Tumor necrosis factor receptor 2 explained

Tumor necrosis factor receptor 2 (TNFR2), also known as tumor necrosis factor receptor superfamily member 1B (TNFRSF1B) and CD120b, is one of two membrane receptors that binds tumor necrosis factor-alpha (TNFα).[1] [2] Like its counterpart, tumor necrosis factor receptor 1 (TNFR1), the extracellular region of TNFR2 consists of four cysteine-rich domains which allow for binding to TNFα.[3] [4] TNFR1 and TNFR2 possess different functions when bound to TNFα due to differences in their intracellular structures, such as TNFR2 lacking a death domain (DD).

Function

The protein encoded by this gene is a member of the tumor necrosis factor receptor superfamily, which also contains TNFRSF1A. This protein and TNF-receptor 1 form a heterocomplex that mediates the recruitment of two anti-apoptotic proteins, c-IAP1 and c-IAP2, which possess E3 ubiquitin ligase activity. The function of IAPs in TNF-receptor signalling is unknown, however, c-IAP1 is thought to potentiate TNF-induced apoptosis by the ubiquitination and degradation of TNF-receptor-associated factor 2 (TRAF2), which mediates anti-apoptotic signals. Knockout studies in mice also suggest a role of this protein in protecting neurons from apoptosis by stimulating antioxidative pathways.[5]

Clinical significance

CNS

At least partly because TNFR2 has no intracellular death domain, TNFR2 is neuroprotective.[6]

Patients with schizophrenia have increased levels of soluble tumor necrosis factor receptor 2 (sTNFR2).[7]

Cancer

Targeting of TNRF2 in tumor cells is associated with increased tumor cell death and decreased progression of tumor cell growth.

Increased expression of TNFR2 is found in breast cancer, cervical cancer, colon cancer, and renal cancer. A link between the expression of TNRF2 in tumor cells and late-stage cancer has been discovered. TNFR2 plays a significant role in tumor cell growth as it has been found that the loss of TNFR2 expression is linked with increased death of associated tumor cells and a significant standstill of further growth. There is therapeutic potential in the targeting of TNFR2 for cancer treatments through TNFR2 inhibition.[8]

Systemic Lupus Erythematous (SLE)

A small scale study of 289 Japanese patients suggested a minor increased predisposition from an amino acid substitution of the 196 allele at exon 6. Genomic testing of 81 SLE patients and 207 healthy patients in a Japanese study showed 37% of SLE patients had a polymorphism on position 196 of exon 6 compared to 18.8% of healthy patients. The TNFR2 196R allele polymorphism suggests that even one 196R allele results in increased risk for SLE. [9]

Interactions

TNFRSF1B has been shown to interact with:

Further reading

Notes and References

  1. Schall TJ, Lewis M, Koller KJ, Lee A, Rice GC, Wong GH, Gatanaga T, Granger GA, Lentz R, Raab H . 6 . Molecular cloning and expression of a receptor for human tumor necrosis factor . Cell . 61 . 2 . 361–370 . April 1990 . 2158863 . 10.1016/0092-8674(90)90816-W . 36187863 .
  2. Santee SM, Owen-Schaub LB . Human tumor necrosis factor receptor p75/80 (CD120b) gene structure and promoter characterization . The Journal of Biological Chemistry . 271 . 35 . 21151–21159 . August 1996 . 8702885 . 10.1074/jbc.271.35.21151 . free .
  3. Wang J, Al-Lamki RS . Tumor necrosis factor receptor 2: its contribution to acute cellular rejection and clear cell renal carcinoma . BioMed Research International . 2013 . 821310 . 2013-11-17 . 24350291 . 10.1155/2013/821310 . 3848079 . free .
  4. Sheng Y, Li F, Qin Z . TNF Receptor 2 Makes Tumor Necrosis Factor a Friend of Tumors . Frontiers in Immunology . 9 . 1170 . 2018 . 29892300 . 10.3389/fimmu.2018.01170 . 5985372 . free .
  5. Web site: Entrez Gene: TNFRSF1B tumor necrosis factor receptor superfamily, member 1B. 8 May 2017.
  6. Chadwick W, Magnus T, Martin B, Keselman A, Mattson MP, Maudsley S . Targeting TNF-alpha receptors for neurotherapeutics . Trends in Neurosciences . 31 . 10 . 504–511 . October 2008 . 18774186 . 2574933 . 10.1016/j.tins.2008.07.005 .
  7. Kudo N, Yamamori H, Ishima T, Nemoto K, Yasuda Y, Fujimoto M, Azechi H, Niitsu T, Numata S, Ikeda M, Iyo M, Ohmori T, Fukunaga M, Watanabe Y, Hashimoto K, Hashimoto R . 6 . Plasma Levels of Soluble Tumor Necrosis Factor Receptor 2 (sTNFR2) Are Associated with Hippocampal Volume and Cognitive Performance in Patients with Schizophrenia . The International Journal of Neuropsychopharmacology . 21 . 7 . 631–639 . July 2018 . 29529289 . 6031046 . 10.1093/ijnp/pyy013 .
  8. Medler J, Wajant H . Tumor necrosis factor receptor-2 (TNFR2): an overview of an emerging drug target . Expert Opinion on Therapeutic Targets . 23 . 4 . 295–307 . April 2019 . 30856027 . 10.1080/14728222.2019.1586886 . 75139844 .
  9. Komata . T. . Tsuchiya . N. . Matsushita . M. . Hagiwara . K. . Tokunaga . K. . Association of tumor necrosis factor receptor 2 (TNFR2) polymorphism with susceptibility to systemic lupus erythematosus: TNFR2 polymorphism in SLE . Tissue Antigens . June 1999 . 53 . 6 . 527–533 . 10.1034/j.1399-0039.1999.530602.x. 10395102 .
  10. Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, Cruciat C, Eberhard D, Gagneur J, Ghidelli S, Hopf C, Huhse B, Mangano R, Michon AM, Schirle M, Schlegl J, Schwab M, Stein MA, Bauer A, Casari G, Drewes G, Gavin AC, Jackson DB, Joberty G, Neubauer G, Rick J, Kuster B, Superti-Furga G . 6 . A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway . Nature Cell Biology . 6 . 2 . 97–105 . February 2004 . 14743216 . 10.1038/ncb1086 . 11683986 .
  11. Song HY, Donner DB . Association of a RING finger protein with the cytoplasmic domain of the human type-2 tumour necrosis factor receptor . The Biochemical Journal . 309 . 3 . 825–829 . August 1995 . 7639698 . 1135706 . 10.1042/bj3090825 .
  12. Takeuchi M, Rothe M, Goeddel DV . Anatomy of TRAF2. Distinct domains for nuclear factor-kappaB activation and association with tumor necrosis factor signaling proteins . The Journal of Biological Chemistry . 271 . 33 . 19935–19942 . August 1996 . 8702708 . 10.1074/jbc.271.33.19935 . free .
  13. Hostager BS, Bishop GA . Role of TNF receptor-associated factor 2 in the activation of IgM secretion by CD40 and CD120b . Journal of Immunology . 168 . 7 . 3318–3322 . April 2002 . 11907088 . 10.4049/jimmunol.168.7.3318 . free .
  14. Rothe M, Xiong J, Shu HB, Williamson K, Goddard A, Goeddel DV . I-TRAF is a novel TRAF-interacting protein that regulates TRAF-mediated signal transduction . Proceedings of the National Academy of Sciences of the United States of America . 93 . 16 . 8241–8246 . August 1996 . 8710854 . 38654 . 10.1073/pnas.93.16.8241 . free . 1996PNAS...93.8241R .
  15. Marsters SA, Ayres TM, Skubatch M, Gray CL, Rothe M, Ashkenazi A . Herpesvirus entry mediator, a member of the tumor necrosis factor receptor (TNFR) family, interacts with members of the TNFR-associated factor family and activates the transcription factors NF-kappaB and AP-1 . The Journal of Biological Chemistry . 272 . 22 . 14029–14032 . May 1997 . 9162022 . 10.1074/jbc.272.22.14029 . free .
  16. Carpentier I, Coornaert B, Beyaert R . Smurf2 is a TRAF2 binding protein that triggers TNF-R2 ubiquitination and TNF-R2-induced JNK activation . Biochemical and Biophysical Research Communications . 374 . 4 . 752–757 . October 2008 . 18671942 . 10.1016/j.bbrc.2008.07.103 .
  17. Pype S, Declercq W, Ibrahimi A, Michiels C, Van Rietschoten JG, Dewulf N, de Boer M, Vandenabeele P, Huylebroeck D, Remacle JE . 6 . TTRAP, a novel protein that associates with CD40, tumor necrosis factor (TNF) receptor-75 and TNF receptor-associated factors (TRAFs), and that inhibits nuclear factor-kappa B activation . The Journal of Biological Chemistry . 275 . 24 . 18586–18593 . June 2000 . 10764746 . 10.1074/jbc.M000531200 . free .

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