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Molecular and Cellular Biology, December 2004, p. 10328-10339, Vol. 24, No. 23
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.23.10328-10339.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Proapoptotic Function of the MET Tyrosine Kinase Receptor through Caspase Cleavage

David Tulasne,^1* Julien Deheuninck,¹ Filipe Calheiros Lourenco,² Fabienne Lamballe,³ Zongling Ji,¹ Catherine Leroy,¹ Emilie Puchois,¹ Anice Moumen,³ Flavio Maina,³ Patrick Mehlen,² and Véronique Fafeur¹

Institut de Biologie de Lille, Institut Pasteur de Lille, Lille,¹ Université Claude Bernard, Villeurbanne,² IBDM, Campus de Luminy, Marseille, France³

Received 23 March 2004/ Returned for modification 29 April 2004/ Accepted 3 September 2004

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.

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* Corresponding author. Mailing address: CNRS UMR 8117, Institut de Biologie de Lille, Institut Pasteur de Lille, B.P. 447, 59021 Lille, France. Phone: 00 33 3 20 87 10 91. Fax: 00 33 3 20 87 11 11. E-mail: david.tulasne{at}ibl.fr.

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Molecular and Cellular Biology, December 2004, p. 10328-10339, Vol. 24, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.23.10328-10339.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

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