Tumour necrosis factor-related figure 2 apoptosis-inducing ligand (TRAIL) is a member of the TNF ligand superfamily (Ashkenazi and Dixit, 1998). TRAIL induces apoptosis on binding to its transmembrane, death domain-containing receptors, TRAIL receptors 1 (death receptor 4; DR4) and 2 (death receptor 5; DR5). Three other TRAIL-binding receptors exist, but they are unable to transmit an apoptotic signal and thus considered to be ��decoy receptors’. Decoy receptor 1 (DcR1) lacks the transmembrane and intracellular domains and is anchored to the plasma membrane via a glycosylphosphatidylinositol-tail. Decoy receptor 2 (DcR2) possesses a truncated, non-functional death domain, whereas the third decoy receptor, osteoprotegerin is a secreted, soluble receptor (Ashkenazi and Dixit, 1998).

Binding of homotrimeric TRAIL to DR4 and DR5 induces receptor trimerisation and activation leading to recruitment of adaptor proteins and formation of the death-inducing signalling complex (DISC). Procaspase-8 and/or -10 are recruited to the DISC, leading to their oligomerisation and activation. Active caspase-8/-10 can activate the executioner caspases (procaspase-3, -6 and -7) and/or initiate the mitochondrial apoptotic pathway by cleaving the BH3-only protein Bid. Generally, caspase activation is the main outcome following activation of DR4/5 by TRAIL. However, TRAIL, via adaptor molecules such as TNF receptor-associated factor 2 (TRAF2), receptor-interacting protein (RIP), and the mitogen-activated protein kinase kinases (MKK)-4 and -7, can also activate the c-Jun N-terminal kinase (JNK) pathway (Hu et al, 1999; Lin et al, 2000).

JNK activation is also regulated by scaffold proteins, JNK-interacting protein (JIP) and JNK stress-activated protein kinase-associated protein 1 (JSAP1) (Whitmarsh et al, 1998; Ito et al, 1999). Depending on the cell type and the stimulus, JNK can activate a number of diverse downstream targets including members of the activator protein-1 (AP-1) family, c-Jun, JunD, activating transcriptional factor 2 (ATF2), Bcl-2 proteins, c-Myc and p53 (Bode and Dong, 2007; Lin et al, 2007). Whether JNK induces or suppresses apoptosis is largely dependent on the molecules it activates. For example, JNK can both phosphorylate antiapoptotic Bcl-2 proteins to promote apoptosis or phosphorylate proapoptotic Bcl-2 proteins (e.g. BAD) to inhibit apoptosis (Maundrell et al, 1997; Yu et al, 2004).

JNK proteins are encoded by three genes, jnk1, jnk2 and jnk3. Jnk1 and jnk2 encode ubiquitously expressed JNK proteins whereas the jnk3 protein product is primarily found in the brain, heart and to a lesser extent in the testis (Bode and Dong, 2007). Alternative Carfilzomib splicing of the jnk transcripts results in 10 different JNK isoforms each of which may target different transcription factors (Gupta et al, 1996). JNK1 and -2 have four isoforms each (��1, ��2, ��1 and ��2).