Shedding-Generated Met Receptor Fragments can be Routed to Either the Proteasomal or the Lysosomal Degradation Pathway

Frédéric Ancot, Catherine Leroy, Ghaffar Muharram, Jonathan Lefebvre, Jérôme Vicogne, Arnaud Lemiere, Zoulika Kherrouche, Bénédicte Foveau, Albin Pourtier, Oleg Melnyk, Silvia Giordano, Anne Chotteau-Lelievre, David Tulasne

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)1261-1272
Number of pages12
JournalTraffic
Volume13
Issue number9
DOIs
Publication statusPublished - Sep 2012

Keywords

  • γ-secretase
  • C-Met
  • Degradation
  • Hepatocyte growth factor
  • Lysosome
  • Receptor tyrosine kinase
  • Shedding

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Structural Biology
  • Molecular Biology
  • Genetics

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