RT Journal Article
SR Electronic
T1 Piezo1 channel activates ADAM10 sheddase to regulate Notch1 and gene expression
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 732370
DO 10.1101/732370
A1 Vincenza Caolo
A1 Marjolaine Debant
A1 Naima Endesh
A1 T Simon Futers
A1 Laeticia Lichtenstein
A1 Gregory Parsonage
A1 Elizabeth AV Jones
A1 David J Beech
YR 2019
UL http://biorxiv.org/content/early/2019/08/12/732370.abstract
AB 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.