Met degradation: more than one stone to shoot a receptor down.
The receptor tyrosine kinase Met and its high-affinity ligand, the hepatocyte growth factor/scatter factor (HGF/SF), are essential to embryonic development. Deregulation of their signaling is associated with tumorigenesis and metastasis, notably through receptor overexpression. It is thus important to understand the mechanisms controlling Met expression. The ligand-dependent internalization of Met and its subsequent degradation in the lysosomal compartment are well described. This process is known to attenuate downstream Met signaling pathways. Yet internalized Met takes part directly in intracellular signaling by chaperoning signaling factors in the course of its trafficking. Furthermore, recent studies describe various new degradation mechanisms of membrane-anchored Met, involving proteolytic cleavages or association with novel partners. Although all these degradations are ligand-independent, they share, to different extents, some common features with canonical HGF/SF-dependent degradation. Interestingly, activated Met variants display resistance to degradation, suggesting defective degradation is involved in tumorigenesis. Conversely, forced degradation of Met through reinduction of one or more degradation pathways is a promising therapeutic strategy.
CNRS UMR 8161, Institut de Biologie de Lille, Institut Pasteur de Lille, B.P.447, 59021 Lille, France.
Jonathan
J
Lefebvre
Frédéric
F
Ancot
Catherine
C
Leroy
Ghaffar
G
Muharram
Arnaud
A
Lemière
David
D
Tulasne
D000818:Animals; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D006801:Humans; D000090263:Leucine-Rich Repeat Proteins; D008024:Ligands; D008247:Lysosomes / Q000378:metabolism; D009369:Neoplasms / Q000378:metabolism / Q000628:therapy; D011506:Proteins / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*
D000090263:Leucine-Rich Repeat Proteins; D008024:Ligands; D011506:Proteins; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met