A1 Refereed original research article in a scientific journal
A noncanonical role for Jagged1 in endothelial mechanotransduction
Authors: Suarez Rodriguez, Freddy; Virtanen, Noora; Kiviluoto, Elmeri; Driessen, Rob C. H.; Zhao, Feihu; Bouten, Carlijn V. C.; Stassen, Oscar M. J. A.; Sahlgren, Cecilia M.
Publisher: Wiley
Publication year: 2026
Journal: FEBS Journal
ISSN: 1742-464X
eISSN: 1742-4658
DOI: https://doi.org/10.1111/febs.70466
Publication's open availability at the time of reporting: Open Access
Publication channel's open availability : Partially Open Access publication channel
Web address : https://doi.org/10.1111/febs.70466
Self-archived copy’s web address: https://research.utu.fi/converis/portal/detail/Publication/515747867
Self-archived copy's licence: CC BY
Self-archived copy's version: Publisher`s PDF
The Notch signaling pathway plays a crucial role in regulating endothelial biology. Notch signaling is sensitive to hemodynamic forces and governs mechanically driven cardiovascular development, physiology, and remodeling. However, the mechanisms by which mechanical forces integrate with the Notch pathway remain largely unknown. Here, we uncover a noncanonical role for the Notch ligand protein jagged-1 (Jagged1) in regulating the activity of mechanosensitive kinases in endothelial cells. We show that shear stress induces expression and relocalization of Jagged1 to cell junctions downstream of flow. Jagged1 expression under stress demonstrates magnitude dependence, and peaks at 0.8–1 Pa without impacting the Notch-activation potential of Jagged1. Jagged1 also regulates the activity of mechanosensitive kinases. Deletion of Jagged1 reduces the activity of vascular endothelial growth factor receptor 2 (VEGFR2) and mitogen-activated protein kinase (ERK) in vitro and diminished ERK activity in zebrafish embryos without affecting canonical Notch signaling. Furthermore, direct physical stimulation of Jagged1 using antibody-conjugated beads triggers the activation of VEGFR2 and ERK, mediated by Jagged1-induced proto-oncogene tyrosine-protein kinase Src activation. Taken together, we demonstrate a previously unknown noncanonical role for Jagged1 as a regulator of the activity of pathways involved in endothelial mechanotransduction.
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Funding information in the publication:
This project has received funding from the following sources: European Research Council (ERC) ERC-CoG No 771168 (ForceMorph). European Research Council (ERC) ERC-SynG No 101167065 (Making Blood). Research Council of Finland, Center of Excellence, decision number #374179 (CoEIMMENs). Research Council of Finland, decision number #316882 (SPACE). Research Council of Finland, decision number #330411 (SignalSheets). Research Council of Finland, decision number #336355 (Solutions for Health at Åbo Akademi University). Research Council of Finland, decision number #337531 and #357911 (InFLAMES Flagship Program). Åbo Akademi University Foundation's Centers of Excellence in Cellular Mechanostasis (CellMech) and Bioelectronic Activation of Cell Functions (BACE). The work performed by FSR has been partially funded by personal grants from The Swedish Cultural Foundation in Finland, Instrumentarium Science Foundation and Magnus Ehrnrooth Foundation.
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