J. Exp. Med.
© The Rockefeller University Press
0022-1007/97/10/1165/06 $2.00
Volume 186, Number 7, October 6, 1997 1165-1170

BRIEF DEFINITIVE REPORT:
Cloning and Characterization of TRAIL-R3, a Novel Member of the Emerging TRAIL Receptor Family

By Mariapia A. Degli-Esposti, Pamela J. Smolak, Henning Walczak, Jennifer Waugh, Chang-Pin Huang, Robert F. DuBose, Raymond G. Goodwin, and Craig A. Smith

From the Department of Biochemistry and the Department of Molecular Biology, Immunex Corporation, Seattle, Washington 98101

TRAIL-R3, a new member of the TRAIL receptor family, has been cloned and characterized. TRAIL-R3 encodes a 299 amino acid protein with 58 and 54% overall identity to TRAIL-R1 and -R2, respectively. Transient expression and quantitative binding studies show TRAIL-R3 to be a plasma membrane-bound protein capable of high affinity interaction with the TRAIL ligand. The TRAIL-R3 gene maps to human chromosome 8p22-21, clustered with the genes encoding two other TRAIL receptors. In contrast to TRAIL-R1 and -R2, this receptor shows restricted expression, with transcripts detectable only in peripheral blood lymphocytes and spleen. The structure of TRAIL-R3 is unique when compared to the other TRAIL receptors in that it lacks a cytoplasmic domain and appears to be glycosyl-phosphatidylinositol-linked. Moreover, unlike TRAIL-R1 and -R2, in a transient overexpression system TRAIL-R3 does not induce apoptosis.

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• Kayagaki, N., Yamaguchi, N., Nakayama, M., Kawasaki, A., Akiba, H., Okumura, K., Yagita, H. (1999). Involvement of TNF-Related Apoptosis-Inducing Ligand in Human CD4+ T Cell-Mediated Cytotoxicity. J. Immunol. 162: 2639-2647 [Abstract] [Full Text]  
• Keane, M. M., Ettenberg, S. A., Nau, M. M., Russell, E. K., Lipkowitz, S. (1999). Chemotherapy Augments TRAIL-induced Apoptosis in Breast Cell Lines. Cancer Res. 59: 734-741 [Abstract] [Full Text]  
• Zamai, L., Ahmad, M., Bennett, I. M., Azzoni, L., Alnemri, E. S., Perussia, B. (1998). Natural Killer (NK) Cell-mediated Cytotoxicity: Differential Use of  TRAIL and Fas Ligand by Immature and Mature Primary Human NK Cells. J. Exp. Med. 188: 2375-2380 [Abstract] [Full Text]  
• Spielman, J., Lee, R. K., Podack, E. R. (1998). Perforin/Fas-Ligand Double Deficiency Is Associated with Macrophage Expansion and Severe Pancreatitis. J. Immunol. 161: 7063-7070 [Abstract] [Full Text]  
• Muhlenbeck, F., Haas, E., Schwenzer, R., Schubert, G., Grell, M., Smith, C., Scheurich, P., Wajant, H. (1998). TRAIL/Apo2L Activates c-Jun NH2-terminal Kinase (JNK) via Caspase-dependent and Caspase-independent Pathways. J. Biol. Chem. 273: 33091-33098 [Abstract] [Full Text]  
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• Harrop, J. A., McDonnell, P. C., Brigham-Burke, M., Lyn, S. D., Minton, J., Tan, K. B., Dede, K., Spampanato, J., Silverman, C., Hensley, P., DiPrinzio, R., Emery, J. G., Deen, K., Eichman, C., Chabot-Fletcher, M., Truneh, A., Young, P. R. (1998). Herpesvirus Entry Mediator Ligand (HVEM-L), a Novel Ligand for HVEM/TR2, Stimulates Proliferation of T Cells and Inhibits HT29 Cell Growth. J. Biol. Chem. 273: 27548-27556 [Abstract] [Full Text]  
• Craxton, A., Shu, G., Graves, J. D., Saklatvala, J., Krebs, E. G., Clark, E. A. (1998). p38 MAPK Is Required for CD40-Induced Gene Expression and Proliferation in B Lymphocytes. J. Immunol. 161: 3225-3236 [Abstract] [Full Text]  
• Griffith, T. S., Chin, W. A., Jackson, G. C., Lynch, D. H., Kubin, M. Z. (1998). Intracellular Regulation of TRAIL-Induced Apoptosis in Human Melanoma Cells. J. Immunol. 161: 2833-2840 [Abstract] [Full Text]  
• Thomas, W. D., Hersey, P. (1998). TNF-Related Apoptosis-Inducing Ligand (TRAIL) Induces Apoptosis in Fas Ligand-Resistant Melanoma Cells and Mediates CD4 T Cell Killing of Target Cells. J. Immunol. 161: 2195-2200 [Abstract] [Full Text]  
• Ashkenazi, A., Dixit, V. M. (1998). Death Receptors: Signaling and Modulation. Science 281: 1305-1308 [Abstract] [Full Text]  
• Harrop, J. A., Reddy, M., Dede, K., Brigham-Burke, M., Lyn, S., Tan, K. B., Silverman, C., Eichman, C., DiPrinzio, R., Spampanato, J., Porter, T., Holmes, S., Young, P. R., Truneh, A. (1998). Antibodies to TR2 (Herpesvirus Entry Mediator), a New Member of the TNF Receptor Superfamily, Block T Cell Proliferation, Expression of Activation Markers, and Production of Cytokines. J. Immunol. 161: 1786-1794 [Abstract] [Full Text]  
• Jeremias, I., Kupatt, C., Baumann, B., Herr, I., Wirth, T., Debatin, K.M. (1998). Inhibition of Nuclear Factor kappa B Activation Attenuates Apoptosis Resistance in Lymphoid Cells. Blood 91: 4624-4631 [Abstract] [Full Text]  
• Zhang, C., Xu, Y., Gu, J., Schlossman, S. F. (1998). A cell surface receptor defined by a mAb mediates a unique type of cell death similar to oncosis. Proc. Natl. Acad. Sci. USA 95: 6290-6295 [Abstract] [Full Text]  
• Schneider, P., Holler, N., Bodmer, J.-L., Hahne, M., Frei, K., Fontana, A., Tschopp, J. (1998). Conversion of Membrane-bound Fas(CD95) Ligand to Its Soluble Form Is Associated with Downregulation of Its Proapoptotic Activity and Loss of Liver Toxicity. J. Exp. Med. 187: 1205-1213 [Abstract] [Full Text]  
• Katsikis, P. D., Garcia-Ojeda, M. E., Torres-Roca, J. F., Tijoe, I. M., Smith, C. A., Herzenberg, L. A., Herzenberg, L. A. (1997). Interleukin-1beta Converting Enzyme-like Protease Involvement in Fas-induced and Activation-induced Peripheral Blood T Cell Apoptosis in HIV Infection. TNF-related Apoptosis-inducing Ligand Can Mediate Activation-induced T Cell Death in HIV Infection. J. Exp. Med. 186: 1365-1372 [Abstract] [Full Text]  

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