Shear stress activates ADAM10 sheddase to regulate Notch1 via the Piezo1 force sensor in endothelial cells

Vincenza Caolo, Marjolaine Debant, Naima Endesh, T Simon Futers, Laeticia Lichtenstein, Fiona Bartoli, Gregory Parsonage, Elizabeth Av Jones*, David J Beech*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

21 Citations (Web of Science)

Abstract

Mechanical force is a determinant of Notch signalling but the mechanism of force detection and its coupling to Notch are unclear. We propose a role for Piezo1 channels, which are mechanically-activated non-selective cation channels. In cultured microvascular endothelial cells, Piezo1 channel activation by either shear stress or a chemical agonist Yoda1 activated a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), a Ca2+-regulated transmembrane sheddase that mediates S2 Notch1 cleavage. Consistent with this observation, we found Piezo1-dependent increase in the abundance of Notch1 intracellular domain (NICD) that depended on ADAM10 and the downstream S3 cleavage enzyme, γ-secretase. Conditional endothelial-specific disruption of Piezo1 in adult mice suppressed the expression of multiple Notch1 target genes in hepatic vasculature, suggesting constitutive functional importance in vivo. The data suggest that Piezo1 is a mechanism conferring force sensitivity on ADAM10 and Notch1 with downstream consequences for sustained activation of Notch1 target genes and potentially other processes.

Original languageEnglish
Article number50684
Number of pages18
JournalElife
Volume9
DOIs
Publication statusPublished - 2 Jun 2020
Externally publishedYes

Keywords

  • ADAM10 Protein/metabolism
  • Amyloid Precursor Protein Secretases/metabolism
  • Animals
  • Cells, Cultured
  • Endothelial Cells/metabolism
  • Enzyme Activation
  • Gene Expression Regulation
  • Humans
  • Ion Channels/antagonists & inhibitors
  • Male
  • Membrane Proteins/metabolism
  • Mice
  • Mice, Inbred C57BL
  • Protein Domains
  • Receptor, Notch1/metabolism
  • Stress, Mechanical
  • Transcription Factor HES-1/genetics
  • HOMEOSTASIS
  • PRESSURE
  • DISINTEGRIN
  • ION-CHANNEL
  • INHIBITORS
  • HEALTH

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