TNFRSF12A

Last updated
TNFRSF12A
Protein TNFRSF12A PDB 2EQP.png
Available structures
PDB Ortholog search: PDBe RCSB
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
Orthologs
SpeciesHumanMouse
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]

Contents

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]

Related Research Articles

<span class="mw-page-title-main">TRAIL</span> Mammalian protein

In the field of cell biology, TNF-related apoptosis-inducing ligand (TRAIL), is a protein functioning as a ligand that induces the process of cell death called apoptosis.

Lymphotoxin is a member of the tumor necrosis factor (TNF) superfamily of cytokines, whose members are responsible for regulating the growth and function of lymphocytes and are expressed by a wide variety of cells in the body.

<span class="mw-page-title-main">CD137</span> Member of the tumor necrosis factor (TNF) receptor family

CD137, a member of the tumor necrosis factor (TNF) receptor family, is a type 1 transmembrane protein, expressed on surfaces of leukocytes and non-immune cells. Its alternative names are tumor necrosis factor receptor superfamily member 9 (TNFRSF9), 4-1BB, and induced by lymphocyte activation (ILA). It is of interest to immunologists as a co-stimulatory immune checkpoint molecule, and as a potential target in cancer immunotherapy.

<span class="mw-page-title-main">Lymphotoxin beta receptor</span>

Lymphotoxin beta receptor (LTBR), also known as tumor necrosis factor receptor superfamily member 3 (TNFRSF3), is a cell surface receptor for lymphotoxin involved in apoptosis and cytokine release. It is a member of the tumor necrosis factor receptor superfamily.

<span class="mw-page-title-main">CD27</span> Member of the tumor necrosis factor receptor superfamily.

CD27 is a member of the tumor necrosis factor receptor superfamily. It is currently of interest to immunologists as a co-stimulatory immune checkpoint molecule, and is the target of an anti-cancer drug in clinical trials.

<span class="mw-page-title-main">Death receptor 4</span> Protein found in humans

Death receptor 4 (DR4), also known as TRAIL receptor 1 (TRAILR1) and tumor necrosis factor receptor superfamily member 10A (TNFRSF10A), is a cell surface receptor of the TNF-receptor superfamily that binds TRAIL and mediates apoptosis.

<span class="mw-page-title-main">Lymphotoxin alpha</span> Protein found in humans

Lymphotoxin-alpha (LT-α) formerly known as tumor necrosis factor-beta (TNF-β) is a protein that in humans is encoded by the LTA gene. Belonging to the hematopoietic cell line, LT-α exhibits anti-proliferative activity and causes the cellular destruction of tumor cell lines. As a cytotoxic protein, LT-α performs a variety of important roles in immune regulation depending on the form that it is secreted as. Unlike other members of the TNF superfamily, LT-α is only found as a soluble homotrimer, when found at the cell surface it is found only as a heterotrimer with LTβ.

<span class="mw-page-title-main">APRIL (protein)</span> Protein-coding gene in the species Homo sapiens

A proliferation-inducing ligand (APRIL), also known as tumor necrosis factor ligand superfamily member 13 (TNFSF13), is a protein of the TNF superfamily recognized by the cell surface receptor TACI. It is encoded by the TNFSF13 gene.

<span class="mw-page-title-main">LIGHT (protein)</span> Secreted protein of the TNF superfamily

LIGHT, also known as tumor necrosis factor superfamily member 14 (TNFSF14), is a secreted protein of the TNF superfamily. It is recognized by herpesvirus entry mediator (HVEM), as well as decoy receptor 3.

<span class="mw-page-title-main">TNFSF12</span> Protein-coding gene in the species Homo sapiens

Tumor necrosis factor ligand superfamily member 12 also known as TNF-related weak inducer of apoptosis (TWEAK) is a protein that in humans is encoded by the TNFSF12 gene.

<span class="mw-page-title-main">Decoy receptor 3</span> Protein found in humans

Decoy receptor 3 (Dcr3), also known as tumor necrosis factor receptor superfamily member 6B (TNFRSF6B), TR6 and M68, is a soluble protein of the tumor necrosis factor receptor superfamily which inhibits Fas ligand-induced apoptosis.

<span class="mw-page-title-main">Decoy receptor 1</span> Protein-coding gene in the species Homo sapiens

Decoy receptor 1 (DCR1), also known as TRAIL receptor 3 (TRAILR3) and tumor necrosis factor receptor superfamily member 10C (TNFRSF10C), is a human cell surface receptor of the TNF-receptor superfamily.

<span class="mw-page-title-main">Decoy receptor 2</span> Protein-coding gene in the species Homo sapiens

Decoy receptor 2 (DCR2), also known as TRAIL receptor 4 (TRAILR4) and tumor necrosis factor receptor superfamily member 10D (TNFRSF10D), is a human cell surface receptor of the TNF-receptor superfamily.

<span class="mw-page-title-main">Vascular endothelial growth inhibitor</span> Protein-coding gene in the species Homo sapiens

Vascular endothelial growth inhibitor (VEGI), also known as TNF-like ligand 1A (TL1A) and TNF superfamily member 15 (TNFSF15), is protein that in humans is encoded by the TNFSF15 gene. VEGI is an anti-angiogenic protein. It belongs to tumor necrosis factor (ligand) superfamily, where it is member 15. It is the sole known ligand for death receptor 3, and it can also be recognized by decoy receptor 3.

<span class="mw-page-title-main">TNFRSF18</span> Protein-coding gene in the species Homo sapiens

Tumor necrosis factor receptor superfamily member 18 (TNFRSF18), also known as glucocorticoid-induced TNFR-related protein (GITR) or CD357. GITR is encoded and tnfrsf18 gene at chromosome 4 in mice. GITR is type I transmembrane protein and is described in 4 different isoforms. GITR human orthologue, also called activation-inducible TNFR family receptor (AITR), is encoded by the TNFRSF18 gene at chromosome 1.

<span class="mw-page-title-main">TNFSF18</span> Protein-coding gene in the species Homo sapiens

Tumor necrosis factor ligand superfamily member 18 is a protein that in humans is encoded by the TNFSF18 gene.

<span class="mw-page-title-main">TNFSF12-TNFSF13</span> Protein-coding gene in the species Homo sapiens

Tumor necrosis factor (ligand) superfamily, member 12-member 13, also known as TNFSF12-TNFSF13, is a human gene.

<span class="mw-page-title-main">TNFAIP1</span> Protein-coding gene in the species Homo sapiens

BTB/POZ domain-containing protein TNFAIP1 is a protein that in humans is encoded by the TNFAIP1 gene.

<span class="mw-page-title-main">Tumor necrosis factor receptor 2</span> Membrane receptor protein found in humans

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). 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. 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).

<span class="mw-page-title-main">IL17RD</span>

Interleukin 17 receptor D is a protein that in humans is encoded by the IL17RD gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000006327 - Ensembl, May 2017
  2. 1 2 3 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. 1 2 3 4 5 6 7 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. 1 2 3 4 5 6 7 8 9 10 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. 1 2 3 4 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. 1 2 3 4 5 6 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. 1 2 3 4 5 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

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