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Confluence switch signaling regulates ECM composition and the plasmin proteolytic cascade in keratinocytes.

Authors
  • Botta, Adrien
  • Delteil, Frédéric
  • Mettouchi, Amel
  • Vieira, Andhira
  • Estrach, Soline
  • Négroni, Luc
  • Stefani, Caroline
  • Lemichez, E
  • Meneguzzi, Guerrino
  • Gagnoux-Palacios, Laurent
Type
Published Article
Journal
Journal of Cell Science
Publisher
The Company of Biologists
Publication Date
Sep 14, 2012
Volume
125
Issue
Pt 18
Pages
4241–4252
Identifiers
DOI: 10.1242/jcs.096289
PMID: 22641690
Source
Medline
License
Unknown

Abstract

In culture, cell confluence generates signals that commit actively growing keratinocytes to exit the cell cycle and differentiate to form a stratified epithelium. Using a comparative proteomic approach, we studied this 'confluence switch' and identified a new pathway triggered by cell confluence that regulates basement membrane (BM) protein composition by suppressing the uPA-uPAR-plasmin pathway. Indeed, confluence triggers adherens junction maturation and enhances TGF-β and activin A activity, resulting in increased deposition of PAI-1 and perlecan in the BM. Extracellular matrix (ECM)-accumulated PAI-1 suppresses the uPA-uPAR-plasmin pathway and further enhances perlecan deposition by inhibiting its plasmin-dependent proteolysis. We show that perlecan deposition in the ECM strengthens cell adhesion, inhibits keratinocyte motility and promotes additional accumulation of PAI-1 in the ECM at confluence. In agreement, during wound-healing, perlecan concentrates at the wound-margin, where BM matures to stabilize keratinocyte adhesion. Our results demonstrate that confluence-dependent signaling orchestrates not only growth inhibition and differentiation, but also controls ECM proteolysis and BM formation. These data suggest that uncontrolled integration of confluence-dependent signaling, might favor skin disorders, including tumorigenesis, not only by promoting cell hyperproliferation, but also by altering protease activity and deposition of ECM components.

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