TNFRSF12A explained

Tumor necrosis factor receptor superfamily member 12A also known as the TWEAK receptor (TWEAKR) is a protein that in humans is encoded by the TNFRSF12A gene.[1] [2] [3]

Other names used when talking about  TNFRSF12A are fibroblast growth factor-inducible immediate-early response protein 14 (FN14).[4] TNFRSF12A is a unique member of the Tumor Necrosis Factor Receptor superfamily. TNFRSF12A is the smallest member of the Tumor Necrosis Factor Receptor superfamily and the gene expression is highly regulated in a live organism and a petri dish. TNFRSF12A is the receptor for the TWEAK which is its ligand. Many other members of the Tumor necrosis factor superfamily can bind to other ligands but this receptor can only bind to TNFRSF12.[5] TNFRSF12A is found in many human tissues, including the heart, placenta, lung, skeletal muscle, kidney, and pancreas. It is involved in several biological processes, such as inflammatory reactions, angiogenesis, cell proliferation, and cell death.

Structure

This receptor can be found in chromosome 16 in humans[6] and chromosome 17 in mice.[2] The TNFRSF12A receptors in mice and humans are 93 percent similar. This receptor is made of one hundred and twenty-eight amino acids and one cysteine-rich domain[7] then once fully developed the amino acids drop to one hundred and two amino acids. This receptor is a type I transmembrane protein because of the disulfide bonds that form the cysteine-rich domains without a death domain.[8] Although the receptor does not have a death domain it can still produce a weak death cell signal.[4] The receptor is made of helices, the β-sheet, and the loop regions, and disulfide bonds for CRD. For further context, the CRD's tertiary structure consists of a beta-sheet with two strands, followed by a 3(10) helix and a C-terminal alpha-helix, and is held together by three disulfide bonds that connect Cys36-Cys49, Cys52-Cys67, and Cys55-Cys64. When the disulfide bond connectivities and tertiary structures of the Fn14 CRD were compared to those of other CRDs, it was discovered that it is similar to the fourth CRD of TNF receptor 1 (A1-C2 module type), but not to the CRD of B-cell maturation antigen and the second CRD of transmembrane activator and CAML (calcium modulator and cyclophilin ligand) interactor (A1-D2). The cysteine-rich domain is made of 53 amino acid residues which are outside the call of the ligand binding region.

Discovery

In 1997 the discovery of the ligand TNFRSF12[9] led to the discovery of the receptor TNFRSF12A in 1999.[4] The receptor was found in chromosome 17 inside the T-locus on a mouse while doing research about polypeptide growth factors.[2] When they were trying to identify on fibroblast growth factors (FGF) they discovered fibroblast growth factor-inducible immediate-early response protein, FN14, and did not know what protein had similar structures as it as well. When it was discovered they decided to name it FN14 because the projected molecular mass of about 10.8 kilodaltons. Gene expression was also found in many of the major organs of newborn animals, and in the adult heart, kidney, lung, ovary, and skin. This led to the possibility of FN14 being a ligand binding site and more research on this receptor. It was determined that 93 percent of the structure was made of amino acids when comparing the receptor structure of human or mouse form.

Therapeutic Strategies

Tumor necrosis factors are important regulators of many different cells and tissues which makes TNFRSF12A important for expressing many different cells and tissues. TNFRSF12A is expressed in many different cells and tissues due to the function of TNFRSF12.[10] What makes TNFRSF12A stand out other than its size from the other Tumor necrosis factors receptor superfamily is that the gene expression is extremely regulated in a live organism and in a petri dish.[4] There was a recent study done in 2023 about how FN14 signaling contributes to the growth and duplication of tumors (angiogenesis).[11] [4] Increased expressions or interactions of TNFRSF12A and TNFRSF12 have been found to correlate with diseases and morbidity such as acute ischemic stroke, Rheumatoid Arthritis, Systemic Lymphocytic Erythematosus (SLE), Multiple Sclerosis and Cancer.[12] [4] In a clinical study, the overall severity of the disease was found to be reduced by intraperitoneal injection of an anti-TWEAK neutralizing monoclonal antibody in rats and mice.[4] The result of the clinical study implied that Fn14 was a tumor biomarker and that it should be taken into account as a potential new cancer treatment target.[4] This leads to the possibility of blocking the ligand from binding to the receptor to stop the expression of TRNRSF12A to reduce or even stop the gene expression. There are other current clinical studies on how TNFRSF12A is expressed and affects different cell types. Studies have shown that high expression levels can lead to worse outcomes.

Interactions

TNFRSF12A has been shown to interact with TNFRSF12 and TNFR-associated factor (TRAF) 1, 2, 3 and 5.[13] [14]

Further reading

Notes and References

  1. Feng SL, Guo Y, Factor VM, Thorgeirsson SS, Bell DW, Testa JR, Peifley KA, Winkles JA . 6 . The Fn14 immediate-early response gene is induced during liver regeneration and highly expressed in both human and murine hepatocellular carcinomas . The American Journal of Pathology . 156 . 4 . 1253–1261 . April 2000 . 10751351 . 1876890 . 10.1016/S0002-9440(10)64996-6 .
  2. Meighan-Mantha RL, Hsu DK, Guo Y, Brown SA, Feng SL, Peifley KA, Alberts GF, Copeland NG, Gilbert DJ, Jenkins NA, Richards CM, Winkles JA . 6 . The mitogen-inducible Fn14 gene encodes a type I transmembrane protein that modulates fibroblast adhesion and migration . The Journal of Biological Chemistry . 274 . 46 . 33166–33176 . November 1999 . 10551889 . 10.1074/jbc.274.46.33166 . free .
  3. Web site: Entrez Gene: TNFRSF12A tumor necrosis factor receptor superfamily, member 12A.
  4. Winkles JA . The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting . Nature Reviews. Drug Discovery . 7 . 5 . 411–425 . May 2008 . 18404150 . 3018765 . 10.1038/nrd2488 .
  5. Perez JG, Tran NL, Rosenblum MG, Schneider CS, Connolly NP, Kim AJ, Woodworth GF, Winkles JA . 6 . The TWEAK receptor Fn14 is a potential cell surface portal for targeted delivery of glioblastoma therapeutics . Oncogene . 35 . 17 . 2145–2155 . April 2016 . 26300004 . 4850525 . 10.1038/onc.2015.310 .
  6. Web site: TNFRSF12A TNF receptor superfamily member 12A [Homo sapiens (human)] - Gene - NCBI ]. 2023-11-28 . www.ncbi.nlm.nih.gov.
  7. He F, Dang W, Saito K, Watanabe S, Kobayashi N, Güntert P, Kigawa T, Tanaka A, Muto Y, Yokoyama S . 6 . Solution structure of the cysteine-rich domain in Fn14, a member of the tumor necrosis factor receptor superfamily . Protein Science . 18 . 3 . 650–656 . March 2009 . 19241374 . 2760370 . 10.1002/pro.49 .
  8. Locksley RM, Killeen N, Lenardo MJ . The TNF and TNF receptor superfamilies: integrating mammalian biology . Cell . 104 . 4 . 487–501 . February 2001 . 11239407 . 10.1016/S0092-8674(01)00237-9 . 7657797 . free .
  9. Chicheportiche Y, Bourdon PR, Xu H, Hsu YM, Scott H, Hession C, Garcia I, Browning JL . 6 . TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis . The Journal of Biological Chemistry . 272 . 51 . 32401–32410 . December 1997 . 9405449 . 10.1074/jbc.272.51.32401 . free .
  10. Ruiz BI, Lowman XH, Yang Y, Fan Q, Wang T, Wu H, Hanse EA, Kong M . 6 . Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia . Genes . 14 . 9 . 1818 . September 2023 . 37761958 . 10531467 . 10.3390/genes14091818 . free .
  11. Liao M, Liao J, Qu J, Shi P, Cheng Y, Pan Q, Zhao N, Zhang X, Zhang L, Tan Y, Li Q, Zhu JF, Li J, Zhang C, Cai SY, Chai J . 6 . Hepatic TNFRSF12A promotes bile acid-induced hepatocyte pyroptosis through NFκB/Caspase-1/GSDMD signaling in cholestasis . Cell Death Discovery . 9 . 1 . 26 . January 2023 . 36690641 . 9871041 . 10.1038/s41420-023-01326-z .
  12. Polek TC, Talpaz M, Darnay BG, Spivak-Kroizman T . TWEAK mediates signal transduction and differentiation of RAW264.7 cells in the absence of Fn14/TweakR. Evidence for a second TWEAK receptor . The Journal of Biological Chemistry . 278 . 34 . 32317–32323 . August 2003 . 12794080 . 10.1074/jbc.m302518200 . free .
  13. Wiley SR, Winkles JA . TWEAK, a member of the TNF superfamily, is a multifunctional cytokine that binds the TweakR/Fn14 receptor . Cytokine & Growth Factor Reviews . 14 . 3–4 . 241–249 . 2003-06-01 . 12787562 . 10.1016/S1359-6101(03)00019-4 .
  14. Brown SA, Richards CM, Hanscom HN, Feng SL, Winkles JA . The Fn14 cytoplasmic tail binds tumour-necrosis-factor-receptor-associated factors 1, 2, 3 and 5 and mediates nuclear factor-kappaB activation . The Biochemical Journal . 371 . Pt 2 . 395–403 . April 2003 . 12529173 . 1223299 . 10.1042/BJ20021730 .

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