Amplification of apoptosis through sequential caspase cleavage of the MET tyrosine kinase receptor

Cell Death Differ. 2007 Apr;14(4):752-64. doi: 10.1038/sj.cdd.4402080. Epub 2006 Dec 22.

Abstract

Activation of the MET tyrosine kinase receptor by hepatocyte growth factor/scatter factor is classically associated with cell survival. Nonetheless, stress stimuli can lead to a caspase-dependent cleavage of MET within its juxtamembrane region, which generate a proapoptotic 40 kDa fragment (p40 MET). We report here that p40 MET is in fact generated through an additional caspase cleavage of MET within its extreme C-terminal region, which removes only few amino acids. We evidenced a hierarchical organization of these cleavages, with the C-terminal cleavage favoring the juxtamembrane one. As a functional consequence, the removal of the last amino acids of p40 MET increases its apoptotic capacity. Finally, cells expressing a MET receptor mutated at the C-terminal caspase site are unable to generate p40 MET and are resistant to apoptosis, indicating that generation of p40 MET amplifies apoptosis. These results revealed a two-step caspase cleavage of MET resulting in the reshaping of this survival receptor to a proapoptotic factor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis / physiology*
  • Caspases / metabolism*
  • Cell Line
  • Cell Survival / physiology
  • Hepatocyte Growth Factor / metabolism
  • Humans
  • Mice
  • Microscopy, Fluorescence
  • Proto-Oncogene Proteins c-met / metabolism*

Substances

  • Hepatocyte Growth Factor
  • Proto-Oncogene Proteins c-met
  • Caspases