Down-regulation of the met receptor tyrosine kinase by presenilin-dependent regulated intramembrane proteolysis

Bénédicte Foveau, Frédéric Ancot, Catherine Leroy, Annalisa Petrelli, Karina Reiss, Valérie Vingtdeux, Silvia Giordano, Véronique Fafeur, David Tulasne

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Abstract

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 γ-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.

Original languageEnglish
Pages (from-to)2495-2507
Number of pages13
JournalMolecular Biology of the Cell
Volume20
Issue number9
DOIs
Publication statusPublished - May 1 2009

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ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Foveau, B., Ancot, F., Leroy, C., Petrelli, A., Reiss, K., Vingtdeux, V., Giordano, S., Fafeur, V., & Tulasne, D. (2009). Down-regulation of the met receptor tyrosine kinase by presenilin-dependent regulated intramembrane proteolysis. Molecular Biology of the Cell, 20(9), 2495-2507. https://doi.org/10.1091/mbc.E08-09-0969