Amplification of apoptosis through sequential caspase cleavage of the MET tyrosine kinase receptor.
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.
Foveau
B
B
1CNRS UMR 8161, Institut de Biologie de Lille, CNRS-Institut Pasteur de Lille-Université de Lille 1-Université de Lille 2, Lille cedex, France.
Leroy
C
C
Ancot
F
F
Deheuninck
J
J
Ji
Z
Z
Fafeur
V
V
Tulasne
D
D
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D020169:Caspases / Q000378:metabolism*; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D051379:Mice; D008856:Microscopy, Fluorescence; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*
D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D020169:Caspases