Fas activation induces renal tubular epithelial cell ß₈ integrin expression and function in the absence of apoptosis

Cell fate following Fas (CD95) ligand or agonistic anti-Fas antibody stimulation is determined by multiple factors, including Fas expression level, microdomain localization, and modulating cytokines. Highly expressed Fas clusters and activates a canonical apoptosis signaling pathway. In less susceptible cells, Fas transduces apoptosis-independent signals, which are not well defined, but have been linked to inflammation, angiogenesis, and fibrosis. To identify apoptosis-independent Fas pathways, cultured renal tubular epithelial cells were stimulated with agonistic anti-Fas antibodies under conditions that did not cause cell death. Analysis of filter cDNA microarrays revealed β₈ integrin subunit mRNA induction in Fasstimulated cells. β₈ integrin mRNA expression increased within 3-6 h of Fas ligation due to enhanced mRNA stabilization, and mRNA increases were sustained for 48-72 h. Expression of plasma membrane β₈ integrin, as well as its heterodimer partner α_v, was increased by Fas activation with a similar kinetic pattern. Fas-induced α_vβ₈ expression correlated with increased migration to vitronectin, the ligand for α_vβ₈. Results from studies with function-blocking antibodies against other α_vβ integrins or suppression β₈ integrin expression by RNA interference demonstrated that induced β₈ integrin expression mediated Fas-stimulated migration. We conclude that α_vβ₈ integrin induction defines an unexpected role for Fas in cell migration, rather than as a cell death receptor.