Proapoptotic function of the MET tyrosine kinase receptor through caspase cleavage.
The MET tyrosine kinase, the receptor of hepatocyte growth factor-scatter factor (HGF/SF), is known to be essential for normal development and cell survival. We report that stress stimuli induce the caspase-mediated cleavage of MET in physiological cellular targets, such as epithelial cells, embryonic hepatocytes, and cortical neurons. Cleavage occurs at aspartic residue 1000 within the SVD site of the juxtamembrane region, independently of the crucial docking tyrosine residues Y1001 or Y1347 and Y1354. This cleavage generates an intracellular 40-kDa MET fragment containing the kinase domain. The p40 MET fragment itself causes apoptosis of MDCK epithelial cells and embryonic cortical neurons, whereas its kinase-dead version is impaired in proapoptotic activity. Finally, HGF/SF treatment does not favor MET cleavage and apoptosis, confirming the known survival role of ligand-activated MET. Our results show that stress stimuli convert the MET survival receptor into a proapoptotic factor.
Tulasne
David
D
CNRS UMR 8117, Institut de Biologie de Lille, Institut Pasteur de Lille, B.P. 447, 59021 Lille, France. david.tulasne@ibl.fr
Deheuninck
Julien
J
Lourenco
Filipe Calheiros
FC
Lamballe
Fabienne
F
Ji
Zongling
Z
Leroy
Catherine
C
Puchois
Emilie
E
Moumen
Anice
A
Maina
Flavio
F
Mehlen
Patrick
P
Fafeur
Véronique
V
D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis; D001224:Aspartic Acid / Q000737:chemistry / Q000378:metabolism; D015153:Blotting, Western; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism*; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D022781:Hepatocytes / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D008024:Ligands; D051379:Mice; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009474:Neurons / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D014176:Protein Biosynthesis; D017434:Protein Structure, Tertiary; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism / Q000502:physiology*; D011994:Recombinant Proteins / Q000737:chemistry; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry
D016207:Cytokines; D004791:Enzyme Inhibitors; D008024:Ligands; D011994:Recombinant Proteins; D001224:Aspartic Acid; D014443:Tyrosine; D019859:Proto-Oncogene Proteins c-met; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases