Fas activation induces renal tubular epithelial cell beta 8 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 beta(8) integrin subunit mRNA induction in Fas-stimulated cells. beta(8) 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 beta(8) integrin, as well as its heterodimer partner alpha(v), was increased by Fas activation with a similar kinetic pattern. Fas-induced alpha(v)beta(8) expression correlated with increased migration to vitronectin, the ligand for alpha(v)beta(8). Results from studies with function-blocking antibodies against other alpha(v)beta integrins or suppression of beta(8) integrin expression by RNA interference demonstrated that induced beta(8) integrin expression mediated Fas-stimulated migration. We conclude that alpha(v)beta(8) integrin induction defines an unexpected role for Fas in cell migration, rather than as a cell death receptor.
D017209:Apoptosis; D019921:Biotinylation; D015152:Blotting, Northern; D002448:Cell Adhesion; D016923:Cell Death; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D018076:DNA, Complementary / Q000378:metabolism; D003609:Dactinomycin / Q000494:pharmacology; D004847:Epithelial Cells / Q000378:metabolism*; D006801:Humans; D039641:Integrin beta Chains / Q000096:biosynthesis*; D016023:Integrins / Q000378:metabolism; D007684:Kidney Tubules / Q000378:metabolism*; D007700:Kinetics; D020411:Oligonucleotide Array Sequence Analysis; D011485:Protein Binding; D014176:Protein Biosynthesis; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D013997:Time Factors; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D019014:fas Receptor / Q000378:metabolism*
D018076:DNA, Complementary; D039641:Integrin beta Chains; D016023:Integrins; D011500:Protein Synthesis Inhibitors; D012333:RNA, Messenger; D019014:fas Receptor; C403414:integrin alphavbeta8; C094865:integrin beta8; D003609:Dactinomycin