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The Journal of Immunology, Vol 157, Issue 3 1047-1053, Copyright © 1996 by American Association of Immunologists
ARTICLES |
BS Hostager, Y Hsing, DE Harms and GA Bishop
Department of Microbiology, University of Iowa, Iowa City, IA 52242, USA.
Signals delivered to B cells through CD40 are critical to the development of humoral immune responses. In this study we characterize regions of the 62-amino acid cytoplasmic domain of human CD40 (hCD40) that are essential for signal transduction and examine the functional consequences of mutations in these regions. A panel of mutant hCD40 molecules was stably expressed in mouse B cell lines and tested for its ability to stimulate Ab secretion, homotypic adhesion, and increased surface expression of B7, Fas, CD23, LFA-1, and intracellular adhesion molecule-1. Our results indicate that CD40 contains at least two major signaling determinants in the cytoplasmic domain: one disrupted by a truncation of 22 amino acids, and a second disrupted by the removal of 10 additional amino acids. The second determinant includes threonine 234, a residue previously shown to be important in CD40 signal transduction. Our functional analysis of alanine and serine substitutions at position 234 indicates that phosphorylation of this residue may be important for full CD40 signaling activity.
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  A. L. Peters, R. M. Plenge, R. R. Graham, D. M. Altshuler, K. L. Moser, P. M. Gaffney, and G. A. Bishop A novel polymorphism of the human CD40 receptor with enhanced function Blood, September 1, 2008; 112(5): 1863 - 1871. [Abstract] [Full Text] [PDF]
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M. E. Munroe and G. A. Bishop A Costimulatory Function for T Cell CD40 J. Immunol., January 15, 2007; 178(2): 671 - 682. [Abstract] [Full Text] [PDF]
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P. Xie, B. S. Hostager, M. E. Munroe, C. R. Moore, and G. A. Bishop Cooperation between TNF Receptor-Associated Factors 1 and 2 in CD40 Signaling J. Immunol., May 1, 2006; 176(9): 5388 - 5400. [Abstract] [Full Text] [PDF]
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C. R. Moore and G. A. Bishop Differential Regulation of CD40-Mediated TNF Receptor-Associated Factor Degradation in B Lymphocytes J. Immunol., September 15, 2005; 175(6): 3780 - 3789. [Abstract] [Full Text] [PDF]
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 G. Terrazzano, M. Sica, C. Becchimanzi, S. Costantini, B. Rotoli, S. Zappacosta, F. Alfinito, and G. Ruggiero T cells from paroxysmal nocturnal haemoglobinuria (PNH) patients show an altered CD40-dependent pathway J. Leukoc. Biol., July 1, 2005; 78(1): 27 - 36. [Abstract] [Full Text] [PDF]
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L. Mukundan, G. A. Bishop, K. Z. Head, L. Zhang, L. M. Wahl, and J. Suttles TNF Receptor-Associated Factor 6 Is an Essential Mediator of CD40-Activated Proinflammatory Pathways in Monocytes and Macrophages J. Immunol., January 15, 2005; 174(2): 1081 - 1090. [Abstract] [Full Text] [PDF]
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M. E. Munroe and G. A. Bishop Role of Tumor Necrosis Factor (TNF) Receptor-associated Factor 2 (TRAF2) in Distinct and Overlapping CD40 and TNF Receptor 2/CD120b-mediated B Lymphocyte Activation J. Biol. Chem., December 17, 2004; 279(51): 53222 - 53231. [Abstract] [Full Text] [PDF]
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P. Xie and G. A. Bishop Roles of TNF Receptor-Associated Factor 3 in Signaling to B Lymphocytes by Carboxyl-Terminal Activating Regions 1 and 2 of the EBV-Encoded Oncoprotein Latent Membrane Protein 1 J. Immunol., November 1, 2004; 173(9): 5546 - 5555. [Abstract] [Full Text] [PDF]
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 P. Xie, B. S. Hostager, and G. A. Bishop Requirement for TRAF3 in Signaling by LMP1 But Not CD40 in B Lymphocytes J. Exp. Med., March 1, 2004; 199(5): 661 - 671. [Abstract] [Full Text] [PDF]
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S. A. Haxhinasto and G. A. Bishop Synergistic B Cell Activation by CD40 and the B Cell Antigen Receptor: ROLE OF B LYMPHOCYTE ANTIGEN RECEPTOR-MEDIATED KINASE ACTIVATION AND TUMOR NECROSIS FACTOR RECEPTOR-ASSOCIATED FACTOR REGULATION J. Biol. Chem., January 23, 2004; 279(4): 2575 - 2582. [Abstract] [Full Text] [PDF]
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B. S. Hostager, S. A. Haxhinasto, S. L. Rowland, and G. A. Bishop Tumor Necrosis Factor Receptor-associated Factor 2 (TRAF2)-deficient B Lymphocytes Reveal Novel Roles for TRAF2 in CD40 Signaling J. Biol. Chem., November 14, 2003; 278(46): 45382 - 45390. [Abstract] [Full Text] [PDF]
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S. A. Haxhinasto and G. A. Bishop A Novel Interaction between Protein Kinase D and TNF Receptor-Associated Factor Molecules Regulates B Cell Receptor-CD40 Synergy J. Immunol., November 1, 2003; 171(9): 4655 - 4662. [Abstract] [Full Text] [PDF]
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S. A. Haxhinasto, B. S. Hostager, and G. A. Bishop Cutting Edge: Molecular Mechanisms of Synergy Between CD40 and the B Cell Antigen Receptor: Role for TNF Receptor-Associated Factor 2 in Receptor Interaction J. Immunol., August 1, 2002; 169(3): 1145 - 1149. [Abstract] [Full Text] [PDF]
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G. A. Bishop, B. S. Hostager, and K. D. Brown Mechanisms of TNF receptor-associated factor (TRAF) regulation in B lymphocytes J. Leukoc. Biol., July 1, 2002; 72(1): 19 - 23. [Abstract] [Full Text] [PDF]
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K. D. Brown, B. S. Hostager, and G. A. Bishop Regulation of TRAF2 Signaling by Self-induced Degradation J. Biol. Chem., May 24, 2002; 277(22): 19433 - 19438. [Abstract] [Full Text] [PDF]
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B. S. Hostager and G. A. Bishop Role of TNF Receptor-Associated Factor 2 in the Activation of IgM Secretion by CD40 and CD120b J. Immunol., April 1, 2002; 168(7): 3318 - 3322. [Abstract] [Full Text] [PDF]
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 U. Schonbeck and P. Libby CD40 Signaling and Plaque Instability Circ. Res., December 7, 2001; 89(12): 1092 - 1103. [Abstract] [Full Text] [PDF]
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L. K. Busch and G. A. Bishop Multiple Carboxyl-Terminal Regions of the EBV Oncoprotein, Latent Membrane Protein 1, Cooperatively Regulate Signaling to B Lymphocytes Via TNF Receptor-Associated Factor (TRAF)-Dependent and TRAF-Independent Mechanisms J. Immunol., November 15, 2001; 167(10): 5805 - 5813. [Abstract] [Full Text] [PDF]
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B. G. Werneburg, S. J. Zoog, T. T. A. Dang, M. R. Kehry, and J. J. Crute Molecular Characterization of CD40 Signaling Intermediates J. Biol. Chem., November 9, 2001; 276(46): 43334 - 43342. [Abstract] [Full Text] [PDF]
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I. M. Catlett, P. Xie, B. S. Hostager, and G. A. Bishop Signaling Through MHC Class II Molecules Blocks CD95-Induced Apoptosis J. Immunol., May 15, 2001; 166(10): 6019 - 6024. [Abstract] [Full Text] [PDF]
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K. D. Brown, B. S. Hostager, and G. A. Bishop Differential Signaling and Tumor Necrosis Factor Receptor-associated Factor (TRAF) Degradation Mediated by CD40 and the Epstein-Barr Virus Oncoprotein Latent Membrane Protein 1 (LMP1) J. Exp. Med., April 16, 2001; 193(8): 943 - 954. [Abstract] [Full Text] [PDF]
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L. D. Erickson, T. M. Foy, and T. J. Waldschmidt Murine B1 B Cells Require IL-5 for Optimal T Cell-Dependent Activation J. Immunol., February 1, 2001; 166(3): 1531 - 1539. [Abstract] [Full Text] [PDF]
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 A. G. Eliopoulos, C. Davies, P. G. Knox, N. J. Gallagher, S. C. Afford, D. H. Adams, and L. S. Young CD40 Induces Apoptosis in Carcinoma Cells through Activation of Cytotoxic Ligands of the Tumor Necrosis Factor Superfamily Mol. Cell. Biol., August 1, 2000; 20(15): 5503 - 5515. [Abstract] [Full Text]
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S. V. Jalukar, B. S. Hostager, and G. A. Bishop Characterization of the Roles of TNF Receptor-Associated Factor 6 in CD40-Mediated B Lymphocyte Effector Functions J. Immunol., January 15, 2000; 164(2): 623 - 630. [Abstract] [Full Text] [PDF]
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B. Segui, N. Andrieu-Abadie, S. Adam-Klages, O. Meilhac, D. Kreder, V. Garcia, A. P. Bruno, J.-P. Jaffrezou, R. Salvayre, M. Kronke, et al. CD40 Signals Apoptosis through FAN-regulated Activation of the Sphingomyelin-Ceramide Pathway J. Biol. Chem., December 24, 1999; 274(52): 37251 - 37258. [Abstract] [Full Text] [PDF]
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 H. Nakano, S. Sakon, H. Koseki, T. Takemori, K. Tada, M. Matsumoto, E. Munechika, T. Sakai, T. Shirasawa, H. Akiba, et al. Targeted disruption of Traf5 gene causes defects in CD40- and CD27-mediated lymphocyte activation PNAS, August 17, 1999; 96(17): 9803 - 9808. [Abstract] [Full Text] [PDF]
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 M. R. Posner, L. A. Cavacini, M. P. Upton, K. C. Tillman, E. R. Gornstein, and C. M. Norris Jr. Surface Membrane-expressed CD40 Is Present on Tumor Cells from Squamous Cell Cancer of the Head and Neck in Vitro and in Vivo and Regulates Cell Growth in Tumor Cell Lines Clin. Cancer Res., August 1, 1999; 5(8): 2261 - 2270. [Abstract] [Full Text] [PDF]
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B. S. Hostager and G. A. Bishop Cutting Edge: Contrasting Roles of TNF Receptor-Associated Factor 2 (TRAF2) and TRAF3 in CD40-Activated B Lymphocyte Differentiation J. Immunol., June 1, 1999; 162(11): 6307 - 6311. [Abstract] [Full Text] [PDF]
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S. S. Pullen, T. T. A. Dang, J. J. Crute, and M. R. Kehry CD40 Signaling through Tumor Necrosis Factor Receptor-associated Factors (TRAFs). BINDING SITE SPECIFICITY AND ACTIVATION OF DOWNSTREAM PATHWAYS BY DISTINCT TRAFs J. Biol. Chem., May 14, 1999; 274(20): 14246 - 14254. [Abstract] [Full Text] [PDF]
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C. L. Sutherland, D. L. Krebs, and M. R. Gold An 11-Amino Acid Sequence in the Cytoplasmic Domain of CD40 Is Sufficient for Activation of c-Jun N-Terminal Kinase, Activation of MAPKAP Kinase-2, Phosphorylation of I{kappa}B{alpha}, and Protection of WEHI-231 Cells from Anti-IgM-Induced Growth Arrest J. Immunol., April 15, 1999; 162(8): 4720 - 4730. [Abstract] [Full Text] [PDF]
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L. K. Busch and G. A. Bishop The EBV Transforming Protein, Latent Membrane Protein 1, Mimics and Cooperates with CD40 Signaling in B Lymphocytes J. Immunol., March 1, 1999; 162(5): 2555 - 2561. [Abstract] [Full Text] [PDF]
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Y. Hsing and G. A. Bishop Requirement for Nuclear Factor-{kappa}B Activation by a Distinct Subset of CD40-Mediated Effector Functions in B Lymphocytes J. Immunol., March 1, 1999; 162(5): 2804 - 2811. [Abstract] [Full Text] [PDF]
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 J. D. Pound, A. Challa, M. J. Holder, R. J. Armitage, S. K. Dower, W. C. Fanslow, H. Kikutani, S. Paulie, C. D. Gregory, and J. Gordon Minimal cross-linking and epitope requirements for CD40-dependent suppression of apoptosis contrast with those for promotion of the cell cycle and homotypic adhesions in human B cells Int. Immunol., January 1, 1999; 11(1): 11 - 20. [Abstract] [Full Text] [PDF]
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 O. Devergne, E. C. McFarland, G. Mosialos, K. M. Izumi, C. F. Ware, and E. Kieff Role of the TRAF Binding Site and NF-kappa B Activation in Epstein-Barr Virus Latent Membrane Protein 1-Induced Cell Gene Expression J. Virol., October 1, 1998; 72(10): 7900 - 7908. [Abstract] [Full Text] [PDF]
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A. C. Grammer, J. L. Swantek, R. D. McFarland, Y. Miura, T. Geppert, and P. E. Lipsky 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., August 1, 1998; 161(3): 1183 - 1193. [Abstract] [Full Text] [PDF]
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B. S. Hostager, I. M. Catlett, and G. A. Bishop Recruitment of CD40 and Tumor Necrosis Factor Receptor-associated Factors 2 and 3 to Membrane Microdomains during CD40 Signaling J. Biol. Chem., May 12, 2000; 275(20): 15392 - 15398. [Abstract] [Full Text] [PDF]
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