Critical Role for Caspase-8 in Epidermal Growth Factor Signaling

Caspase-8 has a well-defined canonical role as an apical protease of the extrinsic apoptosis pathway. Evidence is growing, however, that the protein has numerous other nonapoptotic functions. We have previously shown that caspase-8 is required for efficient adhesion-induced activation of the extracellular signal-regulated kinase (Erk)-1/2 pathway. We now show that caspase-8 is also necessary for the efficient activation of downstream events associated with epidermal growth factor (EGF) signaling. This promotion of EGF-induced Erk1/2 activation is independent of the proteolytic activity of caspase-8 and can be recapitulated using only the prodomains of the protein. In addition, we identify specific residues within the caspase-8 RXDLL motif that are essential for Erk pathway activation. Furthermore, these residues are also involved in forming a complex with the tyrosine kinase Src. Caspase-8 null cells and cells reconstituted with caspase-8 harboring point mutations of these critical amino acids also show defective EGF-induced migration as compared with cells reconstituted with the wild-type protein. In sum, we provide the first evidence for caspase-8 as an essential component of growth factor signaling and suggest that this may be due to its association with Src. As the EGF/Src pathway activity has been shown to promote oncogenic events, our findings that caspase-8 is necessary for these activities may help explain why it is rarely deleted or silenced in tumors. [Cancer Res 2009;69(12):5023-9]