TNFRSF12A

TNFRSF12A
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2EQP, 2KMZ, 2RPJ
Identifiers
Aliases	TNFRSF12A, CD266, FN14, TWEAKR, tumor necrosis factor receptor superfamily member 12A, TNF receptor superfamily member 12A
External IDs	OMIM: 605914; MGI: 1351484; HomoloGene: 8451; GeneCards: TNFRSF12A; OMA:TNFRSF12A - orthologs
Gene location (Human) Chr. Chromosome 16 (human)[1] Band 16p13.3 Start 3,018,445 bp[1] End 3,022,383 bp[1]
Gene location (Mouse) Chr. Chromosome 17 (mouse)[2] Band 17|17 A3.3 Start 23,894,419 bp[2] End 23,896,442 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in apex of heart ascending aorta body of pancreas beta cell anterior pituitary gallbladder right coronary artery upper lobe of left lung left ventricle Descending thoracic aorta Top expressed in interventricular septum decidua muscle of thigh adrenal gland soleus muscle endothelial cell of lymphatic vessel lip yolk sac right ventricle gastrula More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding Cellular component ruffle integral component of membrane cell surface plasma membrane membrane Biological process apoptotic process substrate-dependent cell migration, cell attachment to substrate multicellular organism development positive regulation of extrinsic apoptotic signaling pathway cell differentiation positive regulation of axon extension cell adhesion tumor necrosis factor-mediated signaling pathway regulation of wound healing regulation of angiogenesis extrinsic apoptotic signaling pathway angiogenesis positive regulation of apoptotic process Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 51330 27279 Ensembl ENSG00000006327 ENSMUSG00000023905 UniProt Q9NP84 Q9CR75 RefSeq (mRNA) NM_016639 NM_001161746 NM_013749 RefSeq (protein) NP_057723 NP_001155218 NP_038777 Location (UCSC) Chr 16: 3.02 – 3.02 Mb Chr 17: 23.89 – 23.9 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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.^[5][6][7]

Other names used when talking about  TNFRSF12A are fibroblast growth factor-inducible immediate-early response protein 14 (FN14).^[8] TNFRSF12A is a unique member of the Tumor Necrosis Factor Receptor superfamily. TNFRSF12A is the smallest member of the Tumor Necrosis Factor Receptor superfamily^[8] and the gene expression is highly regulated in a live organism and a petri dish.^[9] TNFRSF12A is the receptor for the TWEAK which is its ligand.^[8] Many other members of the Tumor necrosis factor superfamily can bind to other ligands but this receptor can only bind to TNFRSF12.^[10] 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.^[11]

Structure

This receptor can be found in chromosome 16 in humans^[12] and chromosome 17 in mice.^[6] The TNFRSF12A receptors in mice and humans are 93 percent similar.^[11] This receptor is made of one hundred and twenty-eight amino acids and one cysteine-rich domain^[13] 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.^[14] Although the receptor does not have a death domain it can still produce a weak death cell signal.^[8] The receptor is made of helices, the β-sheet, and the loop regions, and disulfide bonds for CRD.^[13] 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.^[13] 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).^[13] The cysteine-rich domain is made of 53 amino acid residues which are outside the call of the ligand binding region.^[13]

Discovery

In 1997 the discovery of the ligand TNFRSF12^[15] led to the discovery of the receptor TNFRSF12A in 1999.^[8] The receptor was found in chromosome 17 inside the T-locus on a mouse while doing research about polypeptide growth factors.^[6] 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.^[6] When it was discovered they decided to name it FN14 because the projected molecular mass of about 10.8 kilodaltons.^[6] Gene expression was also found in many of the major organs of newborn animals, and in the adult heart, kidney, lung, ovary, and skin.^[6] This led to the possibility of FN14 being a ligand binding site and more research on this receptor.^[6] It was determined that 93 percent of the structure was made of amino acids when comparing the receptor structure of human or mouse form.^[11]

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.^[9] 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.^[9][8] There was a recent study done in 2023 about how FN14 signaling contributes to the growth and duplication of tumors (angiogenesis).^[11][8] 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.^{[9][16][8][11]} 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.^[8] 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.^[8] 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.^[11]

Interactions

TNFRSF12A has been shown to interact with TNFRSF12 and TNFR-associated factor (TRAF) 1, 2, 3 and 5.^[17][18]

References

1. GRCh38: Ensembl release 89: ENSG00000006327 – Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000023905 – 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. Feng SL, Guo Y, Factor VM, Thorgeirsson SS, Bell DW, Testa JR, et al. (April 2000). "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. doi:10.1016/S0002-9440(10)64996-6. PMC 1876890. PMID 10751351.
6. Meighan-Mantha RL, Hsu DK, Guo Y, Brown SA, Feng SL, Peifley KA, et al. (November 1999). "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. doi:10.1074/jbc.274.46.33166. PMID 10551889.
7. "Entrez Gene: TNFRSF12A tumor necrosis factor receptor superfamily, member 12A".
8. Winkles JA (May 2008). "The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting". Nature Reviews. Drug Discovery. 7 (5): 411–425. doi:10.1038/nrd2488. PMC 3018765. PMID 18404150.
9. Ruiz BI, Lowman XH, Yang Y, Fan Q, Wang T, Wu H, et al. (September 2023). "Alpha-Ketoglutarate Regulates Tnfrsf12a/Fn14 Expression via Histone Modification and Prevents Cancer-Induced Cachexia". Genes. 14 (9): 1818. doi:10.3390/genes14091818. PMC 10531467. PMID 37761958.
10. Perez JG, Tran NL, Rosenblum MG, Schneider CS, Connolly NP, Kim AJ, et al. (April 2016). "The TWEAK receptor Fn14 is a potential cell surface portal for targeted delivery of glioblastoma therapeutics". Oncogene. 35 (17): 2145–2155. doi:10.1038/onc.2015.310. PMC 4850525. PMID 26300004.
11. Liao M, Liao J, Qu J, Shi P, Cheng Y, Pan Q, et al. (January 2023). "Hepatic TNFRSF12A promotes bile acid-induced hepatocyte pyroptosis through NFκB/Caspase-1/GSDMD signaling in cholestasis". Cell Death Discovery. 9 (1): 26. doi:10.1038/s41420-023-01326-z. PMC 9871041. PMID 36690641.
12. "TNFRSF12A TNF receptor superfamily member 12A [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2023-11-28.
13. He F, Dang W, Saito K, Watanabe S, Kobayashi N, Güntert P, et al. (March 2009). "Solution structure of the cysteine-rich domain in Fn14, a member of the tumor necrosis factor receptor superfamily". Protein Science. 18 (3): 650–656. doi:10.1002/pro.49. PMC 2760370. PMID 19241374.
14. Locksley RM, Killeen N, Lenardo MJ (February 2001). "The TNF and TNF receptor superfamilies: integrating mammalian biology". Cell. 104 (4): 487–501. doi:10.1016/S0092-8674(01)00237-9. PMID 11239407. S2CID 7657797.
15. Chicheportiche Y, Bourdon PR, Xu H, Hsu YM, Scott H, Hession C, et al. (December 1997). "TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis". The Journal of Biological Chemistry. 272 (51): 32401–32410. doi:10.1074/jbc.272.51.32401. PMID 9405449.
16. Polek TC, Talpaz M, Darnay BG, Spivak-Kroizman T (August 2003). "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. doi:10.1074/jbc.m302518200. PMID 12794080.
17. Wiley SR, Winkles JA (2003-06-01). "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. doi:10.1016/S1359-6101(03)00019-4. PMID 12787562.
18. Brown SA, Richards CM, Hanscom HN, Feng SL, Winkles JA (April 2003). "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. doi:10.1042/BJ20021730. PMC 1223299. PMID 12529173.

Further reading

• Campbell S, Michaelson J, Burkly L, Putterman C (September 2004). "The role of TWEAK/Fn14 in the pathogenesis of inflammation and systemic autoimmunity" (PDF). Frontiers in Bioscience. 9 (1–3): 2273–2284. doi:10.2741/1395. PMID 15353286. S2CID 29249853. Archived from the original (PDF) on 2019-02-16.
• Wiley SR, Cassiano L, Lofton T, Davis-Smith T, Winkles JA, Lindner V, et al. (November 2001). "A novel TNF receptor family member binds TWEAK and is implicated in angiogenesis". Immunity. 15 (5): 837–846. doi:10.1016/S1074-7613(01)00232-1. PMID 11728344.
• Harada N, Nakayama M, Nakano H, Fukuchi Y, Yagita H, Okumura K (December 2002). "Pro-inflammatory effect of TWEAK/Fn14 interaction on human umbilical vein endothelial cells". Biochemical and Biophysical Research Communications. 299 (3): 488–493. doi:10.1016/S0006-291X(02)02670-0. PMID 12445828.
• Nakayama M, Ishidoh K, Kojima Y, Harada N, Kominami E, Okumura K, Yagita H (January 2003). "Fibroblast growth factor-inducible 14 mediates multiple pathways of TWEAK-induced cell death". Journal of Immunology. 170 (1): 341–348. doi:10.4049/jimmunol.170.1.341. PMID 12496418.
• Tran NL, McDonough WS, Donohue PJ, Winkles JA, Berens TJ, Ross KR, et al. (April 2003). "The human Fn14 receptor gene is up-regulated in migrating glioma cells in vitro and overexpressed in advanced glial tumors". The American Journal of Pathology. 162 (4): 1313–1321. doi:10.1016/S0002-9440(10)63927-2. PMC 1851233. PMID 12651623.
• Tanabe K, Bonilla I, Winkles JA, Strittmatter SM (October 2003). "Fibroblast growth factor-inducible-14 is induced in axotomized neurons and promotes neurite outgrowth". The Journal of Neuroscience. 23 (29): 9675–9686. doi:10.1523/JNEUROSCI.23-29-09675.2003. PMC 6740475. PMID 14573547.
• Jin L, Nakao A, Nakayama M, Yamaguchi N, Kojima Y, Nakano N, et al. (May 2004). "Induction of RANTES by TWEAK/Fn14 interaction in human keratinocytes". The Journal of Investigative Dermatology. 122 (5): 1175–1179. doi:10.1111/j.0022-202X.2004.22419.x. PMID 15140220.
• Tran NL, McDonough WS, Savitch BA, Sawyer TF, Winkles JA, Berens ME (February 2005). "The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)-fibroblast growth factor-inducible 14 (Fn14) signaling system regulates glioma cell survival via NFkappaB pathway activation and BCL-XL/BCL-W expression". The Journal of Biological Chemistry. 280 (5): 3483–3492. doi:10.1074/jbc.M409906200. PMID 15611130.
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, et al. (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–1178. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.
• Chacón MR, Richart C, Gómez JM, Megía A, Vilarrasa N, Fernández-Real JM, et al. (February 2006). "Expression of TWEAK and its receptor Fn14 in human subcutaneous adipose tissue. Relationship with other inflammatory cytokines in obesity". Cytokine. 33 (3): 129–137. doi:10.1016/j.cyto.2005.12.005. PMID 16503147.
• Brown SA, Hanscom HN, Vu H, Brew SA, Winkles JA (July 2006). "TWEAK binding to the Fn14 cysteine-rich domain depends on charged residues located in both the A1 and D2 modules". The Biochemical Journal. 397 (2): 297–304. doi:10.1042/BJ20051362. PMC 1513280. PMID 16526941.
• Muñoz-García B, Martín-Ventura JL, Martínez E, Sánchez S, Hernández G, Ortega L, et al. (August 2006). "Fn14 is upregulated in cytokine-stimulated vascular smooth muscle cells and is expressed in human carotid atherosclerotic plaques: modulation by atorvastatin". Stroke. 37 (8): 2044–2053. doi:10.1161/01.STR.0000230648.00027.00. PMID 16809572.
• Tran NL, McDonough WS, Savitch BA, Fortin SP, Winkles JA, Symons M, et al. (October 2006). "Increased fibroblast growth factor-inducible 14 expression levels promote glioma cell invasion via Rac1 and nuclear factor-kappaB and correlate with poor patient outcome". Cancer Research. 66 (19): 9535–9542. doi:10.1158/0008-5472.CAN-06-0418. PMID 17018610.
• Girgenrath M, Weng S, Kostek CA, Browning B, Wang M, Brown SA, et al. (December 2006). "TWEAK, via its receptor Fn14, is a novel regulator of mesenchymal progenitor cells and skeletal muscle regeneration". The EMBO Journal. 25 (24): 5826–5839. doi:10.1038/sj.emboj.7601441. PMC 1698888. PMID 17124496.
• Dogra C, Hall SL, Wedhas N, Linkhart TA, Kumar A (May 2007). "Fibroblast growth factor inducible 14 (Fn14) is required for the expression of myogenic regulatory factors and differentiation of myoblasts into myotubes. Evidence for TWEAK-independent functions of Fn14 during myogenesis". The Journal of Biological Chemistry. 282 (20): 15000–15010. doi:10.1074/jbc.M608668200. PMC 4149055. PMID 17383968.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.