Src kinase phosphorylates Caspase-8 on Tyr380: a novel mechanism of apoptosis suppression.
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.
Cursi
Silvia
S
Department of Experimental Medicine and Biochemical Sciences, Dulbecco Telethon Institute, University of Rome Tor Vergata, Rome, Italy.
Rufini
Alessandra
A
Stagni
Venturina
V
Condò
Ivano
I
Matafora
Vittoria
V
Bachi
Angela
A
Bonifazi
Antonio Paniccià
AP
Coppola
Luigi
L
Superti-Furga
Giulio
G
Testi
Roberto
R
Barilà
Daniela
D
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*
D019014:fas Receptor; D014443:Tyrosine; D066246:ErbB Receptors; D019061:src-Family Kinases; C505530:CASP8 protein, human; D053181:Caspase 8; D020169:Caspases