Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

TRAIL Receptor 1/2 (Death Receptor 4/5, DR4/5)

  • Eun-Sil SungEmail author
  • Yong-Sung Kim
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_544


Historical Background

The tumor necrosis factor (TNF)-related apoptosis inducing ligand (TRAIL, Apo2L) identified in the middle of 1990s (Pitti et al. 1996; Wiley et al. 1995) was given its name due to its ability of inducing apoptosis and its high homology to other TNF member ligands. Then, its first receptor, death receptor 4 (DR4, TRAIL-R1), was identified by searching an EST database for sequences related to the TNF receptor-1 (TNFR1) death domain (DD) (Pan et al. 1997b). Thereafter, by virtue of its sequence homology to the DR4 DD, death receptor 5 (DR5, TRAIL-R2) was also cloned independently by two groups (MacFarlane et al. 1997; Walczak et al. 1997). Both DR4 and DR5 are belonging to members of the TNF receptor superfamily (TNFRSF). However, unlikely with TNFRSF receptors containing the intracellular DD, such as...

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


  1. Ashkenazi A. Directing cancer cells to self-destruct with pro-apoptotic receptor agonists. Nat Rev Drug Discov. 2008;7(12):1001.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest. 1999;104:155–62.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Cha SS, Sung BJ, Kim YA, Song YL, Kim HJ, Kim S, et al. Crystal structure of TRAIL-DR5 complex identifies a critical role of the unique frame insertion in conferring recognition specificity. J Biol Chem. 2000;275:31171–7.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Chen C, Liu Y, Zheng D. An agonistic monoclonal antibody against DR5 induces ROS production, sustained JNK activation and Endo G release in Jurkat leukemia cells. Cell Res. 2009;19:984–95.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Emery JG, McDonnell P, Burke MB, Deen KC, Lyn S, Silverman C, et al. Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL. J Biol Chem. 1998;273:14363–7.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Fox NL, Humphreys R, Luster TA, Klein J, Gallant G. Tumor Necrosis Factor-related apoptosis-inducing ligand (TRAIL) Receptor-1 and Receptor-2 agonists for cancer therapy. Expert Opin Biol Ther. 2010;10:1–18.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Gonzalvez F, Ashkenazi A. New insights into apoptosis signaling by Apo2L/TRAIL. Oncogene. 2010;29:4752–65.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Jin Z, El-Deiry WS. Distinct signaling pathways in TRAIL- versus tumor necrosis factor-induced apoptosis. Mol Cell Biol. 2006;26:8136–48.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Johnstone RW, Frew AJ, Smyth MJ. The TRAIL apoptotic pathway in cancer onset, progression and therapy. Nat Rev Cancer. 2008;8:782–98.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Lee CH, Park KJ, Sung ES, Kim A, Choi JD, Kim JS, et al. Engineering of a human kringle domain into agonistic and antagonistic binding proteins functioning in vitro and in vivo. Proc Natl Acad Sci U S A. 2010;107:9567–71.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Lin Y, Devin A, Cook A, Keane MM, Kelliher M, Lipkowitz S, et al. The death domain kinase RIP is essential for TRAIL (Apo2L)-induced activation of IkappaB kinase and c-Jun N-terminal kinase. Mol Cell Biol. 2000;20:6638–45.PubMedPubMedCentralCrossRefGoogle Scholar
  12. MacFarlane M, Ahmad M, Srinivasula SM, Fernandes-Alnemri T, Cohen GM, Alnemri ES. Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL. J Biol Chem. 1997;272:25417–20.PubMedPubMedCentralCrossRefGoogle Scholar
  13. MacFarlane M, Kohlhaas SL, Sutcliffe MJ, Dyer MJ, Cohen GM. TRAIL receptor-selective mutants signal to apoptosis via TRAIL-R1 in primary lymphoid malignancies. Cancer Res. 2005;65:11265–70.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Marsters SA, Sheridan JP, Pitti RM, Huang A, Skubatch M, Baldwin D, et al. A novel receptor for Apo2L/TRAIL contains a truncated death domain. Curr Biol. 1997;7:1003–6.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Mills KR, Reginato M, Debnath J, Queenan B, Brugge JS. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is required for induction of autophagy during lumen formation in vitro. Proc Natl Acad Sci U S A. 2004;101:3438–43.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Muhlenbeck F, Schneider P, Bodmer JL, Schwenzer R, Hauser A, Schubert G, et al. The tumor necrosis factor-related apoptosis-inducing ligand receptors TRAIL-R1 and TRAIL-R2 have distinct cross-linking requirements for initiation of apoptosis and are non-redundant in JNK activation. J Biol Chem. 2000;275:32208–13.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Pan G, Ni J, Wei YF, Yu G, Gentz R, Dixit VM. An antagonist decoy receptor and a death domain-containing receptor for TRAIL. Science. 1997a;277:815–8.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Pan G, O’Rourke K, Chinnaiyan AM, Gentz R, Ebner R, Ni J, et al. The receptor for the cytotoxic ligand TRAIL. Science. 1997b;276:111–3.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Park KJ, Lee SH, Kim TI, Lee HW, Lee CH, Kim EH, et al. A human scFv antibody against TRAIL receptor 2 induces autophagic cell death in both TRAIL-sensitive and TRAIL-resistant cancer cells. Cancer Res. 2007;67:7327–34.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Park KJ, Lee SH, Lee CH, Jang JY, Chung J, Kwon MH, et al. Upregulation of Beclin-1 expression and phosphorylation of Bcl-2 and p53 are involved in the JNK-mediated autophagic cell death. Biochem Biophys Res Commun. 2009;382:726–9.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Pavet V, Beyrath J, Pardin C, Morizot A, Lechner MC, Briand JP, et al. Multivalent DR5 peptides activate the TRAIL death pathway and exert tumoricidal activity. Cancer Res. 2010;70:1101–10.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Pennarun B, Meijer A, de Vries EG, Kleibeuker JH, Kruyt F, de Jong S. Playing the DISC: turning on TRAIL death receptor-mediated apoptosis in cancer. Biochim Biophys Acta. 2010;1805:123–40.PubMedPubMedCentralGoogle Scholar
  23. Pitti RM, Marsters SA, Ruppert S, Donahue CJ, Moore A, Ashkenazi A. Induction of apoptosis by Apo-2 ligand, a new member of the tumor necrosis factor cytokine family. J Biol Chem. 1996;271:12687–90.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Sah NK, Munshi A, Kurland JF, McDonnell TJ, Su B, Meyn RE. Translation inhibitors sensitize prostate cancer cells to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) by activating c-Jun N-terminal kinase. J Biol Chem. 2003;278:20593–602.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Screaton GR, Mongkolsapaya J, Xu XN, Cowper AE, McMichael AJ, Bell JI. TRICK2, a new alternatively spliced receptor that transduces the cytotoxic signal from TRAIL. Curr Biol. 1997;7:693–6.PubMedPubMedCentralCrossRefGoogle Scholar
  26. Secchiero P, Gonelli A, Carnevale E, Milani D, Pandolfi A, Zella D, et al. TRAIL promotes the survival and proliferation of primary human vascular endothelial cells by activating the Akt and ERK pathways. Circulation. 2003;107:2250–6.PubMedPubMedCentralCrossRefGoogle Scholar
  27. Sung ES, Park KJ, Lee SH, Jang YS, Park SK, Park YH, et al. A novel agonistic antibody to human death receptor 4 induces apoptotic cell death in various tumor cells without cytotoxicity in hepatocytes. Mol Cancer Ther. 2009;8:2276–85.PubMedPubMedCentralCrossRefGoogle Scholar
  28. Varfolomeev E, Maecker H, Sharp D, Lawrence D, Renz M, Vucic D, et al. Molecular determinants of kinase pathway activation by Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand. J Biol Chem. 2005;280:40599–608.PubMedPubMedCentralCrossRefGoogle Scholar
  29. Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N, et al. TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL. EMBO J. 1997;16:5386–97.PubMedPubMedCentralCrossRefGoogle Scholar
  30. Wiley SR, Schooley K, Smolak PJ, Din WS, Huang CP, Nicholl JK, et al. Identification and characterization of a new member of the TNF family that induces apoptosis. Immunity. 1995;3:673–82.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Department of Molecular Science and TechnologyAjou UniversityYeongtong-Gu, SuwonKorea