title: Identification of a critical tyrosine residue in caspase 8 that promotes cell migration.
abstract: 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.
authors.affiliation: Department of Pathology, University of California San Diego School of Medicine, La Jolla, California 92093, USA.
authors.forename: Simone
authors.initials: S
authors.lastname: Barbero
authors.forename: Daniela
authors.initials: D
authors.lastname: Barilà
authors.forename: Ainhoa
authors.initials: A
authors.lastname: Mielgo
authors.forename: Venturina
authors.initials: V
authors.lastname: Stagni
authors.forename: Kiran
authors.initials: K
authors.lastname: Clair
authors.forename: Dwayne
authors.initials: D
authors.lastname: Stupack
mesh_terms: D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism*; D002448:Cell Adhesion; D002460:Cell Line; D002465:Cell Movement; D006801:Humans; D010766:Phosphorylation; D014443:Tyrosine / Q000235:genetics / Q000378:metabolism; D019061:src-Family Kinases / Q000378:metabolism
chemical_list: D014443:Tyrosine; D019061:src-Family Kinases; D053181:Caspase 8