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...

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Bibliographic Details
Published in:The FASEB journal 2012-04, Vol.26 (4), p.1387-1399
Main Authors: Lefebvre, Jonathan, Ancot, Frédéric, Leroy, Catherine, Muharram, Ghaffar, Lemière, Arnaud, Tulasne, David
Format: Article
Language:English
Subjects:
Animals
caspase
cleavages
hepatocyte growth factor
Hepatocyte Growth Factor - metabolism
Humans
Key Words: receptor tyrosine kinase
Ligands
Lysosomes - metabolism
metalloprotease
Neoplasms - metabolism
Neoplasms - therapy
Proteins - metabolism
Proto-Oncogene Proteins c-met - genetics
Proto-Oncogene Proteins c-met - metabolism
Signal Transduction - physiology
γ‐secretase
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Summary: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.—Lefebvre, J., Ancot, F., Leroy, C., Muharram, G., Lemière, A., Tulasne, D. Met degradation: more than one stone to shoot a receptor down. FASEB J. 26, 1387‐1399 (2012). www.fasebj.org
ISSN:0892-6638
1530-6860
DOI:10.1096/fj.11-197723