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Winkles, J.A. The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting. Nat. Rev. Drug Discov. 7, 411-425

Department of Surgery, Center for Vascular and Inflammatory Diseases, and the Marlene and Stewart Greenebaum Cancer Center, 800 West Baltimore Street, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
dressNature Reviews Drug Discovery (Impact Factor: 37.23). 06/2008; 7(5):411-25. DOI: 10.1038/nrd2488
Source: PubMed

ABSTRACT TWEAK is a multifunctional cytokine that controls many cellular activities including proliferation, migration, differentiation, apoptosis, angiogenesis and inflammation. TWEAK acts by binding to Fn14, a highly inducible cell-surface receptor that is linked to several intracellular signalling pathways, including the nuclear factor-kappaB (NF-kappaB) pathway. The TWEAK-Fn14 axis normally regulates various physiological processes, in particular it seems to play an important, beneficial role in tissue repair following acute injury. Furthermore, recent studies have indicated that TWEAK-Fn14 axis signalling may contribute to cancer, chronic autoimmune diseases and acute ischaemic stroke. This Review provides an overview of TWEAK-Fn14 axis biology and summarizes the available data supporting the proposal that both TWEAK and Fn14 should be considered as potential targets for the development of novel therapeutics.

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Available from: Jeffrey A Winkles, Jan 15, 2015
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    • "Tumor necrosis factor-like weak inducer of apoptosis (Tnfsf12, TWEAK) is a type II transmembrane glycoprotein of the TNF superfamily [1]. TWEAK induces, through its receptor fibroblast growth factorinducible 14 (Fn14), a high number of physiological and pathological processes depending on cell type and environment [1].TWEAK is broadly expressed in healthy and pathological vessels and changes on its expression are moderate [2]. However, Fn14 is expressed at very low levels under normal conditions but its expression is increased under a pathological scenario such as atherosclerosis [2]. "
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    • "Possible issues contributing to this include: (i) adhesive interactions with nontarget structures, (ii) target(s) present on only a relatively small percentage of tumor cells or regions, (iii) target(s) not specific for invading cancer cells [14] [27], and (iv) target(s) changes in the context of treatment(s) and/or disease progression [28]. Fibroblast growth factor-inducible 14 (Fn14) is a member of the tumor necrosis factor receptor (TNFR) superfamily and is an emerging molecular target for GBM and other cancers [29] [30]. Importantly, Fn14 is minimally expressed in normal human brain but highly expressed in high-grade gliomas with more malignant and invasive characteristics [31]. "
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    • "The 4.3-fold FN14 induction post run in tapered MHC IIa fibers aligns with our laboratory’s recent finding that robust FN14 expression after exercise is associated with isolated fast-twitch fiber size increases from resistance training [6], [9]. A member of the TNFα superfamily, FN14 is a cell-surface receptor found on a variety of tissues including skeletal muscle [28] and appears to signal through the diverse NF-Kβ pathway [28], [29]. While linked to atrophy in pathological conditions [30], FN14 also appears necessary for muscle proliferation, differentiation, and regeneration in mice and cell culture [31], [32]. "
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