Shear stress activates ADAM10 sheddase to regulate Notch1 via the Piezo1 force sensor in endothelial cells.
Elife
; 92020 06 02.
Article
em En
| MEDLINE
| ID: mdl-32484440
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.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Células Endoteliais
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Receptor Notch1
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Secretases da Proteína Precursora do Amiloide
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Proteína ADAM10
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Canais Iônicos
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Proteínas de Membrana
Limite:
Animals
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Humans
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Male
Idioma:
En
Revista:
Elife
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Reino Unido