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 phosphorylati...

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Published inThe EMBO journal Vol. 25; no. 9; pp. 1895 - 1905
Main Authors Cursi, Silvia, Rufini, Alessandra, Stagni, Venturina, Condò, Ivano, Matafora, Vittoria, Bachi, Angela, Bonifazi, Antonio Paniccià, Coppola, Luigi, Superti-Furga, Giulio, Testi, Roberto, Barilà, Daniela
Format Journal Article
LanguageEnglish
Published Chichester, UK John Wiley & Sons, Ltd 03.05.2006
Nature Publishing Group UK
Springer Nature B.V
Subjects
Amino Acid Sequence
Amino acids
Apoptosis
cancer
Caspase 8
Caspases - genetics
Caspases - metabolism
Colonic Neoplasms - enzymology
EMBO07
EMBO37
Enzyme Activation
ErbB Receptors - agonists
fas Receptor - pharmacology
Fas-receptor
Gene expression
Humans
Molecular Sequence Data
Mutation
Phosphates
Schizosaccharomyces - enzymology
Src non-receptor tyrosine kinase
src-Family Kinases - metabolism
Tumor Cells, Cultured
Tyrosine - metabolism
apoptosis
cancer
Fas‐receptor
Caspase‐8
Src non‐receptor tyrosine kinase
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Summary: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.
Bibliography:ArticleID:EMBJ7601085
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Supplementary Information
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These authors equally contributed to this work
ISSN:0261-4189
1460-2075
DOI:10.1038/sj.emboj.7601085