Mechanosensitive interactions between Jag1 and Myo1c control Jag1 trafficking in endothelial cells

Oscar M.J.A.  Stassen; Noora Virtanen; Kai-Lan Lin; Freddy Suarez Rodriguez; Matthijs J.M.  Heijmans; Feihu Zhao; Garry L. Corthals; Carlijn V.C. Bouten; Cecilia Sahlgren

doi:10.1016/j.isci.2025.113879

Mechanosensitive interactions between Jag1 and Myo1c control Jag1 trafficking in endothelial cells

Oscar M.J.A. Stassen
, Noora Virtanen
, Kai-Lan Lin
, Freddy Suarez Rodriguez
, Matthijs J.M. Heijmans
, Feihu Zhao
, Garry L. Corthals
, Carlijn V.C. Bouten
, Cecilia Sahlgren

Research output: Contribution to journal › Article › Scientific › peer-review

Abstract

Morphogenesis of the cardiovascular system is responsive to hemodynamic cues sensed by endothelial cells. The organization of morphogenic signaling proteins is regulated by membrane presentation and internalization. Here, we aimed to characterize factors that regulate this flow-dependent protein localization by identifying differential interactors with the Notch ligand Jagged1 in response to shear stress. We cultured endothelial cells expressing Jagged1-APEX2 for proximity labeling on an orbital shaker shear stress platform. Myo1c was identified and confirmed through coimmunoprecipitation as a Jagged1-interacting factor under static conditions, with reduced interaction after exposure to shear. Jagged1 polarization downstream of shear followed by nucleograde transport was inhibited by Myo1c knockout. Further, Myo1c knockdown reduced membrane levels of Jagged1 under static but not shear conditions. Together, our data reveal a role for Myo1c in the hemodynamic control of Jagged1 localization in endothelial cells.

Original language	English
Article number	113879
Journal	iScience
Volume	28
Issue number	12
DOIs	https://doi.org/10.1016/j.isci.2025.113879
Publication status	Published - 19 Dec 2025
MoE publication type	A1 Journal article-refereed

Funding

This project has received funding from the European Research Council (ERC) under grant agreement number 771168 (ForceMorph) and the Academy of Finland under decision numbers 307133, 316882 (SPACE), 330411 (SignalSheets), and 336355 (strategic research profiling area Solutions for Health at Åbo Akademi University). The research has also been supported by the InFLAMES Flagship Programme of the Academy of Finland (decision numbers 337531, 357911, and 359346) and the Åbo Akademi University Foundation’s Center of Excellence in Cellular Mechanostasis (CellMech). K.L.L. was supported by the European Union’s Horizon 2020 research and innovation program under grant agreement 953234 (Tumor-LN-oC). F.S.R. was supported by The Swedish Cultural Foundation in Finland, Instrumentarium Science Foundation, and Magnus Ehrnrooth Foundation. We would like to extend our gratitude to Tim Wezeman for preparing plasmids during COVID-19 restricted lab access, as well as to Iida Laiho, Jaakko Ahlberg, Meike Hulleman, and Anouk van der Net for help screening initial candidate interactors. We thank Peter Paul Franssen for producing a batch of biotinyl tyramide. We thank the Turku Bioscience Center for discussion of proteomics analysis and for imaging at the Cell Imaging and Cytometry Core. Figure 5H and the graphical abstract were created in BioRender, Sahlgren, C. (2025) https://BioRender.com/vuvo5ek & https://BioRender.com/wytwpzw. pLenti PGK Puro DEST (w529-2) and pENTR1A-GFP-N2 (FR1) were gifts from Eric Campeau and Paul Kaufman (RRID:Addgene_19068 & RRID:Addgene_19364) – cDNA3 APEX2NES was a gift from Alice Ting (RRID:Addgene_49386)).

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10.1016/j.isci.2025.113879Licence: CC BY-NC

1-s2.0-S2589004225021406-mainFinal published version, 10.6 MBLicence: CC BY-NC

https://urn.fi/URN:NBN:fi-fe20251204114245

Tumor-LN-oC: Tumor lymph node on a chip
Zergioti, I. (Principal Investigator), J. den Toonder, J. M. (Co-Principal Investigator), Klinakis, A. (Co-Principal Investigator), Sahlgren, C. (Co-Principal Investigator) & Lendl, B. (Co-Principal Investigator)
European Commission
01/05/21 → 31/10/25
Project: EU
SignalSheets: Multilayer mechanosignalling in vascular homeostasis
Sahlgren, C. (Principal Investigator)
01/09/20 → 31/08/24
Project: Research Council of Finland/Other Research Councils
BACE: Center of Excellence in Bioelectronic Activation of Cell Functions
Österbacka, R. (Principal Investigator), Sjöqvist, M. (Co-Principal Investigator), Sahlgren, C. (Co-Principal Investigator), Torsi, L. (Co-Principal Investigator), Lindfelt, M. (Co-Principal Investigator), Hellsten, L. (Co-Investigator), Tewari, A. (Co-Investigator), Luukkonen, A. (Co-Investigator), Martinez Klimova, E. (Co-Investigator), Schmit, A. (Co-Investigator), Eklund, A. (Co-Investigator) & Gounani, Z. (Co-Investigator)
01/03/19 → 31/12/23
Project: Foundation

Cite this

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title = "Mechanosensitive interactions between Jag1 and Myo1c control Jag1 trafficking in endothelial cells",

abstract = "Morphogenesis of the cardiovascular system is responsive to hemodynamic cues sensed by endothelial cells. The organization of morphogenic signaling proteins is regulated by membrane presentation and internalization. Here, we aimed to characterize factors that regulate this flow-dependent protein localization by identifying differential interactors with the Notch ligand Jagged1 in response to shear stress. We cultured endothelial cells expressing Jagged1-APEX2 for proximity labeling on an orbital shaker shear stress platform. Myo1c was identified and confirmed through coimmunoprecipitation as a Jagged1-interacting factor under static conditions, with reduced interaction after exposure to shear. Jagged1 polarization downstream of shear followed by nucleograde transport was inhibited by Myo1c knockout. Further, Myo1c knockdown reduced membrane levels of Jagged1 under static but not shear conditions. Together, our data reveal a role for Myo1c in the hemodynamic control of Jagged1 localization in endothelial cells.",

author = "Stassen, \{Oscar M.J.A.\} and Noora Virtanen and Kai-Lan Lin and \{Suarez Rodriguez\}, Freddy and Heijmans, \{Matthijs J.M.\} and Feihu Zhao and Corthals, \{Garry L.\} and Bouten, \{Carlijn V.C.\} and Cecilia Sahlgren",

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doi = "10.1016/j.isci.2025.113879",

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AU - Stassen, Oscar M.J.A.

AU - Virtanen, Noora

AU - Lin, Kai-Lan

AU - Suarez Rodriguez, Freddy

AU - Heijmans, Matthijs J.M.

AU - Zhao, Feihu

AU - Corthals, Garry L.

AU - Bouten, Carlijn V.C.

AU - Sahlgren, Cecilia

PY - 2025/12/19

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N2 - Morphogenesis of the cardiovascular system is responsive to hemodynamic cues sensed by endothelial cells. The organization of morphogenic signaling proteins is regulated by membrane presentation and internalization. Here, we aimed to characterize factors that regulate this flow-dependent protein localization by identifying differential interactors with the Notch ligand Jagged1 in response to shear stress. We cultured endothelial cells expressing Jagged1-APEX2 for proximity labeling on an orbital shaker shear stress platform. Myo1c was identified and confirmed through coimmunoprecipitation as a Jagged1-interacting factor under static conditions, with reduced interaction after exposure to shear. Jagged1 polarization downstream of shear followed by nucleograde transport was inhibited by Myo1c knockout. Further, Myo1c knockdown reduced membrane levels of Jagged1 under static but not shear conditions. Together, our data reveal a role for Myo1c in the hemodynamic control of Jagged1 localization in endothelial cells.

AB - Morphogenesis of the cardiovascular system is responsive to hemodynamic cues sensed by endothelial cells. The organization of morphogenic signaling proteins is regulated by membrane presentation and internalization. Here, we aimed to characterize factors that regulate this flow-dependent protein localization by identifying differential interactors with the Notch ligand Jagged1 in response to shear stress. We cultured endothelial cells expressing Jagged1-APEX2 for proximity labeling on an orbital shaker shear stress platform. Myo1c was identified and confirmed through coimmunoprecipitation as a Jagged1-interacting factor under static conditions, with reduced interaction after exposure to shear. Jagged1 polarization downstream of shear followed by nucleograde transport was inhibited by Myo1c knockout. Further, Myo1c knockdown reduced membrane levels of Jagged1 under static but not shear conditions. Together, our data reveal a role for Myo1c in the hemodynamic control of Jagged1 localization in endothelial cells.

U2 - 10.1016/j.isci.2025.113879

DO - 10.1016/j.isci.2025.113879

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VL - 28

JO - iScience

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ER -

Mechanosensitive interactions between Jag1 and Myo1c control Jag1 trafficking in endothelial cells

Abstract

Funding

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Projects

Tumor-LN-oC: Tumor lymph node on a chip

SignalSheets: Multilayer mechanosignalling in vascular homeostasis

BACE: Center of Excellence in Bioelectronic Activation of Cell Functions

Cite this