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 language | English |
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Article number | 50684 |
Number of pages | 18 |
Journal | Elife |
Volume | 9 |
DOIs | |
Publication status | Published - 2 Jun 2020 |
Externally published | Yes |
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