Home | Help | Feedback | Subscriptions | Archive | Search | Table of Contents

This Article Full Text Full Text (PDF, 239K) PPT slides of all figures Alert me when this article is cited Citation Map Services Email this article Similar articles in this journal Similar articles in PubMed Alert me to new content in the JEM Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Brumbaugh, K. M. Articles by Leibson, P. J. Search for Related Content PubMed PubMed Citation Articles by Brumbaugh, K. M. Articles by Leibson, P. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL Social Bookmarking                            What's this?

Article

Kathryn M. Brumbaugh^*, Bryce A. Binstadt^*, Daniel D. Billadeau^*, Renee A. Schoon^*, Christopher J. Dick^*, Rosa M. Ten, and Paul J. Leibson^*

From the ^* Department of Immunology, and the Division of Allergy, Mayo Clinic and Foundation, Rochester, Minnesota 55905

Natural killer (NK) cells are named based on their natural cytotoxic activity against a variety of target cells. However, the mechanisms by which sensitive targets activate killing have been difficult to study due to the lack of a prototypic NK cell triggering receptor. Pharmacologic evidence has implicated protein tyrosine kinases (PTKs) in natural killing; however, Lck-deficient, Fyn-deficient, and ZAP-70–deficient mice do not exhibit defects in natural killing despite demonstrable defects in T cell function. This discrepancy implies the involvement of other tyrosine kinases. Here, using combined biochemical, pharmacologic, and genetic approaches, we demonstrate a central role for the PTK Syk in natural cytotoxicity. Biochemical analyses indicate that Syk is tyrosine phosphorylated after stimulation with a panel of NK-sensitive target cells. Pharmacologic exposure to piceatannol, a known Syk family kinase inhibitor, inhibits natural cytotoxicity. In addition, gene transfer of dominant-negative forms of Syk to NK cells inhibits natural cytotoxicity. Furthermore, sensitive targets that are rendered NK-resistant by major histocompatibility complex (MHC) class I transfection no longer activate Syk. These data suggest that Syk activation is an early and requisite signaling event in the development of natural cytotoxicity directed against a variety of cellular targets.

This research was supported by the Mayo Foundation and by grant CA-47752 from the National Institutes of Health.

¹ Abbreviations used in this paper: ADCC, antibody-dependent cell-mediated cytotoxicity; ITAM, immunoreceptor tyrosine-based activation motif; KAR, killer cell activating receptor; KARAP, KAR-associated protein; KIR, killer cell inhibitory receptor; PTK, protein tyrosine kinase.

Kathryn M. Brumbaugh and Bryce A. Binstadt contributed equally to this work.

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

This article has been cited by other articles:

• Starlets, D., Gore, Y., Binsky, I., Haran, M., Harpaz, N., Shvidel, L., Becker-Herman, S., Berrebi, A., Shachar, I. (2006). Cell-surface CD74 initiates a signaling cascade leading to cell proliferation and survival. Blood 107: 4807-4816 [Abstract] [Full Text]  
• Mason, L. H., Willette-Brown, J., Taylor, L. S., McVicar, D. W. (2006). Regulation of Ly49D/DAP12 Signal Transduction by Src-Family Kinases and CD45.. J. Immunol. 176: 6615-6623 [Abstract] [Full Text]  
• Hart, G., Flaishon, L., Becker-Herman, S., Shachar, I. (2005). Tight Regulation of IFN-{gamma} Transcription and Secretion in Immature and Mature B cells by the Inhibitory MHC Class I Receptor, Ly49G2. J. Immunol. 175: 5034-5042 [Abstract] [Full Text]  
• Westgaard, I. H., Berg, S. F., Vaage, J. T., Wang, L. L., Yokoyama, W. M., Dissen, E., Fossum, S. (2004). Rat NKp46 activates natural killer cell cytotoxicity and is associated with Fc{varepsilon}RI{gamma} and CD3{zeta}. J. Leukoc. Biol. 76: 1200-1206 [Abstract] [Full Text]  
• Perez, O. D., Mitchell, D., Jager, G. C., Nolan, G. P. (2004). LFA-1 signaling through p44/42 is coupled to perforin degranulation in CD56+CD8+ natural killer cells. Blood 104: 1083-1093 [Abstract] [Full Text]  
• Gismondi, A., Cifaldi, L., Mazza, C., Giliani, S., Parolini, S., Morrone, S., Jacobelli, J., Bandiera, E., Notarangelo, L., Santoni, A. (2004). Impaired natural and CD16-mediated NK cell cytotoxicity in patients with WAS and XLT: ability of IL-2 to correct NK cell functional defect. Blood 104: 436-443 [Abstract] [Full Text]  
• Lavender, K. J., Ma, B. J., Silver, E. T., Kane, K. P. (2004). The Rat RT1-A1c MHC Molecule Is a Xenogeneic Ligand Recognized by the Mouse Activating Ly-49W and Inhibitory Ly-49G Receptors. J. Immunol. 172: 3518-3526 [Abstract] [Full Text]  
• Kumaran, S., Grucza, R. A., Waksman, G. (2003). The tandem Src homology 2 domain of the Syk kinase: A molecular device that adapts to interphosphotyrosine distances. Proc. Natl. Acad. Sci. USA 100: 14828-14833 [Abstract] [Full Text]  
• Stebbins, C. C., Watzl, C., Billadeau, D. D., Leibson, P. J., Burshtyn, D. N., Long, E. O. (2003). Vav1 Dephosphorylation by the Tyrosine Phosphatase SHP-1 as a Mechanism for Inhibition of Cellular Cytotoxicity. Mol. Cell. Biol. 23: 6291-6299 [Abstract] [Full Text]  
• Yamamoto, N., Takeshita, K., Shichijo, M., Kokubo, T., Sato, M., Nakashima, K., Ishimori, M., Nagai, H., Li, Y.-F., Yura, T., Bacon, K. B. (2003). The Orally Available Spleen Tyrosine Kinase Inhibitor 2-[7-(3,4-Dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino]nicotinamide Dihydrochloride (BAY 61-3606) Blocks Antigen-Induced Airway Inflammation in Rodents. J. Pharmacol. Exp. Ther. 306: 1174-1181 [Abstract] [Full Text]  
• Khurana, D., Leibson, P. J. (2003). Regulation of lymphocyte-mediated killing by GTP-binding proteins. J. Leukoc. Biol. 73: 333-338 [Abstract] [Full Text]  
• Pisegna, S., Zingoni, A., Pirozzi, G., Cinque, B., Cifone, M. G., Morrone, S., Piccoli, M., Frati, L., Palmieri, G., Santoni, A. (2002). Src-Dependent Syk Activation Controls CD69-Mediated Signaling and Function on Human NK Cells. J. Immunol. 169: 68-74 [Abstract] [Full Text]  
• Ticchioni, M., Charvet, C., Noraz, N., Lamy, L., Steinberg, M., Bernard, A., Deckert, M. (2002). Signaling through ZAP-70 is required for CXCL12-mediated T-cell transendothelial migration. Blood 99: 3111-3118 [Abstract] [Full Text]  
• Jiang, K., Zhong, B., Gilvary, D. L., Corliss, B. C., Vivier, E., Hong-Geller, E., Wei, S., Djeu, J. Y. (2002). Syk Regulation of Phosphoinositide 3-Kinase-Dependent NK Cell Function. J. Immunol. 168: 3155-3164 [Abstract] [Full Text]  
• Yu, W.-M., Hawley, T. S., Hawley, R. G., Qu, C.-K. (2002). Role of the docking protein Gab2 in beta 1-integrin signaling pathway-mediated hematopoietic cell adhesion and migration. Blood 99: 2351-2359 [Abstract] [Full Text]  
• Djeu, J. Y., Jiang, K., Wei, S. (2002). A View to a Kill: Signals Triggering Cytotoxicity. Clin. Cancer Res. 8: 636-640 [Abstract] [Full Text]  
• Chuang, S. S., Kumaresan, P. R., Mathew, P. A. (2001). 2B4 (CD244)-Mediated Activation of Cytotoxicity and IFN-{gamma} Release in Human NK Cells Involves Distinct Pathways. J. Immunol. 167: 6210-6216 [Abstract] [Full Text]  
• Lou, Z., Billadeau, D. D., Savoy, D. N., Schoon, R. A., Leibson, P. J. (2001). A Role for a RhoA/ROCK/LIM-Kinase Pathway in the Regulation of Cytotoxic Lymphocytes. J. Immunol. 167: 5749-5757 [Abstract] [Full Text]  
• Vyas, Y. M., Mehta, K. M., Morgan, M., Maniar, H., Butros, L., Jung, S., Burkhardt, J. K., Dupont, B. (2001). Spatial Organization of Signal Transduction Molecules in the NK Cell Immune Synapses During MHC Class I-Regulated Noncytolytic and Cytolytic Interactions. J. Immunol. 167: 4358-4367 [Abstract] [Full Text]  
• Miller, J. S., McCullar, V. (2001). Human natural killer cells with polyclonal lectin and immunoglobulinlike receptors develop from single hematopoietic stem cells with preferential expression of NKG2A and KIR2DL2/L3/S2. Blood 98: 705-713 [Abstract] [Full Text]  
• Jevremovic, D., Billadeau, D. D., Schoon, R. A., Dick, C. J., Leibson, P. J. (2001). Regulation of NK Cell-Mediated Cytotoxicity by the Adaptor Protein 3BP2. J. Immunol. 166: 7219-7228 [Abstract] [Full Text]  
• Silver, E. T., Gong, D.-E., Hazes, B., Kane, K. P. (2001). Ly-49W, an Activating Receptor of Nonobese Diabetic Mice With Close Homology to the Inhibitory Receptor Ly-49G, Recognizes H-2Dk and H-2Dd. J. Immunol. 166: 2333-2341 [Abstract] [Full Text]  
• Yamada, T., Fujieda, S., Yanagi, S., Yamamura, H., Inatome, R., Sunaga, H., Saito, H. (2001). Protein-Tyrosine Kinase Syk Expressed in Human Nasal Fibroblasts and Its Effect on RANTES Production. J. Immunol. 166: 538-543 [Abstract] [Full Text]  
• Wei, S., Gilvary, D. L., Corliss, B. C., Sebti, S., Sun, J., Straus, D. B., Leibson, P. J., Trapani, J. A., Hamilton, A. D., Weber, M. J., Djeu, J. Y. (2000). Direct Tumor Lysis by NK Cells Uses a Ras-Independent Mitogen-Activated Protein Kinase Signal Pathway. J. Immunol. 165: 3811-3819 [Abstract] [Full Text]  
• Trotta, R., Fettucciari, K., Azzoni, L., Abebe, B., Puorro, K. A., Eisenlohr, L. C., Perussia, B. (2000). Differential Role of p38 and c-Jun N-Terminal Kinase 1 Mitogen-Activated Protein Kinases in NK Cell Cytotoxicity. J. Immunol. 165: 1782-1789 [Abstract] [Full Text]  
• Billadeau, D. D., Mackie, S. M., Schoon, R. A., Leibson, P. J. (2000). The Rho Family Guanine Nucleotide Exchange Factor Vav-2 Regulates the Development of Cell-Mediated Cytotoxicity. JEM 192: 381-392 [Abstract] [Full Text]  
• Sancho, D., Nieto, M., Llano, M., Rodriguez-Fernandez, J. L., Tejedor, R., Avraham, S., Cabanas, C., Lopez-Botet, M., Sanchez-Madrid, F. (2000). The Tyrosine Kinase Pyk-2/Raftk Regulates Natural Killer (Nk) Cell Cytotoxic Response, and Is Translocated and Activated upon Specific Target Cell Recognition and Killing. JCB 149: 1249-1262 [Abstract] [Full Text]  
• Gismondi, A., Jacobelli, J., Mainiero, F., Paolini, R., Piccoli, M., Frati, L., Santoni, A. (2000). Cutting Edge: Functional Role for Proline-Rich Tyrosine Kinase 2 in NK Cell-Mediated Natural Cytotoxicity. J. Immunol. 164: 2272-2276 [Abstract] [Full Text]  
• Lou, Z., Jevremovic, D., Billadeau, D. D., Leibson, P. J. (2000). A Balance between Positive and Negative Signals in Cytotoxic Lymphocytes Regulates the Polarization of Lipid Rafts during the Development of Cell-Mediated Killing. JEM 191: 347-354 [Abstract] [Full Text]  
• Mason, L. H., Willette-Brown, J., Mason, A. T., McVicar, D., Ortaldo, J. R. (2000). Interaction of Ly-49D+ NK Cells with H-2Dd Target Cells Leads to Dap-12 Phosphorylation and IFN-{gamma} Secretion. J. Immunol. 164: 603-611 [Abstract] [Full Text]  
• Ortaldo, J. R., Winkler-Pickett, R., Willette-Brown, J., Wange, R. L., Anderson, S. K., Palumbo, G. J., Mason, L. H., McVicar, D. W. (1999). Structure/Function Relationship of Activating Ly-49D and Inhibitory Ly-49G2 NK Receptors ,2. J. Immunol. 163: 5269-5277 [Abstract] [Full Text]  
• Cambien, B., Millet, M.-A., Schmid-Antomarchi, H., Brossette, N., Rossi, B., Schmid-Alliana, A. (1999). Src-Regulated Extracellular Signal-Related Kinase and Syk-Regulated c-Jun N-Terminal Kinase Pathways Act in Conjunction to Induce IL-1 Synthesis in Response to Microtubule Disruption in HL60 Cells. J. Immunol. 163: 5079-5085 [Abstract] [Full Text]  
• Colucci, F., Turner, M., Schweighoffer, E., Guy-Grand, D., Di Bartolo, V., Salcedo, M., Tybulewicz, V. L. J., Di Santo, J. P. (1999). Redundant Role of the Syk Protein Tyrosine Kinase in Mouse NK Cell Differentiation. J. Immunol. 163: 1769-1774 [Abstract] [Full Text]  
• Palmieri, G., Tullio, V., Zingoni, A., Piccoli, M., Frati, L., Lopez-Botet, M., Santoni, A. (1999). CD94/NKG2-A Inhibitory Complex Blocks CD16-Triggered Syk and Extracellular Regulated Kinase Activation, Leading to Cytotoxic Function of Human NK Cells. J. Immunol. 162: 7181-7188 [Abstract] [Full Text]  
• Carlyle, J. R., Martin, A., Mehra, A., Attisano, L., Tsui, F. W., Zuniga-Pflucker, J. C. (1999). Mouse NKR-P1B, a Novel NK1.1 Antigen with Inhibitory Function. J. Immunol. 162: 5917-5923 [Abstract] [Full Text]  
• Bernard, K., Cambiaggi, A., Guia, S., Bertucci, F., Granjeaud, S., Tagett, R., N'Guyen, C., Jordan, B. R., Vivier, E. (1999). Engagement of Natural Cytotoxicity Programs Regulates AP-1 Expression in the NKL Human NK Cell Line. J. Immunol. 162: 4062-4068 [Abstract] [Full Text]  
• Galandrini, R., Palmieri, G., Piccoli, M., Frati, L., Santoni, A. (1999). Role for the Rac1 Exchange Factor Vav in the Signaling Pathways Leading to NK Cell Cytotoxicity. J. Immunol. 162: 3148-3152 [Abstract] [Full Text]  
• Jevremovic, D., Billadeau, D. D., Schoon, R. A., Dick, C. J., Irvin, B. J., Zhang, W., Samelson, L. E., Abraham, R. T., Leibson, P. J. (1999). Cutting Edge: A Role for the Adaptor Protein LAT in Human NK Cell-Mediated Cytotoxicity. J. Immunol. 162: 2453-2456 [Abstract] [Full Text]  
• Trotta, R., Puorro, K. A., Paroli, M., Azzoni, L., Abebe, B., Eisenlohr, L. C., Perussia, B. (1998). Dependence of Both Spontaneous and Antibody-Dependent, Granule Exocytosis-Mediated NK Cell Cytotoxicity on Extracellular Signal-Regulated Kinases. J. Immunol. 161: 6648-6656 [Abstract] [Full Text]  
• McVicar, D. W., Taylor, L. S., Gosselin, P., Willette-Brown, J., Mikhael, A. I., Geahlen, R. L., Nakamura, M. C., Linnemeyer, P., Seaman, W. E., Anderson, S. K., Ortaldo, J. R., Mason, L. H. (1998). DAP12-mediated Signal Transduction in Natural Killer Cells. A DOMINANT ROLE FOR THE Syk PROTEIN-TYROSINE KINASE. J. Biol. Chem. 273: 32934-32942 [Abstract] [Full Text]  
• Binstadt, B. A., Billadeau, D. D., Williams, B. L., Fang, N., Yi, T., Koretzky, G. A., Abraham, R. T., Leibson, P. J. (1998). SLP-76 Is a Direct Substrate of SHP-1 Recruited to Killer Cell Inhibitory Receptors. J. Biol. Chem. 273: 27518-27523 [Abstract] [Full Text]  
• Billadeau, D. D., Brumbaugh, K. M., Dick, C. J., Schoon, R. A., Bustelo, X. R., Leibson, P. J. (1998). The Vav-Rac1 Pathway in Cytotoxic Lymphocytes Regulates the Generation of Cell-mediated Killing. JEM 188: 549-559 [Abstract] [Full Text]  
• Southwood, S., Sidney, J., Kondo, A., del Guercio, M.-F., Appella, E., Hoffman, S., Kubo, R. T., Chesnut, R. W., Grey, H. M., Sette, A. (1998). Several Common HLA-DR Types Share Largely Overlapping Peptide Binding Repertoires. J. Immunol. 160: 3363-3373 [Abstract] [Full Text]  
• Ganju, R. K., Brubaker, S. A., Chernock, R. D., Avraham, S., Groopman, J. E. (2000). beta -Chemokine Receptor CCR5 Signals through SHP1, SHP2, and Syk. J. Biol. Chem. 275: 17263-17268 [Abstract] [Full Text]  

Home | Help | Feedback | Subscriptions | Archive | Search

TABLE OF CONTENTS