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PAR1 Scaffolds TGF beta RII to Downregulate TGF-beta Signaling and Activate ESC Differentiation to Endothelial Cells

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Sassmann,  Antonia
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Offermanns,  Stefan
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Citation

Gong, H., An, S., Sassmann, A., Liu, M., Mastej, V., Mittal, M., et al. (2016). PAR1 Scaffolds TGF beta RII to Downregulate TGF-beta Signaling and Activate ESC Differentiation to Endothelial Cells. STEM CELL REPORTS, 7(6), 1050-1058. doi:10.1016/j.stemcr.2016.10.006.


Cite as: http://hdl.handle.net/21.11116/0000-0001-BD7D-F
Abstract
We studied the function of the G-protein-coupled receptor PAR1 in mediating the differentiation of mouse embryonic stem cells (mESCs) to endothelial cells (ECs) that are capable of inducing neovascularization. We observed that either deletion or activation of PAR1 suppressed mouse embryonic stem cell (mESC) differentiation to ECs and neovascularization in mice. This was mediated by induction of TGF beta RII/TGF beta RI interaction, forming an active complex, which in turn induced SMAD2 phosphorylation. Inhibition of TGF-beta signaling in PAR1-deficient mESCs restored the EC differentiation potential of mESCs. Thus, PAR1 in its inactive unligated state functions as a scaffold for TGF beta RII to downregulate TGF-beta signaling, and thereby promote ESC transition to functional ECs. The PAR1 scaffold function in ESCs is an essential mechanism for dampening TGF-beta signaling and regulating ESC differentiation.