Phosphorylation of the MET receptor on juxtamembrane tyrosine residue 1001 inhibits its caspase-dependent cleavage |
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| Authors: | Julien Deheuninck Gautier Goormachtigh Bénédicte Foveau Zongling Ji Catherine Leroy Frédéric Ancot Vincent Villeret David Tulasne Véronique Fafeur |
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| Institution: | 3. From the Department of Oral Biology, College of Dentistry, University of Nebraska Medical Center, Lincoln, Nebraska 68583,;4. the Eppley Institute for Research in Cancer and Allied Diseases, Omaha, Nebraska 68198,;5. the Department of Dermatology and Cutaneous Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, and;6. the Departments of Cell Biology and Dermatology, Emory University School of Medicine, Atlanta, Georgia 30322;1. Burdock Group, 859 Outer Road, Orlando, FL 32814, United States;2. Product Safety Laboratories, 2394 Highway 130, Dayton, NJ 08810, United States;3. Solazyme, Inc., 225 Gateway Blvd., South San Francisco, CA 94080, United States;3. From the Department of Biochemistry, College of Medicine, Konyang University and Konyang University, Konyang Hospital, Daejeon 302-718, Korea;4. the Department of Surgery, College of Medicine, Konyang University, Konyang Hospital, Daejeon 302-718, Korea;5. the Acupuncture and Meridian Science Research Center, College of Oriental Medicine, Kyung Hee University, Seoul 130-701, Korea;1. Department of Radiation Oncology, Beaumont Health, Royal Oak, MI;2. Oakland University William Beaumont School of Medicine, Rochester, MI;1. Massachusetts General Hospital Cancer Center, Massachusetts General Hospital, Boston, Massachusetts;2. Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts;3. Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts |
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| Abstract: | The MET tyrosine kinase is the hepatocyte growth factor/scatter factor (HGF/SF) receptor, which elicits multiple biological responses in epithelial cells, including cell survival. We previously demonstrated that in stress conditions, the MET receptor is cleaved by caspases within its juxtamembrane region, generating a pro-apoptotic intracellular fragment of 40 kDa. The caspase cleavage site at aspartic acid D1000 is adjacent to tyrosine Y1001, which when phosphorylated upon MET activation, is involved in CBL recruitment, allowing receptor ubiquitination and down regulation. Scanning mutagenesis of the MET juxtamembrane region led us to demonstrate that V999 and D1000 are essential for the caspase cleavage, while D1000 and Y1001 are essential for CBL recruitment. By examining whether overlapping of these sites leads to a functional interference, an inverse relationship was found between generation of p40 MET and phosphorylation of MET, with a direct involvement of phosphorylated Y1001 in protecting MET against its caspase cleavage. A molecular modeling analysis of caspase 3 interaction with the juxtamembrane region of MET confirmed that phosphorylation of this tyrosine is not compatible with its recognition by active caspase 3. These data demonstrate a direct protection mechanism of an activated phosphorylated MET receptor, against its caspase-dependent cleavage. |
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