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Src kinase phosphorylates Caspase‐8 on Tyr380: a novel mechanism of apoptosis suppression
Author(s) -
Cursi Silvia,
Rufini Alessandra,
Stagni Venturina,
Condò Ivano,
Matafora Vittoria,
Bachi Angela,
Bonifazi Antonio Paniccià,
Coppola Luigi,
SupertiFurga Giulio,
Testi Roberto,
Barilà Daniela
Publication year - 2006
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7601085
Subject(s) - biology , phosphorylation , mechanism (biology) , apoptosis , microbiology and biotechnology , kinase , caspase , proto oncogene tyrosine protein kinase src , caspase 8 , caspase 2 , caspase 3 , cancer research , genetics , programmed cell death , philosophy , epistemology
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.