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  • Review Article
  • Published:

The TWEAK–Fn14 cytokine–receptor axis: discovery, biology and therapeutic targeting

Nature Reviews Drug Discovery volume 7, pages 411–425 (2008)Cite this article

Key Points

  • TWEAK (tumour necrosis factor (TNF)-like weak inducer of apoptosis) is a member of the TNF superfamily of structurally related cytokines. It is present on the cell surface but a soluble form can also be produced by proteolytic cleavage within the stalk domain. TWEAK gene expression has been detected in many cell types and tissues.

  • TWEAK binds to Fn14 (fibroblast growth factor-inducible 14), a small (102 amino acids) plasma-membrane-anchored receptor. The Fn14 gene is a growth-factor-inducible, immediate-early response gene, and it is highly expressed following tissue injury and in numerous solid tumour types.

  • TWEAK treatment of cells in culture activates several intracellular signalling pathways, including the nuclear factor-κB (NF-κB) pathway, and induces various cellular responses. TWEAK is a pro-angiogenic and pro-inflammatory cytokine in vivo.

  • Persistent TWEAK–Fn14 engagement or Fn14 overexpression may contribute to acute ischaemic stroke, rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis and cancer.

  • The more unique and also puzzling aspects of TWEAK and Fn14 biology are discussed. In particular, emphasis will be on recent findings supporting the notion that this ligand–receptor axis might contribute to tissue repair after injury and the pathogenesis of several diseases that are responsible for significant morbidity and mortality worldwide. Strategies that may be useful for therapeutically targeting this axis will also be discussed.

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-κB (NF-κB) 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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Figure 1: TWEAK–Fn14 axis publication summary.
Figure 2: The Fn14 receptor.
Figure 3: The Fn14 gene is highly regulated in vivo.
Figure 4: TWEAK-dependent and -independent Fn14 signalling.
Figure 5: Hypothesis: TWEAK expression levels may dictate the predominant signalling mechanism in injured tissues and solid tumours.
Figure 6: Hypothesis: some tumour angiogenic factors may act, at least in part, by increasing TWEAK-dependent Fn14 signalling in sprouting vessels.
Figure 7: Potential therapeutic strategies for inhibiting Fn14-triggered pathological conditions.

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Acknowledgements

I thank my laboratory manager S. Brown and all of my other laboratory colleagues for their important contributions to our TWEAK–Fn14 studies. I also thank my external TWEAK–Fn14 research collaborators (in particular, M. Berens of the Translational Genomics Research Institute and M. Yepes of Emory University School of Medicine) for involving my laboratory in their various projects. I am also grateful to A. Keegan, M. Williams and three anonymous referees for their helpful comments on this article. Research in the author's laboratory is supported by NIH grants R01-HL39727 and R01-NS55126 and Susan G. Komen for the Cure grant BCTR0503968.

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  1. Departments of Surgery and Physiology, 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, 21201, Maryland, USA

    Jeffrey A. Winkles

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The author has applied for patents describing methods for therapeutic inhibition of Fn14 signalling in diseased tissues.

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Glossary

Type II transmembrane protein

An integral membrane protein that is composed of an amino-terminal intracellular region, a transmembrane domain and a carboxy-terminal extracellular region (for example, Ly49).

Type I transmembrane protein

An integral membrane protein that is composed of an amino-terminal extracellular region, a transmembrane domain and a carboxy-terminal intracellular region (for example, T-cell receptors).

Type III transmembrane protein

An integral membrane protein with a similar orientation as a Type I protein but lacking a signal peptide (for example, B-cell maturation antigen (BCMA)).

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Winkles, J. The TWEAK–Fn14 cytokine–receptor axis: discovery, biology and therapeutic targeting. Nat Rev Drug Discov 7, 411–425 (2008). https://doi.org/10.1038/nrd2488

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