<p> The tumour necrosis factor (TNF) receptor (TNFR) superfamily comprises more than 20 type-I transmembrane proteins. Family members are defined based on similarity in their extracellular domain -a region that contains many cysteine residues arranged in a specific repetitive pattern [<cite idref="PUB00046030"/>]. The cysteines allow formation of an extended rod-like structure, responsible for ligand binding [<cite idref="PUB00000892"/>]. </p> <p> Upon receptor activation, different intracellular signalling complexes are assembled for different members of the TNFR superfamily, depending on their intracellular domains and sequences [<cite idref="PUB00046031"/>]. Activation of TNFRs can therefore induce a range of disparate effects, including cell proliferation, differentiation, survival, or apoptotic cell death, depending upon the receptor involved [<cite idref="PUB00046032"/>, <cite idref="PUB00046033"/>]. </p> <p> TNFRs are widely distributed and play important roles in many crucial biological processes, such as lymphoid and neuronal development, innate and adaptive immunity, and maintenance of cellular homeostasis [<cite idref="PUB00046031"/>]. Drugs that manipulate their signalling have potential roles in the prevention and treatment of many diseases, such as viral infections, coronary heart disease, transplant rejection, and immune disease [<cite idref="PUB00046034"/>]. </p> <p> TNF receptor 21, also termed death receptor 6 (DR6), is expressed ubiquitously, with high expression in lymphoid organs, heart, brain and pancreas. The receptor plays an important regulatory role in the generation of adaptive immunity and may be involved in tumour cell survival and immune evasion [<cite idref="PUB00053620"/>]. It has also been implicated in the pathogenesis of Alzheimer's disease, as activation of the receptor by beta-amyloid precursor protein triggers neuronal death via a caspase-dependent pathway [<cite idref="PUB00053621"/>]. </p> Tumour necrosis factor receptor 21