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

Research output: Contribution to journalArticle

73 Citations (Scopus)

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

Fingerprint

Presenilins
Receptor Protein-Tyrosine Kinases
Proteolysis
Hepatocyte Growth Factor
Down-Regulation
Growth
Epithelial Cells
Ligands
Amyloid Precursor Protein Secretases
Membranes
Metalloproteases
Morphogenesis
Carcinogenesis
Antibodies

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Foveau, B., Ancot, F., Leroy, C., Petrelli, A., Reiss, K., Vingtdeux, 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

Down-regulation of the met receptor tyrosine kinase by presenilin-dependent regulated intramembrane proteolysis. / Foveau, Bénédicte; Ancot, Frédéric; Leroy, Catherine; Petrelli, Annalisa; Reiss, Karina; Vingtdeux, Valérie; Giordano, Silvia; Fafeur, Véronique; Tulasne, David.

In: Molecular Biology of the Cell, Vol. 20, No. 9, 01.05.2009, p. 2495-2507.

Research output: Contribution to journalArticle

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, vol. 20, no. 9, pp. 2495-2507. https://doi.org/10.1091/mbc.E08-09-0969
Foveau, Bénédicte ; Ancot, Frédéric ; Leroy, Catherine ; Petrelli, Annalisa ; Reiss, Karina ; Vingtdeux, Valérie ; Giordano, Silvia ; Fafeur, Véronique ; Tulasne, David. / Down-regulation of the met receptor tyrosine kinase by presenilin-dependent regulated intramembrane proteolysis. In: Molecular Biology of the Cell. 2009 ; Vol. 20, No. 9. pp. 2495-2507.
@article{00b7a190af944896be15ad688864033d,
title = "Down-regulation of the met receptor tyrosine kinase by presenilin-dependent regulated intramembrane proteolysis",
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.",
author = "B{\'e}n{\'e}dicte Foveau and Fr{\'e}d{\'e}ric Ancot and Catherine Leroy and Annalisa Petrelli and Karina Reiss and Val{\'e}rie Vingtdeux and Silvia Giordano and V{\'e}ronique Fafeur and David Tulasne",
year = "2009",
month = "5",
day = "1",
doi = "10.1091/mbc.E08-09-0969",
language = "English",
volume = "20",
pages = "2495--2507",
journal = "Molecular Biology of the Cell",
issn = "1059-1524",
publisher = "American Society for Cell Biology",
number = "9",

}

TY - JOUR

T1 - Down-regulation of the met receptor tyrosine kinase by presenilin-dependent regulated intramembrane proteolysis

AU - Foveau, Bénédicte

AU - Ancot, Frédéric

AU - Leroy, Catherine

AU - Petrelli, Annalisa

AU - Reiss, Karina

AU - Vingtdeux, Valérie

AU - Giordano, Silvia

AU - Fafeur, Véronique

AU - Tulasne, David

PY - 2009/5/1

Y1 - 2009/5/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=65649111648&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=65649111648&partnerID=8YFLogxK

U2 - 10.1091/mbc.E08-09-0969

DO - 10.1091/mbc.E08-09-0969

M3 - Article

C2 - 19297528

AN - SCOPUS:65649111648

VL - 20

SP - 2495

EP - 2507

JO - Molecular Biology of the Cell

JF - Molecular Biology of the Cell

SN - 1059-1524

IS - 9

ER -