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]
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 TNFR2 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]
^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.
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^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.
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^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.
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^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.
PMID18671942.
Kollias G,
Kontoyiannis D (2003). "Role of TNF/TNFR in autoimmunity: specific TNF receptor blockade may be advantageous to anti-TNF treatments". Cytokine & Growth Factor Reviews. 13 (4–5): 315–321.
doi:
10.1016/S1359-6101(02)00019-9.
PMID12220546.
Holtmann MH, Schuchmann M, Zeller G, Galle PR, Neurath MF (2003). "The emerging distinct role of TNF-receptor 2 (p80) signaling in chronic inflammatory disorders". Archivum Immunologiae et Therapiae Experimentalis. 50 (4): 279–288.
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