Shedding-generated Met receptor fragments can be routed to either the proteasomal or the lysosomal degradation pathway.
The receptor tyrosine kinase Met and its ligand, the hepatocyte growth factor/scatter factor, are essential for embryonic development, whereas deregulation of Met signaling pathways is associated with tumorigenesis and metastasis. The presenilin-regulated intramembrane proteolysis (PS-RIP) is involved in ligand-independent downregulation of Met. This proteolytic process involves shedding of the Met extracellular domain followed by γ-secretase cleavage, generating labile intracellular fragments degraded by the proteasome. We demonstrate here that upon shedding both generated Met N- and C-terminal fragments are degraded directly in the lysosome, with C-terminal fragments escaping γ-secretase cleavage. PS-RIP and lysosomal degradation are complementary, because their simultaneous inhibition induces synergistic accumulation of fragments. Met N-terminal fragments associate with the high-affinity domain of HGF/SF, confirming its decoy activity which could be reduced through their routing to the lysosome at the expense of extracellular release. Finally, the DN30 monoclonal antibody inducing Met shedding promotes receptor degradation through induction of both PS-RIP and the lysosomal pathway. Thus, we demonstrate that Met shedding initiates a novel lysosomal degradation which participates to ligand-independent downregulation of the receptor.
CNRS UMR 8161, Institut de Biologie de Lille, Institut Pasteur de Lille, Université de Lille 1, Université de Lille 2, Lille cedex, France.
Frédéric
F
Ancot
Catherine
C
Leroy
Ghaffar
G
Muharram
Jonathan
J
Lefebvre
Jérôme
J
Vicogne
Arnaud
A
Lemiere
Zoulika
Z
Kherrouche
Bénédicte
B
Foveau
Albin
A
Pourtier
Oleg
O
Melnyk
Silvia
S
Giordano
Anne
A
Chotteau-Lelievre
David
D
Tulasne
D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D004285:Dogs; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008247:Lysosomes / Q000201:enzymology*; D051379:Mice; D041681:NIH 3T3 Cells; D053763:Presenilins / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D059748:Proteolysis; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering
D053763:Presenilins; D011480:Protease Inhibitors; D034741:RNA, Small Interfering; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D053829:Amyloid Precursor Protein Secretases; D046988:Proteasome Endopeptidase Complex