Identification of a critical tyrosine residue in caspase 8 that promotes cell migration

Caspase 8 is a critical upstream initiator of programmed cell death but, paradoxically, has also been shown to promote cell migration. Here, we show that tyrosine 380 in the linker loop of human Caspase 8 is a critical switch determining Caspase 8 function. Our studies show that, in addition to its cytosolic distribution, Caspase 8 is recruited to lamella of migrating cells. Although the catalytic domain of Caspase 8 is sufficient for recruitment and promotion of cell migration, catalytic activity per se is not required. Instead, we find that integrin-mediated adhesion promotes Caspase 8 phosphorylation on tyrosine 380. Accordingly, mutation of this site compromises localization to the periphery and the potentiation of cell migration. Mechanistically, this linker region of Caspase 8 acts as a Src homology 2 binding site. In particular, tyrosine 380 is critical for interaction with Src homology 2 domains. The results identify a novel mechanism by which Caspase 8 is recruited to the lamella of a migrating cell, promoting cell migration independent of its protease activity.