Death receptor 5 explained

Death receptor 5 (DR5), also known as TRAIL receptor 2 (TRAILR2) and tumor necrosis factor receptor superfamily member 10B (TNFRSF10B), is a cell surface receptor of the TNF-receptor superfamily that binds TRAIL and mediates apoptosis.

Function

The protein encoded by this gene is a member of the TNF-receptor superfamily, and contains an intracellular death domain. This receptor can be activated by tumor necrosis factor-related apoptosis inducing ligand (TNFSF10/TRAIL/APO-2L), and transduces apoptosis signal. Mice have a homologous gene, tnfrsf10b, that has been essential in the elucidation of the function of this gene in humans. Studies with FADD-deficient mice suggested that FADD, a death domain containing adaptor protein, is required for the apoptosis mediated by this protein.^[1]

Interactions

DR5 has been shown to interact with:

• Caspase 8,
• Caspase 10,^[2]
• FADD,^{[3] [4]} and
• TRAIL.^{[5] [6] [7]}

Cancer therapy

Monoclonal antibodies targeting DR5 have been developed and are currently under clinical trials for patients suffer from a variety of cancer types, see Tigatuzumab (CS-1008).

Luminescent iridium complex-peptide hybrids, serving as TRAIL mimics, have been designed, which target the death receptors DR4 and DR5 on cancer cells and induce their apoptosis.^[8]

See also

• Cluster of differentiation
• Tumor necrosis factor receptor
• Tigatuzumab

Further reading

• Abe K, Kurakin A, Mohseni-Maybodi M, Kay B, Khosravi-Far R . The complexity of TNF-related apoptosis-inducing ligand . Annals of the New York Academy of Sciences . 926 . 1 . 52–63 . 2001 . 11193041 . 10.1111/j.1749-6632.2000.tb05598.x . 45991330 .
• Cha SS, Song YL, Oh BH . Specificity of molecular recognition learned from the crystal structures of TRAIL and the TRAIL:sDR5 complex . Vitamins and Hormones . 67 . 1–17 . 2004 . 15110168 . 10.1016/S0083-6729(04)67001-4 . 978-0-12-709867-8 .
• Kimberley FC, Screaton GR . Following a TRAIL: update on a ligand and its five receptors . Cell Research . 14 . 5 . 359–72 . Oct 2004 . 15538968 . 10.1038/sj.cr.7290236 . free .
• 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 . 277 . 5327 . 815–8 . Aug 1997 . 9242610 . 10.1126/science.277.5327.815 .
• Sheridan JP, Marsters SA, Pitti RM, Gurney A, Skubatch M, Baldwin D, Ramakrishnan L, Gray CL, Baker K, Wood WI, Goddard AD, Godowski P, Ashkenazi A . Control of TRAIL-induced apoptosis by a family of signaling and decoy receptors . Science . 277 . 5327 . 818–21 . Aug 1997 . 9242611 . 10.1126/science.277.5327.818 .
• 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 . Current Biology . 7 . 9 . 693–6 . Sep 1997 . 9285725 . 10.1016/S0960-9822(06)00297-1 . 17740648 . free . 1997CBio....7..693S .
• Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N, Timour MS, Gerhart MJ, Schooley KA, Smith CA, Goodwin RG, Rauch CT . TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL . The EMBO Journal . 16 . 17 . 5386–97 . Sep 1997 . 9311998 . 1170170 . 10.1093/emboj/16.17.5386 .
• 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 . The Journal of Biological Chemistry . 272 . 41 . 25417–20 . Oct 1997 . 9325248 . 10.1074/jbc.272.41.25417 . free.
• Wu GS, Burns TF, McDonald ER, Jiang W, Meng R, Krantz ID, Kao G, Gan DD, Zhou JY, Muschel R, Hamilton SR, Spinner NB, Markowitz S, Wu G, el-Deiry WS . KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene . Nature Genetics . 17 . 2 . 141–3 . Oct 1997 . 9326928 . 10.1038/ng1097-141 . 7037468 .
• Schneider P, Bodmer JL, Thome M, Hofmann K, Holler N, Tschopp J . Characterization of two receptors for TRAIL . FEBS Letters . 416 . 3 . 329–34 . Oct 1997 . 9373179 . 10.1016/S0014-5793(97)01231-3 . 83145771 . free .
• Marsters SA, Sheridan JP, Pitti RM, Huang A, Skubatch M, Baldwin D, Yuan J, Gurney A, Goddard AD, Godowski P, Ashkenazi A . A novel receptor for Apo2L/TRAIL contains a truncated death domain . Current Biology . 7 . 12 . 1003–6 . Dec 1997 . 9382840 . 10.1016/S0960-9822(06)00422-2 . 21645158 . free . 1997CBio....7.1003M .
• Chaudhary PM, Eby M, Jasmin A, Bookwalter A, Murray J, Hood L . Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway . Immunity . 7 . 6 . 821–30 . Dec 1997 . 9430227 . 10.1016/S1074-7613(00)80400-8 . free .
• Schneider P, Thome M, Burns K, Bodmer JL, Hofmann K, Kataoka T, Holler N, Tschopp J . TRAIL receptors 1 (DR4) and 2 (DR5) signal FADD-dependent apoptosis and activate NF-kappaB . Immunity . 7 . 6 . 831–6 . Dec 1997 . 9430228 . 10.1016/S1074-7613(00)80401-X . free .
• Pai SI, Wu GS, Ozören N, Wu L, Jen J, Sidransky D, El-Deiry WS . Rare loss-of-function mutation of a death receptor gene in head and neck cancer . Cancer Research . 58 . 16 . 3513–8 . Aug 1998 . 9721851 .
• Arai T, Akiyama Y, Okabe S, Saito K, Iwai T, Yuasa Y . Genomic organization and mutation analyses of the DR5/TRAIL receptor 2 gene in colorectal carcinomas . Cancer Letters . 133 . 2 . 197–204 . Nov 1998 . 10072170 . 10.1016/S0304-3835(98)00230-4 .
• Mongkolsapaya J, Grimes JM, Chen N, Xu XN, Stuart DI, Jones EY, Screaton GR . Structure of the TRAIL-DR5 complex reveals mechanisms conferring specificity in apoptotic initiation . Nature Structural Biology . 6 . 11 . 1048–53 . Nov 1999 . 10542098 . 10.1038/14935 . 6604122 .
• Hymowitz SG, Christinger HW, Fuh G, Ultsch M, O'Connell M, Kelley RF, Ashkenazi A, de Vos AM . Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5 . Molecular Cell . 4 . 4 . 563–71 . Oct 1999 . 10549288 . 10.1016/S1097-2765(00)80207-5 . free .
• Kuang AA, Diehl GE, Zhang J, Winoto A . FADD is required for DR4- and DR5-mediated apoptosis: lack of trail-induced apoptosis in FADD-deficient mouse embryonic fibroblasts . The Journal of Biological Chemistry . 275 . 33 . 25065–8 . Aug 2000 . 10862756 . 10.1074/jbc.C000284200 . free .
• Trauzold A, Wermann H, Arlt A, Schütze S, Schäfer H, Oestern S, Röder C, Ungefroren H, Lampe E, Heinrich M, Walczak H, Kalthoff H . CD95 and TRAIL receptor-mediated activation of protein kinase C and NF-kappaB contributes to apoptosis resistance in ductal pancreatic adenocarcinoma cells . Oncogene . 20 . 31 . 4258–69 . Jul 2001 . 11464292 . 10.1038/sj.onc.1204559 . free .

Notes and References

1. Web site: Entrez Gene: TNFRSF10B tumor necrosis factor receptor superfamily, member 10b.
2. MacFarlane M, Ahmad M, Srinivasula SM, Fernandes-Alnemri T, Cohen GM, Alnemri ES . Oct 1997 . Identification and molecular cloning of two novel receptors for the cytotoxic ligand TRAIL . J. Biol. Chem. . 272 . 41 . 25417–20 . 9325248 . 10.1074/jbc.272.41.25417. free.
3. Gajate C, Mollinedo F . Mar 2005 . Cytoskeleton-mediated death receptor and ligand concentration in lipid rafts forms apoptosis-promoting clusters in cancer chemotherapy . J. Biol. Chem. . 280 . 12 . 11641–7 . 15659383 . 10.1074/jbc.M411781200. free .
4. Chaudhary PM, Eby M, Jasmin A, Bookwalter A, Murray J, Hood L . Dec 1997 . Death receptor 5, a new member of the TNFR family, and DR4 induce FADD-dependent apoptosis and activate the NF-kappaB pathway . Immunity . 7 . 6 . 821–30 . 9430227 . 10.1016/s1074-7613(00)80400-8. free .
5. Kaptein A, Jansen M, Dilaver G, Kitson J, Dash L, Wang E, Owen MJ, Bodmer JL, Tschopp J, Farrow SN . Nov 2000 . Studies on the interaction between TWEAK and the death receptor WSL-1/TRAMP (DR3) . FEBS Lett. . 485 . 2–3 . 135–41 . 11094155 . 10.1016/s0014-5793(00)02219-5. 38403545 . free .
6. Walczak H, Degli-Esposti MA, Johnson RS, Smolak PJ, Waugh JY, Boiani N, Timour MS, Gerhart MJ, Schooley KA, Smith CA, Goodwin RG, Rauch CT . Sep 1997 . TRAIL-R2: a novel apoptosis-mediating receptor for TRAIL . EMBO J. . 16 . 17 . 5386–97 . 9311998 . 1170170 . 10.1093/emboj/16.17.5386.
7. Hymowitz SG, Christinger HW, Fuh G, Ultsch M, O'Connell M, Kelley RF, Ashkenazi A, de Vos AM . Oct 1999 . Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5 . Mol. Cell . 4 . 4 . 563–71 . 10549288 . 10.1016/S1097-2765(00)80207-5. free .
8. Masum AA, Yokoi K, Hisamatsu Y, Naito K, Shashni B, Aoki S . Design and synthesis of a luminescent iridium complex-peptide hybrid (IPH) that detects cancer cells and induces their apoptosis . Bioorganic & Medicinal Chemistry . 26 . 17 . 4804–4816 . September 2018 . 30177492 . 10.1016/j.bmc.2018.08.016 . 52149418 .