Tumor necrosis factor receptor 2

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).[5][6] 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.[7][8] 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).[7]

TNFRSF1B
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesTNFRSF1B, CD120b, TBPII, TNF-R-II, TNF-R75, TNFBR, TNFR1B, TNFR2, TNFR80, p75, p75TNFR, tumor necrosis factor receptor superfamily member 1B, TNF receptor superfamily member 1B
External IDsOMIM: 191191 MGI: 1314883 HomoloGene: 829 GeneCards: TNFRSF1B
Orthologs
SpeciesHumanMouse
Entrez

7133

21938

Ensembl

ENSG00000028137

ENSMUSG00000028599

UniProt

P20333

P25119

RefSeq (mRNA)

NM_001066

NM_011610

RefSeq (protein)

NP_001057

NP_035740

Location (UCSC)Chr 1: 12.17 – 12.21 MbChr 4: 144.94 – 144.97 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[9]

Clinical significance

CNS

At least partly because TNRF2 has no intracellular death domain, TNFR2 is neuroprotective.[10]

Patients with schizophrenia have increased levels of soluble tumor necrosis factor receptor 2 (sTNFR2).[11]

Cancer

Targeting of TNRF2 in tumor cells is associated with increased tumor cell death and decreased progression of tumor cell growth.[8]

Increased expression of TNFR2 is found in breast cancer, cervical cancer, colon cancer, and renal cancer.[8] A link between the expression of TNRF2 in tumor cells and late-stage cancer has been discovered.[8] 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.[8] There is therapeutic potential in the targeting of TNFR2 for cancer treatments through TNFR2 inhibition.[12]

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. [13]

Interactions

TNFRSF1B has been shown to interact with:

References
  1. GRCh38: Ensembl release 89: ENSG00000028137 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000028599 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Schall TJ, Lewis M, Koller KJ, Lee A, Rice GC, Wong GH, et al. (April 1990). "Molecular cloning and expression of a receptor for human tumor necrosis factor". Cell. 61 (2): 361–370. doi:10.1016/0092-8674(90)90816-W. PMID 2158863. S2CID 36187863.
  6. Santee SM, Owen-Schaub LB (August 1996). "Human tumor necrosis factor receptor p75/80 (CD120b) gene structure and promoter characterization". The Journal of Biological Chemistry. 271 (35): 21151–21159. doi:10.1074/jbc.271.35.21151. PMID 8702885.
  7. Wang J, Al-Lamki RS (2013-11-17). "Tumor necrosis factor receptor 2: its contribution to acute cellular rejection and clear cell renal carcinoma". BioMed Research International. 2013: 821310. doi:10.1155/2013/821310. PMC 3848079. PMID 24350291.
  8. Sheng Y, Li F, Qin Z (2018). "TNF Receptor 2 Makes Tumor Necrosis Factor a Friend of Tumors". Frontiers in Immunology. 9: 1170. doi:10.3389/fimmu.2018.01170. PMC 5985372. PMID 29892300.
  9. "Entrez Gene: TNFRSF1B tumor necrosis factor receptor superfamily, member 1B". Retrieved 8 May 2017.
  10. Chadwick W, Magnus T, Martin B, Keselman A, Mattson MP, Maudsley S (October 2008). "Targeting TNF-alpha receptors for neurotherapeutics". Trends in Neurosciences. 31 (10): 504–511. doi:10.1016/j.tins.2008.07.005. PMC 2574933. PMID 18774186.
  11. Kudo N, Yamamori H, Ishima T, Nemoto K, Yasuda Y, Fujimoto M, et al. (July 2018). "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. doi:10.1093/ijnp/pyy013. PMC 6031046. PMID 29529289.
  12. Medler J, Wajant H (April 2019). "Tumor necrosis factor receptor-2 (TNFR2): an overview of an emerging drug target". Expert Opinion on Therapeutic Targets. 23 (4): 295–307. doi:10.1080/14728222.2019.1586886. PMID 30856027. S2CID 75139844.
  13. Komata, T.; Tsuchiya, N.; Matsushita, M.; Hagiwara, K.; Tokunaga, K. (June 1999). "Association of tumor necrosis factor receptor 2 ( TNFR2 ) polymorphism with susceptibility to systemic lupus erythematosus: TNFR2 polymorphism in SLE". Tissue Antigens. 53 (6): 527–533. doi:10.1034/j.1399-0039.1999.530602.x. PMID 10395102.
  14. Bouwmeester T, Bauch A, Ruffner H, Angrand PO, Bergamini G, Croughton K, et al. (February 2004). "A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway". Nature Cell Biology. 6 (2): 97–105. doi:10.1038/ncb1086. PMID 14743216. S2CID 11683986.
  15. Song HY, Donner DB (August 1995). "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. doi:10.1042/bj3090825. PMC 1135706. PMID 7639698.
  16. Takeuchi M, Rothe M, Goeddel DV (August 1996). "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. doi:10.1074/jbc.271.33.19935. PMID 8702708.
  17. Hostager BS, Bishop GA (April 2002). "Role of TNF receptor-associated factor 2 in the activation of IgM secretion by CD40 and CD120b". Journal of Immunology. 168 (7): 3318–3322. doi:10.4049/jimmunol.168.7.3318. PMID 11907088.
  18. Rothe M, Xiong J, Shu HB, Williamson K, Goddard A, Goeddel DV (August 1996). "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. Bibcode:1996PNAS...93.8241R. doi:10.1073/pnas.93.16.8241. PMC 38654. PMID 8710854.
  19. Marsters SA, Ayres TM, Skubatch M, Gray CL, Rothe M, Ashkenazi A (May 1997). "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. doi:10.1074/jbc.272.22.14029. PMID 9162022.
  20. Carpentier I, Coornaert B, Beyaert R (October 2008). "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. doi:10.1016/j.bbrc.2008.07.103. PMID 18671942.
  21. Pype S, Declercq W, Ibrahimi A, Michiels C, Van Rietschoten JG, Dewulf N, et al. (June 2000). "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. doi:10.1074/jbc.M000531200. PMID 10764746.

Further reading
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