Down-regulation of the met receptor tyrosine kinase by presenilin-dependent regulated intramembrane proteolysis.
Hepatocyte growth factor/scatter factor (HGF/SF) acts through the membrane-anchored Met receptor tyrosine kinase to induce invasive growth. Deregulation of this signaling is associated with tumorigenesis and involves, in most cases, overexpression of the receptor. We demonstrate that Met is processed in epithelial cells by presenilin-dependent regulated intramembrane proteolysis (PS-RIP) independently of ligand stimulation. The proteolytic process involves sequential cleavage by metalloproteases and the gamma-secretase complex, leading to generation of labile fragments. In normal epithelial cells, although expression of cleavable Met by PS-RIP is down-regulated, uncleavable Met displayed membrane accumulation and induced ligand-independent motility and morphogenesis. Inversely, in transformed cells, the Met inhibitory antibody DN30 is able to promote Met PS-RIP, resulting in down-regulation of the receptor and inhibition of the Met-dependent invasive growth. This demonstrates the original involvement of a proteolytic process in degradation of the Met receptor implicated in negative regulation of invasive growth.
Foveau
Bénédicte
B
CNRS UMR 8161, Institut de Biologie de Lille-Institut Pasteur de Lille-Université de Lille 1-Université de Lille 2, 59021 Lille cedex, France.
Ancot
Frédéric
F
Leroy
Catherine
C
Petrelli
Annalisa
A
Reiss
Karina
K
Vingtdeux
Valérie
V
Giordano
Silvia
S
Fafeur
Véronique
V
Tulasne
David
D
D051722:ADAM Proteins / Q000037:antagonists & inhibitors; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D000906:Antibodies; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000201:enzymology*; D049109:Cell Proliferation / Q000187:drug effects; D004285:Dogs; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D017228:Hepatocyte Growth Factor / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D045726:Metalloproteases / Q000037:antagonists & inhibitors; D051379:Mice; D010446:Peptide Fragments / Q000378:metabolism; D053763:Presenilins / Q000378:metabolism*; D061988:Proteasome Inhibitors; D011499:Protein Processing, Post-Translational / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism
D000906:Antibodies; D004791:Enzyme Inhibitors; D008024:Ligands; D010446:Peptide Fragments; D053763:Presenilins; D061988:Proteasome Inhibitors; D011994:Recombinant Proteins; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met; D053829:Amyloid Precursor Protein Secretases; D045726:Metalloproteases; D051722:ADAM Proteins; D000072198:ADAM17 Protein