Caolo, V orcid.org/0000-0001-6215-2702, Debant, M, Endesh, N et al. (6 more authors) (2020) Shear stress activates ADAM10 sheddase to regulate Notch1 via the Piezo1 force sensor in endothelial cells. eLife, 9. ISSN 2050-084X
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, g-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.
Metadata
Authors/Creators: |
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Keywords: | Ion channel; Notch signalling; Proteinase; Endothelial cell. | ||||||||
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Institution: | The University of Leeds | ||||||||
Academic Units: | The University of Leeds > Faculty of Medicine and Health (Leeds) > School of Medicine (Leeds) > Leeds Institute of Cardiovascular and Metabolic Medicine (LICAMM) > Discovery & Translational Science Dept (Leeds) | ||||||||
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Depositing User: | Symplectic Publications | ||||||||
Date Deposited: | 09 Jun 2020 11:29 | ||||||||
Last Modified: | 09 Jun 2020 11:29 | ||||||||
Status: | Published online | ||||||||
Publisher: | eLife Sciences Publications, Ltd | ||||||||
Identification Number: | https://doi.org/10.7554/elife.50684 |