TWEAK, a member of the TNF superfamily, is a multifunctional cytokine that binds the TweakR/Fn14 receptor

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Abstract

The cytokine tumor necrosis factor-like weak inducer of apoptosis (TWEAK) was initially described as a member of the tumor necrosis factor (TNF) superfamily in 1997. TWEAK is a cell surface-associated type II transmembrane protein, but a smaller, biologically active form can also be shed into the extracellular milieu. There is one receptor currently known to bind TWEAK with physiological affinity, and it is a type I transmembrane protein that is referred to in the literature as either TWEAK receptor (TweakR) or fibroblast growth factor-inducible 14 (Fn14). TweakR/Fn14 is the smallest member of the TNF receptor (TNFR) superfamily described to date, and it appears to signal via recruitment of several different TNFR-associated factors. TWEAK has multiple biological activities, including stimulation of cell growth and angiogenesis, induction of inflammatory cytokines, and under some experimental conditions, stimulation of apoptosis. In this report, we summarize the results from recent studies focused on the TWEAK cytokine. Although these studies have contributed a significant amount of new information, numerous questions still remain regarding the role of TWEAK in both normal physiology and the pathogenesis of human disease.

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).

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