Disease relevance of TNFRSF12A

• Soluble TweakR inhibits endothelial cell migration in vitro and corneal angiogenesis in vivo [1].
• Consistent with this, we have observed elevated protein levels of the Tweak receptor, Fn14, in human breast tumor cell lines and xenograft models as well as in primary human breast tumors [2].

High impact information on TNFRSF12A

• Five different assays demonstrate TWEAK-TweakR binding, and the interaction affinity constant (Kd) is within a physiologically relevant range of 2.3 +/- 0.1 nM [1].
• The mature form of TweakR has only one hundred and two amino acids and six cysteine residues in its extracellular region [1].
• By generating mice deficient in the TWEAK receptor Fn14, we further showed that Fn14-deficient primary myoblasts displayed significantly reduced proliferative capacity and altered myotube formation [3].
• The crystal structure of human fibronectin (FN) type III repeats 12-14 reveals the primary heparin-binding site, a clump of positively charged residues in FN13, and a putative minor site approximately 60 A away in FN14 [4].
• Recently, fibroblast growth factor-inducible 14 (Fn14) has been identified to be a TWEAK receptor, which was responsible for TWEAK-induced proliferation of endothelial cells and angiogenesis [5].

Biological context of TNFRSF12A

• Four years later, researchers at the biotechnology company Immunex (now part of Amgen) reported the cloning and characterization of the human TWEAK receptor [6].
• Moreover, Fn14/TweakR-neutralizing antibodies did not block TWEAK-induced RAW cell differentiation into osteoclasts [7].

Anatomical context of TNFRSF12A

• Primary cultured normal human keratinocytes constitutively expressed a TWEAK receptor, fibroblast growth factor-inducible 14 (Fn14), and produced regulated on activation, normal T expressed and secreted (RANTES) upon TWEAK stimulation in a concentration-dependent manner [8].
• Reverse transcription-polymerase chain reaction (RT-PCR) analysis and immunohistochemistry revealed that TWEAK and the TWEAK receptor, fibroblast growth factor-inducible 14 (Fn14), mRNA and protein were expressed in periodontally diseased tissues [9].
• We report cloning of a receptor for TWEAK (TweakR) from a human umbilical vein endothelial cell (HUVEC) library [1].
• A human bronchial epithelial cell line, BEAS2B, expressed a TWEAK receptor, fibroblast growth factor-inducible 14 (Fn14), and produced IL-8 and GM-CSF upon TWEAK stimulation in a dose-dependent manner, which was abrogated by anti-Fn14 blocking antibody [10].
• The expression of TWEAK (TNFSF12) and TweakR/Fn14 was detected in regions rich in macrophage/foam cells in atherosclerotic plaques [11].

Analytical, diagnostic and therapeutic context of TNFRSF12A

• Flow cytometry analysis did not reveal the expression of Fn14/TweakR on RAW cells [7].

References