title: The TWEAK-Fn14 system as a potential drug target.
abstract: Fibroblast growth factor-inducible 14 (Fn14) is a member of the tumour necrosis factor (TNF) receptor family that is induced in a variety of cell types in situations of tissue injury. Fn14 becomes activated by TNF-like weak inducer of apoptosis (TWEAK), a typical member of the TNF ligand family. TWEAK is constitutively expressed by monocytes and some tumour cell lines and also shows cytokine inducible expression in various other cell types. Fn14 activation results in stimulation of signalling pathways culminating in the activation of NFκB transcription factors and various MAPKs but might also trigger the PI3K/Akt pathway and GTPases of the Rho family. In accordance with its tissue damage-associated expression pattern and its pleiotropic proinflammatory signalling capabilities, the TWEAK-Fn14 system has been implicated in a huge number of pathologies. The use of TWEAK- and Fn14-knockout mice identified the TWEAK-Fn14 system as a crucial player in muscle atrophy, cerebral ischaemia, kidney injury, atherosclerosis and infarction as well as in various autoimmune scenarios including experimental autoimmune encephalitis, rheumatoid arthritis and inflammatory bowel disease. Moreover, there is increasing preclinical evidence that Fn14 targeting is a useful option in tumour therapy. Based on a discussion of the signalling capabilities of TWEAK and Fn14, this review is focused on two major issues. On the one hand, on the molecular and cellular basis of the TWEAK/Fn14-related pathological outcomes in the aforementioned diseases and on the other hand, on the preclinical experience that have been made so far with TWEAK and Fn14 targeting drugs.
authors: Division of Molecular Internal Medicine, Department of Internal Medicine II, University Hospital Würzburg, Würzburg, Germany.
authors: Harald
authors: H
authors: Wajant
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000074049:Cytokine TWEAK; D015195:Drug Design; D006801:Humans; D008024:Ligands; D058990:Molecular Targeted Therapy; D018124:Receptors, Tumor Necrosis Factor / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D000074050:TWEAK Receptor; D048069:Tumor Necrosis Factors / Q000378:metabolism* / Q000494:pharmacology
chemical_list: D000906:Antibodies; D000074049:Cytokine TWEAK; D008024:Ligands; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; C000613297:TNFRSF12A protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; D048069:Tumor Necrosis Factors
keywords: Fn14; TWEAK; antibodies; autoimmune disease; cancer; fibrosis; ischaemia; nuclear factor of kappaB; tumour necrosis factor ligand and receptor family
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