title: Src kinase phosphorylates Caspase-8 on Tyr380: a novel mechanism of apoptosis suppression.
abstract: We identified Caspase-8 as a new substrate for Src kinase. Phosphorylation occurs on Tyr380, situated in the linker region between the large and the small subunits of human Procaspase-8, and results in downregulation of Caspase-8 proapoptotic function. Src activation triggers Caspase-8 phosphorylation on Tyr380 and impairs Fas-induced apoptosis. Accordingly, Src failed to protect Caspase-8-defective human cells in which a Caspase-8-Y380F mutant is expressed from Fas-induced cell death. Remarkably, Src activation upon EGF-receptor stimulation triggers endogenous Caspase-8 phosphorylation and prevents Fas-induced apoptosis. Tyr380 is phosphorylated also in human colon cancers where Src is aberrantly activated. These data provide the first evidence for a direct role of tyrosine phosphorylation in the control of caspases and reveal a new mechanism through which tyrosine kinases inhibit apoptosis and participate in tumor progression.
authors.affiliation: Department of Experimental Medicine and Biochemical Sciences, Dulbecco Telethon Institute, University of Rome Tor Vergata, Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Cursi
authors.forename: Alessandra
authors.initials: A
authors.lastname: Rufini
authors.forename: Venturina
authors.initials: V
authors.lastname: Stagni
authors.forename: Ivano
authors.initials: I
authors.lastname: Condò
authors.forename: Vittoria
authors.initials: V
authors.lastname: Matafora
authors.forename: Angela
authors.initials: A
authors.lastname: Bachi
authors.forename: Antonio Paniccià
authors.initials: AP
authors.lastname: Bonifazi
authors.forename: Luigi
authors.initials: L
authors.lastname: Coppola
authors.forename: Giulio
authors.initials: G
authors.lastname: Superti-Furga
authors.forename: Roberto
authors.initials: R
authors.lastname: Testi
authors.forename: Daniela
authors.initials: D
authors.lastname: Barilà
mesh_terms: D000595:Amino Acid Sequence; D017209:Apoptosis; D053181:Caspase 8; D020169:Caspases / Q000235:genetics / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000201:enzymology*; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000819:agonists; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D012568:Schizosaccharomyces / Q000201:enzymology; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism*; D019014:fas Receptor / Q000494:pharmacology; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D019014:fas Receptor; D014443:Tyrosine; D066246:ErbB Receptors; D019061:src-Family Kinases; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases