Caspase-8 is a well characterized protease of the “extrinsic” apoptotic pathway known to be important in death receptor-mediated killing. Recruitment of caspase-8 to activated death receptors results in its dimerization, activation, subsequent auto-processing and initiation of the “effector” caspase activity associated with classical apoptosis (1
). This death receptor mediated apoptosis has been the focus of various attempts to induce cell death in tumors. Indeed, Tumor necrosis factor- Related Apoptosis- Inducing Ligand (TRAIL) has been shown to induce apoptosis in a variety of tumor, but not normal, cells (5
). Whilst resistance to death receptor ligands currently limits their efficacy, deletion or silencing of essential proteins of the cascade, such as caspase-8, occur only extremely infrequently in cancers (7
). Caspase-8 has in fact been shown to have increased expression in lung cancers (8
) supporting the hypothesis that the protein may be involved in other non-apoptotic but potentially pro-tumorigenic events.
Mounting evidence to support alternative non-apoptotic functions for caspase-8 has emerged in recent years (reviewed in (9
)). Several reports have shown a role for caspase-8 in hematopoetic cell proliferation and “maturation” (e.g. (12
)), whilst other laboratories have shown caspase-8 to be essential for activation of NF-kB (15
). Further data describing a role for caspase-8 in adhesion and cell motility have recently accumulated. Involvement of caspase-8 in cell motility has been described by several independent laboratories (18
). We recently demonstrated an essential role for caspase-8 in promoting cell adhesion-induced activation of the Erk 1/2 pathway via an association with Src (7
). Intriguingly, this activation is independent of the catalytic activity of caspase-8 and can be re-capitulated in caspase-8 null cells using only the N-terminal “Death Effector Domains” (DEDs). Indeed, the DEDs alone are capable of forming a protein complex with Src and act indistinguishably from full-length caspase-8 in these biochemical and physiological analyses.
Here we show that caspase-8 is also critical for EGF-induced activation of the Erk pathway. Again the DEDs alone of caspase-8 are sufficient for this activation and we identify residues within the so called “RXDLL motif” that are essential for the promulgation of EGF signaling. We show that caspase-8 is required for EGF-induced cell migration and that point mutants of the RXDLL motif show impaired motility similar to that of caspase-8 null cells. In sum, we provide the first evidence that caspase-8 is an essential component of growth factor signaling pathways and that its effects in this regard may be due to the DEDs ability to associate with a protein complex containing Src. That caspase-8 is involved not only in adhesion- but also in growth factor-induced signaling may help explain why it is so seldom silenced or deleted in tumors. In addition, these findings suggest that potentially driving caspase-8 from non-apoptotic to more canonical pro-apoptotic signaling may be an important therapeutic intervention point in cancers.