TWEAK, a member of the TNF superfamily, is a multifunctional cytokine that binds the TweakR/Fn14 receptor
Introduction
TWEAK is a member of the tumor necrosis factor superfamily (TNFSF) of structurally-related cytokines that generally function as both type II transmembrane proteins and as cleaved soluble molecules [1], [2]. The archetypal member of this family, TNF, was first identified as the agent responsible for hemorrhagic necrosis of tumors [3]. TNF was later shown to be identical to cachectin, an agent that could induce shock and wasting syndrome [4], [5]. TNF-like cytokines interact with an even larger family of structurally-related cognate receptors that together comprise the TNF receptor superfamily (TNFRSF). TWEAK was recently identified as a ligand for the TNFRSF member named TweakR/Fn14 [6]. Ligand-mediated aggregation of TNFRSF receptors is responsible for a variety of biological activities, many of which are associated with immune system development and function [1], [2]. This article will describe recent developments regarding TWEAK gene expression, receptor recognition, biological activity, and signal transduction.
Section snippets
Identification
Many of the most recently described TNFSF members were identified by searching public or commercially available expressed sequence tag databases for cDNAs with sequence homology to known family members. However, in the case of TWEAK, a murine cDNA clone was isolated fortuitously during a search for erythopoietin-related mRNAs in adherent peritoneal macrophages [7]. Subsequently, a search of the public expressed sequence tag database identified a human TWEAK cDNA homolog. A full-length human
Identification
In 1998, Marsters et al. [8] reported that TWEAK was a ligand for the TNFRSF member named DR3, also known as Apo3 or TRAMP. However, subsequent ligand-binding studies by several groups were unable to confirm a TWEAK–DR3 interaction [6], [20], [21], [22]. These observations, in combination with other results demonstrating that TWEAK can bind to cells that do not express DR3 [11], [12], [21], indicated that another TWEAK receptor was likely to exist. This is now known to be the case (see below).
Apoptosis
There have been several reports indicating that TWEAK is a cytotoxic factor for certain human tumor cell lines, including IFNγ-treated HT-29 colon carcinoma cells [7], [12], [21] and KATO-III gastric adenocarcinoma cells [12], cycloheximide pre-treated MCF-7 breast carcinoma cells [8], Kym-1 rhabdomyosarcoma cells [11], and HSC3 oral squamous carcinoma cells [12]. Another study reported that TWEAK was involved in CD4+ T-cell killing of D10 monocytes, but these investigators utilized a
TWEAK signal transduction
Many TNFRSF members contain sequence motifs within their cytoplasmic domain that promote their association with TRAFs, a family of six adaptor proteins that activate downstream signal transduction molecules [1], [30], [31]. A major consensus sequence motif for TRAF2 binding, (P/S/A/T)-X-(Q/E)-E, was identified by Ye et al. [41] and the key residues of TRAF2 that recognize this motif are also conserved in TRAF1, TRAF3 and TRAF5 [42]. The human and murine TweakR/Fn14 cytoplasmic tail contains the
Summary
The TWEAK and TweakR/Fn14 transcripts appear to be co-expressed in a variety of cell types and tissues; therefore, TWEAK released from these cells may function in an autocrine manner to influence cell behavior. Furthermore, TweakR/Fn14 mRNA levels have been shown to increase in response to stimuli from other cytokines and by physical tissue damage. This cellular response might provide a mechanism for amplifying TWEAK-mediated effects under certain physiological or pathological conditions.
Acknowledgements
This work was supported in part by National Institutes of Health grant HL-39727 (to JAW).
References (44)
- et al.
The TNF and TNF receptor superfamilies: integrating mammalian biology
Cell
(2001) - et al.
The molecular architecture of the TNF superfamily
Trends Biochem. Sci.
(2002) - et al.
A novel TNF receptor family member binds TWEAK and is implicated in angiogenesis
Immunity
(2001) - et al.
TWEAK, a new secreted ligand in the tumor necrosis factor family that weakly induces apoptosis
J. Biol. Chem.
(1997) - et al.
Crystal structure of the soluble human 55 kDa TNF receptor–human TNF beta complex: implications for TNF receptor activation
Cell
(1993) - et al.
Death-inducing tumour necrosis factor (TNF) superfamily ligands and receptors are transcribed in human placentae, cytotrophoblasts, placental macrophages and placental cell lines
Placenta
(2001) - et al.
Down-regulated expression of TWEAK mRNA in acute and chronic inflammatory pathologies
Biochem. Biophys. Res. Commun.
(2000) - et al.
TWEAK induces angiogenesis and proliferation of endothelial cells
J. Biol. Chem.
(1999) - et al.
Studies on the interaction between TWEAK and the death receptor WSL-1/TRAMP (DR3)
FEBS Lett.
(2000) - et al.
TL1A is a TNF-like ligand for DR3 and TR6/DcR3 and functions as a T cell costimulator
Immunity
(2002)