Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Tumor Necrosis Factor-Like Weak Inducer of Apoptosis (TNFSFS12)

  • Luis M. Blanco-ColioEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101976


Historical Background

Tumor necrosis factor superfamily (TNFSF) members are implicated in numerous cellular processes such as proliferation, migration, inflammation, and cell death. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) was first identified as a novel member of the tumor necrosis factor superfamily of proteins displaying pro-apoptotic activity on interferon gamma (INF-γ)-treated human HT-29 colon carcinoma cells (Chicheportiche et al. 1997). The human TWEAK gene is located at chromosomal position 17p13.1 and encodes a 249-amino acid (aa) type II transmembrane-bound protein (mTWEAK). mTWEAK comprises an intracellular N-terminal domain, which contains a potential protein kinase C phosphorylation site, a transmembrane domain, and an extracellular TNF homology domain (THD) containing the receptor-binding site (Chicheportiche et al. 1997) (Fig. 1). mTWEAK is...
This is a preview of subscription content, log in to check access.


  1. Blanco-Colio LM. TWEAK/Fn14 Axis: a promising target for the treatment of cardiovascular diseases. Front Immunol. 2014;5:3.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Blanco-Colio LM, Martín-Ventura JL, Muñóz-García B, Orbe J, Páramo JA, Michel JB, Ortiz A, Meilhac O, Egido J. Identification of soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) as a possible biomarker of subclinical atherosclerosis. Arterioscler Thromb Vasc Biol. 2007;27:916–22.PubMedPubMedCentralCrossRefGoogle Scholar
  3. Bover LC, Cardó-Vila M, Kuniyasu A, Sun J, Rangel R, Takeya M, Aggarwal BB, Arap W, Pasqualini R. A previously unrecognized protein-protein interaction between TWEAK and CD163: potential biological implications. J Immunol. 2007;178:8183–94.PubMedPubMedCentralCrossRefGoogle Scholar
  4. Brown SA, Richards CM, Hanscom HN, Feng SL, Winkles JA. The Fn14 cytoplasmic tail binds tumor-necrosis-factor-receptor-associated factors 1, 2, 3 and 5 and mediates nuclear factor-kappa B activation. Biochem J. 2003;371:395–403.PubMedPubMedCentralCrossRefGoogle Scholar
  5. Burkly LC, Michaelson JS, Hahm K, Jakubowski A, Zheng TS. TWEAKing tissue remodeling by a multifunctional cytokine: role of TWEAK/Fn14 pathway in health and disease. Cytokine. 2007;40:1–16.PubMedPubMedCentralCrossRefGoogle Scholar
  6. Burkly LC, Michaelson JS, Zheng TS. TWEAK/Fn14 pathway; an immunological swith for shapping tissue responses. Immunol Rev. 2011;244:99–114.PubMedPubMedCentralCrossRefGoogle Scholar
  7. Chicheportiche Y, Bourdon PR, Xu H, Hsu YM, Scott H, Hession C, Garcia I, Browning JL. TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis. J Biol Chem. 1997;272:32401–10.PubMedPubMedCentralCrossRefGoogle Scholar
  8. Di Martino L, Dave M, Menghini P, Xin W, Arseneau K, Pizarro T, Cominelli F. Protective role for TWEAK/Fn14 in regulating acute intestinal inflammation and colitis-associated tumorigenesis. Cancer Res. 2016;76:6533–6542.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Fernández-Laso V, Sastre C, Valdivielso JM, Betriu A, Fernández E, Egido J, Martín-Ventura JL, Blanco-Colio LM. Soluble TWEAK and major adverse cardiovascular events in patients with CKD. Clin J Am Soc Nephrol. 2016;11:413–22.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Fick A, Lang I, Schäfer V, Seher A, Trebing J, Weisenberger D, Wajant H. Studies of binding of tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) to fibroblast growth factor inducible 14 (Fn14). J Biol Chem. 2012;287:484–95.PubMedPubMedCentralCrossRefGoogle Scholar
  11. Jarr KU, Eschricht S, Burkly LC, Preusch M, Katus HA, Frey N, Chorianopoulos E. TNF-like weak inducer of apoptosis aggravates left ventricular dysfunction after myocardial infarction in mice. Mediat Inflamm. 2014;2014:131950.Google Scholar
  12. Kristiansen M, Graversen JH, Jacobsen C, Sonne O, Hoffman HJ, Law SK, Moestrup SK. Identification of the haemoglobin scavenger receptor. Nature. 2001;409:198–201.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Maecker H, Varfolomeev E, Kischkel F, Lawrence D, Leblanc H, Lee W, Hurst S, Danilenko D, Li J, Filvaroff E, Yang B, Daniel D, Ashkenazi A. TWEAK attenuates the transition from innate to adaptive immunity. Cell. 2005;123:931–44.PubMedPubMedCentralCrossRefGoogle Scholar
  14. Meulendijks D, Lassen UN, Siu LL, Huitema AD, Karanikas V, Mau-Sorensen M, Jonker DJ, Hansen AR, Simcox ME, Schostack KJ, Bottino D, Zhong H, Roessler M, Vega-Harring SM, Jarutat T, Geho D, Wang K, DeMario M, Goss GD, Schellens JH. Exposure and tumor Fn14 expression as determinants of pharmacodynamics of the anti-TWEAK monoclonal antibody RG7212 in patients with Fn14-positive solid tumors. Clin Cancer Res. 2016;22(4):858–67.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Moreno JA, Sastre C, Madrigal-Matute J, Muñoz-García B, Ortega L, Burkly LC, Egido J, Martín-Ventura JL, Blanco-Colio LM. HMGB1 expression and secretion are increased via TWEAK-Fn14 interaction in atherosclerotic plaques and cultured monocytes. Arterioscler Thromb Vasc Biol. 2013;33:612–20.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Muñoz-García B, Moreno JA, López-Franco O, Sanz AB, Martín-Ventura JL, Blanco J, Jakubowski A, Burkly LC, Ortiz A, Egido J, Blanco-Colio LM. Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) enhances vascular and renal damage induced by hyperlipidemic diet in ApoE-knockout mice. Arterioscler Thromb Vasc Biol. 2009;29:2061–8.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Polavarapu R, Gongora MC, Winkles JA, Yepes M. Tumor necrosis factor-like weak inducer of apoptosis increases the permeability of the neurovascular unit through nuclear factor-kappa B pathway activation. J Neurosci. 2005;25:10094–100.PubMedPubMedCentralCrossRefGoogle Scholar
  18. Sanz AB, Sanchez-Nino MD, Izquierdo MC, Jakubowski A, Justo P, Blanco-Colio LM, Ruiz-Ortega M, Egido J, Ortiz A. Tweak induces proliferation in renal tubular epithelium: a role in uninephrectomy induced renal hyperplasia. J Cell Mol Med. 2009;13:3329–42.PubMedPubMedCentralCrossRefGoogle Scholar
  19. Sanz AB, Izquierdo MC, Sanchez-Niño MD, Ucero AC, Egido J, Ruiz-Ortega M, Ramos AM, Putterman C, Ortiz A. TWEAK and the progression of renal disease: clinical translation. Nephrol Dial Transplant. 2014;29(Suppl 1):i54–62.PubMedPubMedCentralCrossRefGoogle Scholar
  20. Sastre C, Fernández-Laso V, Madrigal-Matute J, Muñoz-García B, Moreno JA, Pastor-Vargas C, Llamas-Granda P, Burkly LC, Egido J, Martín-Ventura JL, Blanco-Colio LM. Genetic deletion or TWEAK blocking antibody administration reduce atherosclerosis and enhance plaque stability in mice. J Cell Mol Med. 2014;18:721–34.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Tarín C, Fernández-Laso V, Sastre C, Madrigal-Matute J, Gómez M, Zaragoza C, Egido J, Burkly LC, Martín-Ventura JL, Blanco-Colio LM. Tumor necrosis factor-like weak inducer of apoptosis or Fn14 deficiency reduce elastase perfusion-induced aortic abdominal aneurysm in mice. J Am Heart Assoc. 2014;3. pii: e000723.PubMedPubMedCentralCrossRefGoogle Scholar
  22. Tirnitz-Parker JE, Viebahn CS, Jakubowski A, Klopcic BR, Olynyk JK, Yeoh GC, Knight B. Tumor necrosis factor-like weak inducer of apoptosis is a mitogen for liver progenitor cells. Hepatology. 2010;52:291–302.PubMedPubMedCentralCrossRefGoogle Scholar
  23. Wiley SR, Cassiano L, Lofton T, Davis-Smith T, Winkles JA, Lindner V, Liu H, Daniel TP, Smith CA, Fanslow WC. A novel TNF receptor family member binds TWEAK and is implicated in angiogenesis. Immunity. 2001;15:837–46.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Winkles JA. The TWEAK-Fn14 cytokine-receptor axis: discovery, biology and therapeutic targeting. Nat Rev Drug Discov. 2008;7:411–25.PubMedPubMedCentralCrossRefGoogle Scholar
  25. Wisniacki N, Amaravadi L, Galluppi GR, Zheng TS, Zhang R, Kong J, Burkly LC. Safety, tolerability, pharmacokinetics, and pharmacodynamics of anti-TWEAK monoclonal antibody in patients with rheumatoid arthritis. Clin Ther. 2013;35:1137–49.PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Vascular Research LabFIIS-Fundación Jiménez DíazMadridSpain
  2. 2.Biomedical Research Center in Cardiovascular MedicineCIBERCVSpain