Zhang, J., Salojin, K. V., Gao, J.-X., Cameron, M. J., Bergerot, I., Delovitch, T. L. (1999). p38 Mitogen-Activated Protein Kinase Mediates Signal Integration of TCR/CD28 Costimulation in Primary Murine T Cells. J. Immunol. 162: 3819-3829 [Abstract] [Full Text]  
• Sadra, A., Cinek, T., Arellano, J. L., Shi, J., Truitt, K. E., Imboden, J. B. (1999). Identification of Tyrosine Phosphorylation Sites in the CD28 Cytoplasmic Domain and Their Role in the Costimulation of Jurkat T Cells. J. Immunol. 162: 1966-1973 [Abstract] [Full Text]  
• Tournier, C., Whitmarsh, A. J., Cavanagh, J., Barrett, T., Davis, R. J. (1999). The MKK7 Gene Encodes a Group of c-Jun NH2-Terminal Kinase Kinases. Mol. Cell. Biol. 19: 1569-1581 [Abstract] [Full Text]  
• Nishina, H, Vaz, C, Billia, P, Nghiem, M, Sasaki, T, De la Pompa, J., Furlonger, K, Paige, C, Hui, C, Fischer, K., Kishimoto, H, Iwatsubo, T, Katada, T, Woodgett, J., Penninger, J. (1999). Defective liver formation and liver cell apoptosis in mice lacking the stress signaling kinase SEK1/MKK4. Development 126: 505-516 [Abstract]  
• Kong, Y.-Y., Fischer, K.-D., Bachmann, M. F., Mariathasan, S., Kozieradzki, I., Nghiem, M. P., Bouchard, D., Bernstein, A., Ohashi, P. S., Penninger, J. M. (1998). Vav Regulates Peptide-specific Apoptosis in Thymocytes. JEM 188: 2099-2111 [Abstract] [Full Text]  
• Nishina, H., Radvanyi, L., Raju, K., Sasaki, T., Kozieradzki, I., Penninger, J. M. (1998). Impaired TCR-Mediated Apoptosis and Bcl-XL Expression in T Cells Lacking the Stress Kinase Activator SEK1/MKK4. J. Immunol. 161: 3416-3420 [Abstract] [Full Text]  
• Harhaj, E. W., Sun, S.-C. (1998). Ikappa B Kinases Serve as a Target of CD28 Signaling. J. Biol. Chem. 273: 25185-25190 [Abstract] [Full Text]  
• Grammer, A. C., Swantek, J. L., McFarland, R. D., Miura, Y., Geppert, T., Lipsky, P. E. (1998). TNF Receptor-Associated Factor-3 Signaling Mediates Activation of p38 and Jun N-Terminal Kinase, Cytokine Secretion, and Ig Production Following Ligation of CD40 on Human B Cells. J. Immunol. 161: 1183-1193 [Abstract] [Full Text]  
• Matsuda, S., Moriguchi, T., Koyasu, S., Nishida, E. (1998). T Lymphocyte Activation Signals for Interleukin-2 Production Involve Activation of MKK6-p38 and MKK7-SAPK/JNK Signaling Pathways Sensitive to Cyclosporin A. J. Biol. Chem. 273: 12378-12382 [Abstract] [Full Text]  
• Kaga, S., Ragg, S., Rogers, K. A., Ochi, A. (1998). Activation of p21-CDC42/Rac-Activated Kinases by CD28 Signaling: p21-Activated Kinase (PAK) and MEK Kinase 1 (MEKK1) May Mediate the Interplay Between CD3 and CD28 Signals. J. Immunol. 160: 4182-4189 [Abstract] [Full Text]  
• Hoffmeyer, A., Avots, A., Flory, E., Weber, C. K., Serfling, E., Rapp, U. R. (1998). The GABP-responsive Element of the Interleukin-2 Enhancer Is Regulated by JNK/SAPK-activating Pathways in T Lymphocytes. J. Biol. Chem. 273: 10112-10119 [Abstract] [Full Text]  
• Foltz, I. N., Gerl, R. E., Wieler, J. S., Luckach, M., Salmon, R. A., Schrader, J. W. (1998). Human Mitogen-activated Protein Kinase Kinase 7 (MKK7) Is a Highly Conserved c-Jun N-terminal Kinase/Stress-activated Protein Kinase (JNK/SAPK) Activated by Environmental Stresses and Physiological Stimuli. J. Biol. Chem. 273: 9344-9351 [Abstract] [Full Text]  
• Yao, Z., Diener, K., Wang, X. S., Zukowski, M., Matsumoto, G., Zhou, G., Mo, R., Sasaki, T., Nishina, H., Hui, C. C., Tan, T.-H., Woodgett, J. P., Penninger, J. M. (1997). Activation of Stress-activated Protein Kinases/c-Jun N-terminal Protein Kinases (SAPKs/JNKs) by a Novel Mitogen-activated Protein Kinase Kinase (MKK7). J. Biol. Chem. 272: 32378-32383 [Abstract] [Full Text]  
• Thangaraju, M., Kaufmann, S. H., Couch, F. J. (2000). BRCA1 Facilitates Stress-induced Apoptosis in Breast and Ovarian Cancer Cell Lines. J. Biol. Chem. 275: 33487-33496 [Abstract] [Full Text]  
• Moller, A., Dienz, O., Hehner, S. P., Droge, W., Schmitz, M. L. (2001). Protein Kinase C theta Cooperates with Vav1 to Induce JNK Activity in T-cells. J. Biol. Chem. 276: 20022-20028 [Abstract] [Full Text]  
• Wada, T., Nakagawa, K., Watanabe, T., Nishitai, G., Seo, J., Kishimoto, H., Kitagawa, D., Sasaki, T., Penninger, J. M., Nishina, H., Katada, T. (2001). Impaired Synergistic Activation of Stress-activated Protein Kinase SAPK/JNK in Mouse Embryonic Stem Cells Lacking SEK1/MKK4. DIFFERENT CONTRIBUTION OF SEK2/MKK7 ISOFORMS TO THE SYNERGISTIC ACTIVATION. J. Biol. Chem. 276: 30892-30897 [Abstract] [Full Text]  
• Katagiri, T., Takahashi, T., Sasaki, T., Nakamura, S., Hattori, S. (2000). Protein-tyrosine Kinase Pyk2 Is Involved in Interleukin-2 Production by Jurkat T Cells via Its Tyrosine 402. J. Biol. Chem. 275: 19645-19652 [Abstract] [Full Text]  
• Conze, D., Krahl, T., Kennedy, N., Weiss, L., Lumsden, J., Hess, P., Flavell, R. A., Le Gros, G., Davis, R. J., Rincon, M. (2002). c-Jun NH2-Terminal Kinase (JNK)1 and JNK2 Have Distinct Roles in CD8+ T Cell Activation. JEM 195: 811-823 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS