Skip to main content
Springer Nature Link
Log in

TRAF Proteins in CD40 Signaling

  • Chapter
TNF Receptor Associated Factors (TRAFs)

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 597))

Abstract

The tumor necrosis factor receptor (TNFR) superfamily molecule CD40 is expressed by a wide variety of cell types following activation signals, and constitutively on B lymphocytes, macrophages, and dendritic cells. CD40 signals to cells stimulate kinase activation, gene expression, production of a antibody and a variety of cytokines, expression or upregulation of surface molecules, and protection or promotion of apoptosis. Initial steps in CD40-mediated signal cascades involve the interactions of CD40 with various members of the TNFR-associated factor (TRAF) family of cytoplasmic proteins. This review summarizes current understanding of the nature of these interactions, and how they induce and regulate CD40 functions.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Chapter
USD 29.95
Price excludes VAT (Canada)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (Canada)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (Canada)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (Canada)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Similar content being viewed by others

References

  1. Disanto JP, Bonnefoy JY, Gauchat JF et al. CD40 ligand mutations in X-linked immunodeficiency with hyper-IgM. Nature 1993; 361(6412):541–543.

    PubMed  CAS  Google Scholar 

  2. Fuleihan R, Ramesh N, Loh R et al. Defective expression of the CD40 ligand in X chromosome-linked Ig deficiency with normal or elevated IgM. Proc Natl Acad Sci USA 1993; 90:2170–2173.

    PubMed  CAS  Google Scholar 

  3. Korthauer U, Graf D, Mages HW et al. Defective expression of T-cell CD40 ligand causes X-linked immunodeficiency with hyper-IgM. Nature 1993; 361(6412):539–541.

    PubMed  CAS  Google Scholar 

  4. Castigli E, Alt FW, Davidson L et al. CD40-deficient mice generated by recombination-activating gene-2-deficient blastocyst complementation. Proc Natl Acad Sci USA 1994; 91:12135–12139.

    PubMed  CAS  Google Scholar 

  5. Kawabe T, Naka T, Yoshida K et al. The immune responses in CD40-deficient mice: Impaired Ig class switching and germinal center formation. Immunity 1994; 1:167–178.

    PubMed  CAS  Google Scholar 

  6. Xu J, Foy TM, Laman JD et al. Mice deficient for the CD40 ligand. Immunity 1994; 1:423–431.

    PubMed  CAS  Google Scholar 

  7. Noelle RJ, Ledbetter JA, Aruffo A. CD40 and its ligand, an essential ligand-receptor pair for thymus-dependent B-cell activation. I 1992; 13(11):431–433.

    CAS  Google Scholar 

  8. Kehry MR. CD40-mediated signaling in B cells. I 1996; 156(7):2345–2348.

    CAS  Google Scholar 

  9. Calderhead DM, Kosaka Y, Manning EM et al. CD40-CD154 interactions in B-cell signaling. Curr Topics Microbiol Immunol 2000; 245:73–99.

    CAS  Google Scholar 

  10. Bishop GA, Hostager BS. Signaling by CD40 and its mimics in B cell activation. Immunol Res 2001; 24(2):97–109.

    PubMed  CAS  Google Scholar 

  11. Bishop GA, Hostager BS. The CD40-CD154 interaction in B cell-T cell liaisons. Cytokine and Growth Factor Reviews 2003; 14:297–309.

    PubMed  CAS  Google Scholar 

  12. Banchereau J, Dubois B, Fayette J et al. Functional CD40 antigen on B cells, FDC and fibroblasts. Dendritic Cells in Fundamental and Clinical Immunology 1995; 2:79–83.

    Google Scholar 

  13. Stout RD, Suttles J. The many roles of CD40 in cell-mediated inflammatory responses. I 1996; 17(10):487–492.

    CAS  Google Scholar 

  14. Kennedy MK, Mohler KM, Shanebeck KD et al. Induction of B cell costimulatory function by recombinant CD40 ligand. Eur J Immunol 1994; 24:116–123.

    PubMed  CAS  Google Scholar 

  15. Cella M, Scheidegger D, Palmer-Lehmann K et al. Ligation of CD40 on dendritic cells triggers production of high levels of IL-12 and enhances T cell stimulatory capacity: T-T help via APC activation. I 1996; 184(2):747–752.

    CAS  Google Scholar 

  16. Grewal IS, Flavell RA. A central role of CD40L in the regulation of CD4+ T-cell responses. Immunol Today 1996; 17(9):410–414.

    PubMed  CAS  Google Scholar 

  17. Grourard G, Durand I, Filgueira L et al. Dendritic cells capable of stimulating T cells in germinal centres. Nature 1996; 384(28 Nov):364–367.

    Google Scholar 

  18. Caux C, Massacrier C, Vanbervliet B et al. Activation of human dendritic cells through CD40 cross-linking. I 1994; 180(4):1263–1272.

    CAS  Google Scholar 

  19. Shu U, Kiniwa M, Wu CY et al. Activated T cells induce IL-12 production by monocytes via CD40-CD40L interaction. Eur J Immunol 1995; 25:1125–1128.

    PubMed  CAS  Google Scholar 

  20. Worm M, Geha RS. Activation of TNF-α and lymphotoxin-β via anti-CD40 in human B cells. Int Arch Allergy Immunol 1995; 107:368–369.

    PubMed  CAS  Google Scholar 

  21. Maruo S, Oh-hora M, Ahn H-J et al. B cells regulate CD40L-induced IL-12 production in APC during T cell/APC interactions. I 1997; 158(1):120–126.

    CAS  Google Scholar 

  22. Baccam M, Bishop GA. Membrane-bound CD154, but not anti-CD40 mAbs, induces NF-κB independent B cell IL-6 production. Eur J Immunol 1999; 29(12):3855–3866.

    PubMed  CAS  Google Scholar 

  23. Wiley JA, Harmsen AG. CD40 ligand is required for resolution of Pneumocystis carinii pheumonia in mice. J Immunol 1995; 155(7):3525–3529.

    PubMed  CAS  Google Scholar 

  24. Campbell KA, Ovendale PJ, Kennedy MK et al. CD40L is required for protective cell-mediated immunity to Leishmania major. Immunity 1996; 4(3):283–289.

    PubMed  CAS  Google Scholar 

  25. Soong L, Xu J-C, Grewal IS et al. Disruption of CD40-CD40L interactions results in an enhanced susceptibility to Leishmania amazonesis infection. Immunity 1996; 4(3):263–273.

    PubMed  CAS  Google Scholar 

  26. Stout RD, Suttles J, Xu J et al. Impaired T cell-mediated macrophage activation in CD40 ligand-deficient mice. I 1996; 156(1):8–11.

    CAS  Google Scholar 

  27. Kamanaka M, Yu P, Yasui T et al. Protective role of CD40 in Leishmania major infection at two distinct phases of cell-mediated immunity. Immunity 1996; 4(3):275–281.

    PubMed  CAS  Google Scholar 

  28. Paulie S, Ehlin-Henriksson B, Mellstedt H et al. A p50 surface antigen restricted to human urinary bladder carcinomas and B lymphocytes. Cancer Immunol Immunother 1985; 20:23–28.

    PubMed  CAS  Google Scholar 

  29. Stamenkovic I, Clark EA, Seed B. A B-lymphocyte activation molecule related to the nerve growth factor receptor and induced by cytokines in carcinomas. EMBO J 1989; 8:1403–1410.

    PubMed  CAS  Google Scholar 

  30. Eliopoulos AG, Stack M, Dawson CW et al. EBV-encoded LMP1 and CD40 mediate IL-6 production in epithelial cells via an NF-kB pathway involving TRAFs. Oncogene 1997; 14(24):2899–2916.

    PubMed  CAS  Google Scholar 

  31. Rokhlin OW, Bishop GA, Hostager BS et al. Fas-mediated apoptosis in human prostatic carcinoma cell lines. Cancer Res 1997; 57:1758–1768.

    PubMed  CAS  Google Scholar 

  32. Altenburg A, Baldus SE, Smola H et al. CD40L-CD40 interaction induces chemokines in cervical carcinoma cells in synergism with IFN-γ. J Immunol 1999; 162(7):4140–4147.

    PubMed  CAS  Google Scholar 

  33. Fries KM, Sempowski GD, Gaspari AA et al. CD40 expression by human fibroblasts. Clin Immunol Immunopathol 1995; 77:42–51.

    PubMed  CAS  Google Scholar 

  34. Yellin MJ, Winikoff S, Fortune SM et al. Ligation of CD40 on fibroblasts induces CD54 (ICAM-1) and CD106 (VCAM-1) upregulation and IL-6 production and proliferation. J Leuk Biol 1995; 58:209–216.

    CAS  Google Scholar 

  35. Sempowski GD, Chess PR, Phipps RP. CD40 is a functional activation antigen and B7-independent T cell costimulatory molecule on normal human lung fibroblasts. J Immunol 1997; 158(10):4670–4677.

    PubMed  CAS  Google Scholar 

  36. Hollenbaugh D, Mischel-Petty N, Edwards CP et al. Expression of functional CD40 by vascular endothelial cells. J Immunol 1995; 182(1):33–40.

    CAS  Google Scholar 

  37. Karmann K, Hughes CCW, Schechner J et al. CD40 on human endothelial cells: Inducibility by cytokines and functional regulation of adhesion molecule expression. Proc Natl Acad Sci USA 1995; 92:4342–4346.

    PubMed  CAS  Google Scholar 

  38. Yellin MJ, Brett J, Baum D et al. Functional interactions of T cells with endothelial cells: The role of CD40L-CD40-mediated signals. J Immunol 1995; 182(6):1857–1864.

    CAS  Google Scholar 

  39. Zhang Y, Cao HJ, Graf B et al. CD40 engagement up-regulates Cox-2 expression and PGE2 production in human lung fibroblasts. J Immunol 1998; 160(3):1053–1057.

    PubMed  CAS  Google Scholar 

  40. Brouty-Boyé D, Pottin-Clémenceau C, Doucet C et al. Chemokines and CD40 expression in human fibroblasts. Eur J Immunol 2000; 30(3):914–919.

    PubMed  Google Scholar 

  41. Schönbeck U, Mach F, Bonnefoy J et al. Ligation of CD40 activates ICE activity in vascular smooth muscle and endothelial cells and promotes elaboration of active IL-1β. J Biol Chem 1997; 272(31):19569–19574.

    PubMed  Google Scholar 

  42. Déchanet J, Grosset C, Taupin J et al. CD40L stimulates proinflammatory cytokine production by human endothelial cells. J Immunol 1997; 159(11):5640–5647.

    PubMed  Google Scholar 

  43. Flaxenburg JA, Melter M, Lapchak PH et al. The CD40-induced signaling pathway in endothelial cells resulting in the overexpression of vascular endothelial growth factor involves Ras and PI3-kinase. J Immunol 2004; 172(12):7503–7509.

    PubMed  CAS  Google Scholar 

  44. Schultze JL, Grabbe S, von Bergwelt-Baildon MS. DCs and CD40-activated B cells: Current and future avenues to cellular cancer immunotherapy. TRENDS Immunol 25(12):659–664.

    Google Scholar 

  45. Hill SC, Youde SJ, Man S et al. Activation of CD40 in cervical carcinoma cells facilitates CTL responses and augments chemotherapy-induced apoptosis. J Immunol 2005; 174(1):41–50.

    PubMed  CAS  Google Scholar 

  46. Dongari-Bagtsoglou AI, Warren WD, Berton MT et al. CD40 expression by gingival fibroblasts: Correlation of phenotype with function. I 1997; 9(9):1233–1241.

    Google Scholar 

  47. Rissoan MC, Van Kooten C, Chomarat P et al. The functional CD40 antigen of fibroblasts may contribute to the proliferation of rheumatoid synovium. Clin Exp Immunol 1996; 106:481–490.

    PubMed  CAS  Google Scholar 

  48. Henn V, Slupsky JR, Gräfe M et al. CD40L on activated platelets triggers an inflammatory reaction of endothelial cells. Nature 1998; 391:591–594.

    PubMed  CAS  Google Scholar 

  49. Hess S, Gottfried E, Smola H et al. CD40 induces resistance to TNF-mediated apoptosis in a fibroblast cell line. Eur J Immunol 1998; 28(11):3594–3604.

    PubMed  CAS  Google Scholar 

  50. Cho C, Cho M, Min S et al. CD40 engagement on synovial fibroblast up-regulates production of vascular endothelial growth factor. J Immunol 2000; 164(11):5055–5061.

    PubMed  CAS  Google Scholar 

  51. Deregibus MC, Buttiglieri S, Russo S et al. CD40-dependent activation of PI3K/Akt pathway mediates endothelial cell survival and in vitro angiogenesis. J Biol Chem 2003; 278(20):18008–18014.

    PubMed  CAS  Google Scholar 

  52. Costello RT, Gastaut J, Olive D. What is the real role of CD40 in cancer immunotherapy? Immunol Today 1999; 20(11):488–493.

    PubMed  CAS  Google Scholar 

  53. Hu HM, O’Rourke K, Boguski MS et al. A novel RING finger protein interacts with the cytoplasmic domain of CD40. J Biol Chem 1994; 269:30069–30072.

    PubMed  CAS  Google Scholar 

  54. Cheng G, Cleary AM, Ye Z et al. Involvement of CRAF1, a relative of TRAF, in CD40 signaling. Science 1995; 267:1494–1498.

    PubMed  CAS  Google Scholar 

  55. Rothe M, Wong SC, Henzel WJ et al. A novel family of putative signal transducers associated with the cytoplasmic domain of the 75 kDa tumor necrosis factor receptor. Cell 1994; 78(4):681–692.

    PubMed  CAS  Google Scholar 

  56. Rothe M, Sarma V, Dixit VM et al. TRAF2-mediated activation of NF-κB by TNF receptor 2 and CD40. Science 1995; 269:1424–1427.

    PubMed  CAS  Google Scholar 

  57. Pullen SS, Miller HG, Everdeen DS et al. CD40-TRAF interactions: Regulation of CD40 signaling through multiple TRAF binding sites and TRAF hetero-oligomerization. Biochem 1998; 37:11836–11845.

    CAS  Google Scholar 

  58. Ishida T, Mizushima S, Azuma S et al. Identification of TRAF6, a novel TRAF protein that mediates signaling from an amino-terminal domain of the CD40 cytoplasmic region. J Biol Chem 1996; 271(46):28745–28748.

    PubMed  CAS  Google Scholar 

  59. Ishida T, Tojo T, Aoki T et al. TRAF5, a novel TNF-R-associated factor family protein, mediates CD40 signaling. Proc Natl Acad Sci USA 1996; 93:9437–9442.

    PubMed  CAS  Google Scholar 

  60. Nakano H, Oshima H, Chung W et al. TRAF5, an activator of NF-κB and putative signal transducer for the LT-β receptor. J Biol Chem 1996; 271(25):14661–14664.

    PubMed  CAS  Google Scholar 

  61. Xu L-G, Li L-Y, Shu H. TRAF7 potentiates MEKK3-induced AP1 and CHOP activation and induces apoptosis. J Biol Chem 2004; 279:17278–17282.

    PubMed  CAS  Google Scholar 

  62. McWhirter SM, Pullen SS, Holton JM et al. Crystallographic analysis of CD40 recognition and signaling by human TRAF2. Proc Natl Acad Sci USA 1999; 96:8408–8413.

    PubMed  CAS  Google Scholar 

  63. Ni C, Welsh K, Leo E et al. Molecular basis for CD40 signaling mediated by TRAF3. Proc Natl Acad Sci USA 2000; 97(19):10395–10399.

    PubMed  CAS  Google Scholar 

  64. Lee SY, Reichlin A, Santana A et al. TRAF2 is essential for JNK but not NF-κB activation and regulates lymphocyte proliferation and survival. Immunity 1997; 7:701–713.

    Google Scholar 

  65. Hsing Y, Hostager BS, Bishop GA. Characterization of CD40 signaling determinants regulating NF-κB activation in lymphocytes. J Immunol 1997; 159(10):4898–4906.

    PubMed  CAS  Google Scholar 

  66. Hostager BS, Haxhinasto SA, Rowland SR et al. TRAF2-deficient B lymphocytes reveal novel roles for TRAF2 in CD40 signaling. J Biol Chem 2003; 278:45382–45390.

    PubMed  CAS  Google Scholar 

  67. Munroe ME, Bishop GA. Role of TRAF2 in distinct and overlapping CD40 and TNFR2/CD120b-mediated B lymphocyte activation. J Biol Chem 2004; 279(51):53222–53231.

    PubMed  CAS  Google Scholar 

  68. Grech AP, Amesbury M, Chan T et al. TRAF2 differentially regulates the canonical and noncanonical pathways of NF-κB activation in mature B cells. Immunity 2004; 21:629–642.

    PubMed  CAS  Google Scholar 

  69. Habelhah H, Takahashi S, Cho S-G et al. Ubiquitination and translocation of TRAF2 is required for activation of JNK but not of p38 or NF-κB. EMBO J 2004; 23(2):322–332.

    PubMed  CAS  Google Scholar 

  70. Haxhinasto SA, Hostager BS, Bishop GA. Cutting Edge: Molecular mechanisms of synergy between CD40 and the BCR: Role for TRAF2 in receptor interaction. J Immunol 2002; 169(3):1145–1149.

    PubMed  CAS  Google Scholar 

  71. Hostager BS, Bishop GA. Cutting Edge: Contrasting roles of TRAF2 and TRAF3 in CD40-mediated B lymphocyte activation. I 1999; 162(11):6307–6311.

    CAS  Google Scholar 

  72. Jalukar SV, Hostager BS, Bishop GA. Characterization of the roles of TRAF6 in CD40-mediated B lymphocyte effector functions. J Immunol 2000; 164(2):623–630.

    PubMed  CAS  Google Scholar 

  73. Inui S, Kaisho T, Kikutani H et al. Identification of the intracytoplasmic region essential for signal transduction through a B cell activation molecule, CD40. Eur J Immunol 1990; 20:1747–1753.

    PubMed  CAS  Google Scholar 

  74. Goldstein MD, Watts TH. Identification of distinct domains in CD40 involved in B7-1 induction or growth inhibition. J Immunol 1996; 157(7):2837–2843.

    PubMed  CAS  Google Scholar 

  75. Hostager BS, Hsing Y, Harms DE et al. Different CD40-mediated signaling events require distinct CD40 structural features. J Immunol 1996; 157(3):1047–1053.

    PubMed  CAS  Google Scholar 

  76. Pullen SS, Dang TTA, Crute JJ et al. CD40 signaling through TRAFs. Binding site specificity and activation of downstream pathways by distinct TRAFs. J Biol Chem 1999; 274(20):14246–14254.

    PubMed  CAS  Google Scholar 

  77. Sutherland CL, Krebs DL, Gold MR. An 11-amino acid sequence in the cytoplasmic domain of CD40 is sufficient for activation of JNK, activation of MAPKAP kinase-2, phosphorylation of IκBα, and protection of WEHI-231 cells from anti-IgM-induced growth arrest. J Immunol 1999; 162(8):4720–4730.

    PubMed  CAS  Google Scholar 

  78. Yasui T, Muraoka M, Takaoka-Shichijo Y et al. Dissection of B cell differentiation during primary immune responses in mice with altered CD40 signals. Int Immunol 2002; 14(3):319–329.

    PubMed  CAS  Google Scholar 

  79. Jabara HH, Laouini D, Tsitsikov E et al. The binding site for TRAF2 and TRAF3 but not for TRAF6 is essential for CD40-mediated Ig class switching. Immunity 2002; 17(3):265–276.

    PubMed  CAS  Google Scholar 

  80. Ahonen CL, Manning EM, Erickson LD et al. The CD40-TRAF6 axis controls affinity maturation and the generation of long-lived plasma cells. Nat Immunol 2002; 3:451–456.

    PubMed  CAS  Google Scholar 

  81. Xu Y, Cheng G, Baltimore D. Targeted disruption of TRAF3 leads to postnatal lethality and defective T-dependent immune responses. Immunity 1996; 5(5):407–415.

    PubMed  CAS  Google Scholar 

  82. Yeh W, Shahinian A, Speiser D et al. Early lethality, functional NF-kB activation, and increased sensitivity to TNF-induced cell death in TRAF2-deficient mice. Immunity 1997; 7(5):715–725.

    PubMed  CAS  Google Scholar 

  83. Lomaga MA, Yeh WC, Sarosi I et al. TRAF6 deficiency results in osteopetrosis and defective IL-1, CD40, and LPS signaling. Genes Devel 1999; 13:1015–1021.

    PubMed  CAS  Google Scholar 

  84. Tsitsikov E, Laouini D, Dunn IF et al. TRAF1 is a negative regulator of TNF signaling: Enhanced TNF signaling in TRAF1-deficient mice. Immunity 2001; 15(4):647–657.

    PubMed  CAS  Google Scholar 

  85. Kühn R, Schwenk F, Aguet M et al. Inducible gene targeting in mice. Science 1995; 269:1427–1429.

    PubMed  Google Scholar 

  86. Xie P, Hostager BS, Bishop GA. Requirement for TRAF3 in signaling by LMP1, but not CD40, in B lymphocytes. J Exp Med 2004; 199(5):661–671.

    PubMed  CAS  Google Scholar 

  87. Xie P, Hostager BS, Munroe ME et al. Cooperation between TRAFs 1 and 2 in CD40-mediated B lymphocyte activation. Manuscript submitted 2005.

    Google Scholar 

  88. Takeuchi M, Rothe M, Goeddel DV. Anatomy of TRAF2. Distinct domains for NF-κB activation and association with TNF signaling proteins. J Biol Chem 1996; 271(33):19935–19942.

    PubMed  CAS  Google Scholar 

  89. Bishop GA. The multifaceted roles of TRAFs in the regulation of B cell function. Nat Rev Immunol 2004; 4:775–786.

    PubMed  CAS  Google Scholar 

  90. Yuasa T, Ohno S, Kehrl JH et al. TNF signaling to SAPK/JNK and p38. Germinal center kinase couples TRAF2 to MAPK/ERK kinase kinase 1 and SAPK while RIP associates with a MAPKKK upstream of MKK6 and p38. J Biol Chem 1998; 273:22681–22692.

    PubMed  CAS  Google Scholar 

  91. Malinin NL, Boldin MP, Kovalenko AV et al. MAP3K-related kinase involved in NF-κB induction by TNF, CD95 and IL-1. Nature 1997; 385:540–544.

    PubMed  CAS  Google Scholar 

  92. Gotoh Y, Oishi K, Shibata H et al. Protein kinase PKN1 associates with TRAF2 and is involved in TRAF2-NF-[kappa]B signaling pathway. Biochemical and Biophysical Research Communications 2004; 314(3):688–694.

    PubMed  CAS  Google Scholar 

  93. Nishitoh H, Saitoh M, Mochida Y et al. ASK1 is essential for JNK/SAPK activation by TRAF2. Mol Cell 1998; 2:389–395.

    PubMed  CAS  Google Scholar 

  94. Xia P, Wang L, Moretti PAB et al. Sphingosine kinase interacts with TRAF2 and dissects TNFα signaling. J Biol Chem 2002; 277(10):7996–8003.

    PubMed  CAS  Google Scholar 

  95. Nguyen LT, Duncan GS, Mirtsos C et al. TRAF2 deficiency results in hyperactivity of certain TNFR1 signals and impairment of CD40-mediated responses. Immunity 1999; 11(3):379–389.

    PubMed  CAS  Google Scholar 

  96. Hostager BS, Bishop GA. Role of TRAF2 in the activation of IgM secretion by CD40 and CD120b. J Immunol 2002; 168(7):3318–3322.

    PubMed  CAS  Google Scholar 

  97. Hsu H, Shu H-B, Pan M-G et al. TRADD-TRAF2 and TRADD-FADD interactions define two distinct TNFR1 signal transduction pathways. Cell 1996; 84(2):299–308.

    PubMed  CAS  Google Scholar 

  98. Lu L, Cook WJ, Lin L et al. CD40 signaling through a newly identified TRAF2 binding site. J Biol Chem 2003; 278(46):45414–45418.

    PubMed  CAS  Google Scholar 

  99. Deng L, Wang C, Spencer E et al. Activation of the IκB kinase complex by TRAF6 requires a dimeric ubiquitin-conjugating enzyme complex and a unique polyubiquitin chain. Cell 2000; 103(2):351–361.

    PubMed  CAS  Google Scholar 

  100. Brown KD, Hostager BS, Bishop GA. Regulation of TRAF2 signaling by self-induced degradation. J Biol Chem 2002; 277(22):19433–19438.

    PubMed  CAS  Google Scholar 

  101. Shi C-S, Kehrl JH. TNF-induced GCKR and SAPK activation depends upon the E2/E3 complex UBC13-Uev1A/TRAF2. J Biol Chem 2003; 278(17):15429–15434.

    PubMed  CAS  Google Scholar 

  102. Wu CJ, Conze DB, Li X et al. TNF-alpha induced c-IAP1/TRAF2 complex translocation to a Ubc6-containing compartment and TRAF2 ubiquitination. EMBO J 2005; 24(10):1886–1898.

    PubMed  CAS  Google Scholar 

  103. Lee TH, Shank J, Cusson N et al. The kinase activity of Rip 1 is not required for TNFα-induced IkB kinase or p38 MAPK activation or for the ubiquitination of Rip1 by Traf2. J Biol Chem 2004; 279(32):33185–33191.

    PubMed  CAS  Google Scholar 

  104. Park S-M, Yoon J-B, Lee TH. Receptor interacting protein is ubiquitinated by cellular inhibitor of apoptosis proteins (c-IAP1 and c-IAP2) in vitro. FEBS Letters 2004; 566(1–3):151–156.

    PubMed  CAS  Google Scholar 

  105. Moore CR, Bishop GA. Differential regulation of CD40-mediated TRAF degradation in B lymphocytes. J Immunol 2005; in press.

    Google Scholar 

  106. Haxhinasto SA, Bishop GA. Synergistic B cell activation by CD40 and the BCR: Role of BCR-mediated kinase activation and TRAF regulation. J Biol Chem 2004; 279(4):2575–2582.

    PubMed  CAS  Google Scholar 

  107. Haxhinasto SA, Bishop GA. A novel interaction between PKD and TRAFs regulates BCR-CD40 synergy. J Immunol 2003; 171(9):4655–4662.

    PubMed  CAS  Google Scholar 

  108. Arron JR, Pewzner-Jung Y, Walsh MC et al. Regulation of the subcellular localization of TRAF2 by TRAF1 reveals mechanisms of TRAF2 signaling. J Exp Med 2002; 196(7):923–934.

    PubMed  CAS  Google Scholar 

  109. Sato T, Irie S, Reed JC. A novel member of the TRAF family of putative signal transducing proteins binds to the cytosolic domain of CD40. FEBS Lett 1995; 358:113–118.

    PubMed  CAS  Google Scholar 

  110. Mosialos G, Birkenback M, Yalamanchili R et al. The EBV transforming protein LMP1 engages signaling proteins for the TNF-R family. Cell 1995; 80(3):389–399.

    PubMed  CAS  Google Scholar 

  111. Wajant H, Henkler F, Scheurich P. The TRAF family: Scaffold molecules for cytokine receptors, kinases, and their regulators. Cell Signaling 2001; 13:389–400.

    CAS  Google Scholar 

  112. Locksley RM, Kileen N, Lenardo MJ. The TNF and TNFR superfamilies: Integrating mammalian biology. Cell 2001; 104:487–501.

    PubMed  CAS  Google Scholar 

  113. Rolink AG, Melchers F. BAFFled B cells survive and thrive: Roles of BAFF in B-cell development. Curr Opin Immunol 2002; 14(2):266–275.

    PubMed  CAS  Google Scholar 

  114. Xu L, Shu H. TRAF3 is associated with BAFF-R and negatively regulates BAFF-R-mediated NF-κB activation and IL-10 production. J Immunol 2002; 169(12):6883–6889.

    PubMed  CAS  Google Scholar 

  115. van Kooten C, Banchereau J. CD40-CD40 ligand. J Leuk Biol 2000; 67:2–17.

    Google Scholar 

  116. Arch RH, Gedrich RW, Thompson CB. TRAFs — a family of adapter proteins that regulates life and death. Genes Devel 1998; 12:2821–2830.

    PubMed  CAS  Google Scholar 

  117. Chung JY, Park YC, Ye H et al. All TRAFs are not created equal: Common and distinct molecular mechanisms of TRAF-mediated signal transduction. J Cell Sci 2002; 115:679–688.

    PubMed  CAS  Google Scholar 

  118. Lee HH, Dempsey PW, Parks TP et al. Specificities of CD40 signaling: Involvement of TRAF2 in CD40-induced NF-kB activation and ICAM-1 upregulation. Proc Natl Acad Sci USA 1999; 96:1421–1426.

    PubMed  CAS  Google Scholar 

  119. Grammer AC, Lipsky PE. CD40-mediated regulation of immune responses by TRAF-dependent and TRAF-independent signaling mechanisms. Adv Immunol 2000; 76:61–178.

    PubMed  CAS  Google Scholar 

  120. Dadgostar H, Cheng G. Membrane localization of TRAF 3 enables JNK activation. J Biol Chem 2000; 275(4):2539–2544.

    PubMed  CAS  Google Scholar 

  121. Ha YJ, Lee JR. Role of TRAF3 in the CD40 signaling by production of reactive oxygen species through association with p40phox, a cytosolic subunit of NADPH oxidase. J Immunol 2004; 172(1):231–239.

    PubMed  CAS  Google Scholar 

  122. Hatzivassiliou E, Mosialos G. Cellular signaling pathways engaged by the Epstein-Barr virus transforming protein LMP1. Front Biosci 2002; 7:d319–329.

    PubMed  CAS  Google Scholar 

  123. Eliopoulos AG, Waites ER, Blake SMS et al. TRAF1 is a critical regulator of JNK signaling by the TRAF-binding domain of the EBV LMP1 but not CD40. J virol 77(2):1316–1328.

    Google Scholar 

  124. Lam N, Sugden B. CD40 and its viral mimic, LMP1: Similar means to different ends. Cell Signal 2003; 15(1):9–16.

    Google Scholar 

  125. Grammer AC, Swantek JL, McFarland RD et al. TRAF3 signaling mediates activation of p38 and JNK, cytokine secretion, and Ig production following ligation of CD40 on human B cells. J Immunol 1998; 161(3):1183–1193.

    PubMed  CAS  Google Scholar 

  126. Bishop GA, Hostager BS, Brown KD. Mechanisms of tumor necrosis factor receptor associated factor (TRAF) regulation in B lymphocytes. J Leuk Biol 2002; 72:19–23.

    CAS  Google Scholar 

  127. van Eyndhoven WG, Gamper CJ, Cho E et al. TRAF-3 mRNA splice-deletion variants encode isoforms that induce NF-kappaB activation. Mol Immunol 1999; 36(10):647–658.

    PubMed  Google Scholar 

  128. Gamper C, Omene CO, van Eyndhoven WG et al. Expression and function of TRAF-3 splice-variant isoforms in human lymphoma cell lines. Hum Immunol 2001; 62(10):1167–1177.

    PubMed  CAS  Google Scholar 

  129. Basaki Y, Ikizawa K, Kajiwara K et al. CD40-mediated tumor necrosis factor receptor-associated factor 3 signaling upregulates IL-4-induced germline Cepsilon transcription in a human B cell line. Arch Biochem Biophys 2002; 405(2):199–204.

    PubMed  CAS  Google Scholar 

  130. He L, Grammer AC, Wu X et al. TRAF3 forms heterotrimers with TRAF2 and modulates its ability to mediate NF-κB activation. J Biol Chem 2004; 279(53):55855–55865.

    PubMed  CAS  Google Scholar 

  131. Xie P, Bishop GA. Roles of TRAF3 in signaling to B lymphocytes by CTAR regions 1 and 2 of the EBV-encoded oncoprotein LMP1. J Immunol 2004; 173(9):5546–5555.

    PubMed  CAS  Google Scholar 

  132. Schonbeck U, Libby P. The CD40/CD154 receptor/ligand dyad. Cell Mol Life Sci 2001; 58(1):4–43.

    PubMed  CAS  Google Scholar 

  133. Propst SM, Estell K, Schwiebert LM. CD40-mediated activation of NF-κB in airway epithelial cells. J Biol Chem 2002; 277(40):37054–37063.

    PubMed  CAS  Google Scholar 

  134. Urbich C, Mallat Z, Tedgui A et al. Upregulation of TRAF-3 by shear stress blocks CD40-mediated endothelial activation. J Clin Invest 2001; 108(10):1451–1458.

    PubMed  CAS  Google Scholar 

  135. Hostager BS, Catlett IM, Bishop GA. Recruitment of CD40, TRAF2 and TRAF3 to membrane microdomains during CD40 signaling. J Biol Chem 2000; 275(20):15392–15398.

    PubMed  CAS  Google Scholar 

  136. Fotin-Mleczek M, Henkler F, Hausser A et al. TRAF1 regulates CD40-induced TRAF-mediated NF-κB activation. J Biol Chem 2004; 279(1):677–685.

    PubMed  CAS  Google Scholar 

  137. Lee ZH, Lee SE, Kwack K et al. Caspase-mediated cleavage of TRAF3 in FasL-stimulated Jurkat-T cells. J Leukoc Biol 2001; 69(3):490–496.

    PubMed  CAS  Google Scholar 

  138. Brown KD, Hostager BS, Bishop GA. Differential signaling and TRAF degradation by CD40 and the EBV oncoprotein LMP1. J Exp Med 2001; 193(8):943–954.

    PubMed  CAS  Google Scholar 

  139. Qian Y, Zhao Z, Jiang Z et al. Role of NF-κB activator Actl in CD40-mediated signaling in epithelial cells. Proc Natl Acad Sci USA 2002; 99(14):9386–9391.

    PubMed  CAS  Google Scholar 

  140. Gamper C, van Eyndhoven WG, Schweiger E et al. TRAF-3 interacts with p62 nucleoporin, a component of the nuclear pore central plug that binds classical NLS-containing import complexes. Mol Immunol 2000; 37(1–2):73–84.

    PubMed  CAS  Google Scholar 

  141. Ling L, Goeddel DV. MIP-T3, a novel protein linking tumor necrosis factor receptor-associated factor 3 to the microtubule network. J Biol Chem 2000; 275(31):23852–23860.

    PubMed  CAS  Google Scholar 

  142. Dadgostar H, Doyle SE, Shahangian A et al. T3JAM, a novel protein that specifically interacts with TRAF3 and promotes the activation of JNK(1). FEBS Lett 2003; 553(3):403–407.

    PubMed  CAS  Google Scholar 

  143. Meylan E, Martinon F, Thome M et al. RIP4 (DIK/PKK), a novel member of the RIP kinase family, activates NF-ΚB and is processed during apoptosis. EMBO Rep 3(12):1201–1208.

    Google Scholar 

  144. Hu WH, Mo XM, Walters WM et al. TNAP, a novel repressor of NIK, suppresses NF-ΚB activation. J Biol Chem 2004; 279(34):35975–35983.

    PubMed  CAS  Google Scholar 

  145. Pype S, Declercq W, Ibrahimi A et al. TTRAP, a novel protein that associates with CD40, tumor necrosis factor (TNF) receptor-75 and TRAFs, and that inhibits NF-ΚB activation. J Biol Chem 2000; 275(24):18586–18593.

    PubMed  CAS  Google Scholar 

  146. Song HY, Régnier CH, Kirschning CJ et al. TNF-mediated kinase cascades: Bifurcation of NF-κB and JNK/SAPK pathways at TRAF2. Proc Natl Acad Sci USA 1997; 94(18):9792–9796.

    PubMed  CAS  Google Scholar 

  147. Liao G, Zhang M, Harhaj EW et al. Regulation of NIK by TRAF3-induced degradation. J Biol Chem 2004; 279(25):26243–26250.

    PubMed  CAS  Google Scholar 

  148. Wong BR, Besser D, Kim N et al. TRANCE, a TNF family member, activates Akt/PKB through a signaling complex involving TRAF6 and c-Src. Mol Cell 1999; 4:1041–1049.

    PubMed  CAS  Google Scholar 

  149. Hsu H, Huang J, Shu H-B et al. TNF-dependent recruitment of the protein kinase RIP to the TNFR1 signaling complex. Immunity 1996; 4(4):387–396.

    PubMed  CAS  Google Scholar 

  150. Chen MC, Hwang MJ, Chou YC et al. The role of apoptosis signal-regulating kinase 1 in lymphotoxin-beta receptor-mediated cell death. J Biol Chem 2003; 278(18):16073–16081.

    PubMed  CAS  Google Scholar 

  151. Qian Y, Qin J, Cui G et al. Act1, a negative regulator in CD40 and BAFF-mediated B cell survival. Immunity 2004; 21:575–587.

    PubMed  CAS  Google Scholar 

  152. Tsukamoto N, Kobayashi N, Azuma S et al. Two differently regulated NF-ΚB activation pathways triggered by the cytoplasmic tail of CD40. Proc Natl Acad Sci USA 1999; 96:1234–1239.

    PubMed  CAS  Google Scholar 

  153. Leo E, Welsh K, Matsuzawa S et al. Differential requirements for TRAF family proteins in CD40-mediated induction of NF-κB and JNK activation. J Biol Chem 1999; 274(32):22414–22422.

    PubMed  CAS  Google Scholar 

  154. Hauer J, Püschner S, Ramakrishnan P et al. TRAF3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-ΚB pathway by TRAF-binding TNFRs. Proc Natl Acad Sci USA 2005; 102(8):2874–2879.

    PubMed  CAS  Google Scholar 

  155. Nakano H, Sakon S, Koseki H et al. Targeted disruption of Traf5 gene causes defects in CD40 and CD27-mediated lymphocyte activation. Proc Natl Acad Sci USA 1999; 96:9803–9808.

    PubMed  CAS  Google Scholar 

  156. Pullen SS, Miller HG, Everdeen DS et al. CD40-TRAF interactions: Regulation of CD40 signaling through multiple TRAF binding sites and TRAF hetero-oligomerization. Biochemistry 1998; 37(34):11836–11845.

    PubMed  CAS  Google Scholar 

  157. Darnay BG, Ni J, Moore PA et al. Activation of NF-ΚB by RANK equires tumor necrosis factor receptor-associated factor (TRAF) 6 and NF-kappaB-inducing kinase. Identification of a novel TRAF6 interaction motif. J Biol Chem 1999; 274(12):7724–7731.

    PubMed  CAS  Google Scholar 

  158. Jabara H, Laouini D, Tsitsikov E et al. The binding site for TRAF2 and TRAF3 but not for TRAF6 is essential for CD40-mediated immunoglobulin class switching. Immunity 2002; 17(3):265–276.

    PubMed  CAS  Google Scholar 

  159. Kashiwada M, Shirakata Y, Inoue J et al. TRAF6 stimulates ERK activity in CD40 signaling along a ras-independent pathway. J Exp Med 1998; 187(2):237–244.

    PubMed  CAS  Google Scholar 

  160. Coope HJ, Atkinson PG, Huhse B et al. CD40 regulates the processing of NF-kappaB2 p100 to p52. EMBO J 2002; 21(20):5375–5385.

    PubMed  CAS  Google Scholar 

  161. Hauer J, Puschner S, Ramakrishnan P et al. TNF receptor (TNFR)-associated factor (TRAF) 3 serves as an inhibitor of TRAF2/5-mediated activation of the noncanonical NF-ΚB pathway by TRAF-binding TNFRs. Proc Natl Acad Sci USA 2005; 102(8):2874–2879.

    PubMed  CAS  Google Scholar 

  162. Eliopoulos AG, Wang C-C, Dumitru CD et al. Tpl2 transduces CD40 and TNF signals that activate ERK and regulate IgE induction by CD40. EMBO J 2003; 22(15):3855–3864.

    PubMed  CAS  Google Scholar 

  163. Manning E, Pullen SS, Souza DJ et al. Cellular responses to murine CD40 in a mouse B cell line may be TRAF dependent or independent. Eur J Immunol 2002; 32:39–49.

    PubMed  CAS  Google Scholar 

  164. Aicher A, Shu GL, Magaletti D et al. Differential role for p38 MAPK in regulating CD40-induced gene expression in DC and B cells. J Immunol 1999; 163(11):5786–5795.

    PubMed  CAS  Google Scholar 

  165. Yun TJ, Tallquist MD, Aicher A et al. Osteoprotegerin, a crucial regulator of bone metabolism, also regulates B cell development and function. J Immunol 2001; 166(3):1482–1491.

    PubMed  CAS  Google Scholar 

  166. Boone DL, Turer EE, Lee EG et al. The ubiquitin-modifying enzyme A20 is required for termination of TLR responses. Nat Immunol 2004; 5(10):1052–1060.

    PubMed  CAS  Google Scholar 

  167. Leo E, Zapata JM, Reed JC. CD40 mediated activation of Ig-Cγ1 and Ig-Cε germline promoters involves multiple TRAF family proteins. Eur J Immunol 1999; 29(12):3908–3913.

    PubMed  CAS  Google Scholar 

  168. Ahonen C, Manning E, Erickson LD et al. The CD40-TRAF6 axis controls affinity maturation and the generation of long-lived plasma cells. Nat Immunol 2002; 3(5):451–456.

    PubMed  CAS  Google Scholar 

  169. Naito A, Azuma S, Tanaka S et al. Severe osteopetrosis, defective interleukin-1 signalling and lymph node organogenesis in TRAF6-deficient mice. Genes Cells 1999; 4(6):353–362.

    PubMed  CAS  Google Scholar 

  170. Kobayashi T, Walsh PT, Walsh MC et al. TRAF6 is a critical factor for DC maturation and development. Immunity 2003; 19:353–363.

    PubMed  CAS  Google Scholar 

  171. Baud V, Liu Z, Bennett B et al. Signaling by proinflammatory cytokines: Oligomerization of TRAF2 and TRAF6 is sufficient for JNK and IKK activation and target gene induction via an amino-terminal effector domain. Genes Devel 1999; 13:1297–1308.

    PubMed  CAS  Google Scholar 

  172. Cao Z, Xiong J, Takeuchi M et al. TRAF6 is a signal transducer for IL-1. Nature 1996; 383:443–446.

    PubMed  CAS  Google Scholar 

  173. Xiong H, Li H, Chen Y et al. Interaction of TRAF6 with MAST205 regulates NF-ΚB activation and MAST205 stability. J Biol Chem 2004; 279(42):43675–43683.

    PubMed  CAS  Google Scholar 

  174. Kobayashi T, Walsh MC, Choi Y. The role of TRAF6 in signal transduction and the immune response. Microbes Infect 2004; 6(14):1333–1338.

    PubMed  CAS  Google Scholar 

  175. Mukundan L, Bishop GA, Head KZ et al. TRAF6 is an essential mediator of CD40-activated proinflammatory pathways in monocytes and macrophages. J Immunol 2005; 174:1081–1090.

    PubMed  CAS  Google Scholar 

  176. Benhamou LE, Cazenave PA, Sarthou P. Anti-immunoglobulins induce death by apoptosis in WEHI-231 B lymphoma cells. Eur J Immunol 1990; 20(6):1405–1407.

    PubMed  CAS  Google Scholar 

  177. Hasbold J, Klaus GG. Anti-immunoglobulin antibodies induce apoptosis in immature B cell lymphomas. Eur J Immunol 1990; 20(8):1685–1690.

    PubMed  CAS  Google Scholar 

  178. Tsubata T, Wu J, Honjo T. B-cell apoptosis induced by antigen receptor crosslinking is blocked by a T-cell signal through CD40. Nature 1993; 364(6438):645–648.

    PubMed  CAS  Google Scholar 

  179. Hornung M, Lindemann D, Kraus C et al. The CD40 TRAF family member interacting motif carries the information to rescue WEHI 231 cells from anti-IgM-induced growth arrest. Eur J Immunol 1998; 28(11):3812–3823.

    PubMed  CAS  Google Scholar 

  180. Benson RE, Hostager BS, Bishop GA. Rapid CD40-mediated rescue from CD95-induced apoptosis requires TRAF6 and PI3K. Manuscript submitted 2005.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Microbiology and Internal Medicine, Interdisciplinary Graduate Program in Immunology, University of Iowa, Iowa City, Iowa, 52242, USA

    Gail A. Bishop

  2. Iowa City VAMC, Iowa City, Iowa, 52242, USA

    Gail A. Bishop

Authors
  1. Gail A. Bishop
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carissa R. Moore
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ping Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Laura L. Stunz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Zachary J. Kraus
    View author publications

    You can also search for this author in PubMed Google Scholar

Editor information

Editors and Affiliations

  1. Department of Biochemistry, Weill Medical College of Cornell University, New York, New York, USA

    Hao Wu Ph.D.

Rights and permissions

Reprints and permissions

Copyright information

© 2007 Landes Bioscience and Springer Science+Business Media

About this chapter

Cite this chapter

Bishop, G.A., Moore, C.R., Xie, P., Stunz, L.L., Kraus, Z.J. (2007). TRAF Proteins in CD40 Signaling. In: Wu, H. (eds) TNF Receptor Associated Factors (TRAFs). Advances in Experimental Medicine and Biology, vol 597. Springer, New York, NY. https://doi.org/10.1007/978-0-387-70630-6_11

Download citation

Publish with us

Policies and ethics

Search

Navigation