Src kinase phosphorylates Caspase-8 on Tyr380: a novel mechanism of apoptosis suppression

EMBO J. 2006 May 3;25(9):1895-905. doi: 10.1038/sj.emboj.7601085. Epub 2006 Apr 13.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Apoptosis*
  • Caspase 8
  • Caspases / genetics
  • Caspases / metabolism*
  • Colonic Neoplasms / enzymology*
  • Enzyme Activation
  • ErbB Receptors / agonists
  • Humans
  • Molecular Sequence Data
  • Mutation
  • Schizosaccharomyces / enzymology
  • Tumor Cells, Cultured
  • Tyrosine / metabolism*
  • fas Receptor / pharmacology
  • src-Family Kinases / metabolism*


  • fas Receptor
  • Tyrosine
  • ErbB Receptors
  • src-Family Kinases
  • CASP8 protein, human
  • Caspase 8
  • Caspases