Caolo, V, Debant, M, Endesh, N et al. (5 more authors) (2019) Piezo1 channel activates ADAM10 sheddase to regulate Notch1 and gene expression. [Preprint - bioRxiv]
Abstract
Mechanical force has emerged as a determinant of Notch signalling but the mechanisms of force sensing and coupling to Notch are unclear. Here we propose a role for Piezo1 channels, the recently identified mechanosensors of mammalian systems. Piezo1 channel opening in response to shear stress or a chemical agonist led to activation of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10), a Ca2+-regulated transmembrane sheddase that mediates S2 Notch1 cleavage. Consistent with this observation there was increased Notch1 intracellular domain (NICD) that depended on ADAM10 and the downstream S3 cleavage enzyme, γ-secretase. Endothelial-specific disruption of Piezo1 in mice led to decreased Notch1-regulated gene expression in hepatic vasculature, consistent with prior evidence that Notch1 controls hepatic perfusion. The data suggest Piezo1 as a mechanism for coupling physiological force at the endothelium to ADAM10, Notch1, gene expression and vascular function.
Metadata
Item Type: | Preprint |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. |
Dates: |
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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) |
Funding Information: | Funder Grant number British Heart Foundation RG/17/11/33042 Wellcome Trust 110044/Z/15/Z |
Depositing User: | Symplectic Publications |
Date Deposited: | 21 Feb 2025 16:12 |
Last Modified: | 21 Feb 2025 16:12 |
Publisher: | Cold Spring Harbor Laboratory |
Identification Number: | 10.1101/732370 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:152806 |