Identification of a critical tyrosine residue in caspase 8 that promotes cell migration

J Biol Chem. 2008 May 9;283(19):13031-4. doi: 10.1074/jbc.M800549200. Epub 2008 Jan 23.

Abstract

Caspase 8 is a critical upstream initiator of programmed cell death but, paradoxically, has also been shown to promote cell migration. Here, we show that tyrosine 380 in the linker loop of human caspase 8 is a critical switch determining caspase 8 function. Our studies show that, in addition to its cytosolic distribution, caspase 8 is recruited to lamella of migrating cells. Although the catalytic domain of caspase 8 is sufficient for recruitment and promotion of cell migration, catalytic activity per se is not required. Instead, we find that integrin-mediated adhesion promotes caspase 8 phosphorylation on tyrosine 380. Accordingly, mutation of this site compromises localization to the periphery and the potentiation of cell migration. Mechanistically, this linker region of caspase 8 acts as a Src homology 2 binding site. In particular, tyrosine 380 is critical for interaction with Src homology 2 domains. The results identify a novel mechanism by which caspase 8 is recruited to the lamella of a migrating cell, promoting cell migration independent of its protease activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caspase 8 / genetics
  • Caspase 8 / metabolism*
  • Cell Adhesion
  • Cell Line
  • Cell Movement*
  • Humans
  • Phosphorylation
  • Tyrosine / genetics
  • Tyrosine / metabolism
  • src-Family Kinases / metabolism

Substances

  • Tyrosine
  • src-Family Kinases
  • Caspase 8