title: PAR1 Scaffolds TGFβRII to Downregulate TGF-β Signaling and Activate ESC Differentiation to Endothelial Cells.
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 TGFβRII/TGFβRI interaction, forming an active complex, which in turn induced SMAD2 phosphorylation. Inhibition of TGF-β signaling in PAR1-deficient mESCs restored the EC differentiation potential of mESCs. Thus, PAR1 in its inactive unligated state functions as a scaffold for TGFβRII to downregulate TGF-β signaling, and thereby promote ESC transition to functional ECs. The PAR1 scaffold function in ESCs is an essential mechanism for dampening TGF-β signaling and regulating ESC differentiation.
authors.affiliation: Department of Pharmacology, University of Illinois, College of Medicine, 835 South Wolcott Avenue, Room E403, Chicago, IL 60612, USA; The Center for Lung and Vascular Biology, University of Illinois, College of Medicine, 835 South Wolcott Avenue, Room E403, Chicago, IL 60612, USA.
authors.forename: Haixia
authors.initials: H
authors.lastname: Gong
authors.affiliation: Department of Pharmacology, University of Illinois, College of Medicine, 835 South Wolcott Avenue, Room E403, Chicago, IL 60612, USA; The Center for Lung and Vascular Biology, University of Illinois, College of Medicine, 835 South Wolcott Avenue, Room E403, Chicago, IL 60612, USA.
authors.forename: Shejuan
authors.initials: S
authors.lastname: An
authors.affiliation: Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim 61231, Germany.
authors.forename: Antonia
authors.initials: A
authors.lastname: Sassmann
authors.affiliation: Department of Pharmacology, University of Illinois, College of Medicine, 835 South Wolcott Avenue, Room E403, Chicago, IL 60612, USA; The Center for Lung and Vascular Biology, University of Illinois, College of Medicine, 835 South Wolcott Avenue, Room E403, Chicago, IL 60612, USA.
authors.forename: Menglin
authors.initials: M
authors.lastname: Liu
authors.affiliation: Department of Pharmacology, University of Illinois, College of Medicine, 835 South Wolcott Avenue, Room E403, Chicago, IL 60612, USA; The Center for Lung and Vascular Biology, University of Illinois, College of Medicine, 835 South Wolcott Avenue, Room E403, Chicago, IL 60612, USA.
authors.forename: Victoria
authors.initials: V
authors.lastname: Mastej
authors.affiliation: Department of Pharmacology, University of Illinois, College of Medicine, 835 South Wolcott Avenue, Room E403, Chicago, IL 60612, USA; The Center for Lung and Vascular Biology, University of Illinois, College of Medicine, 835 South Wolcott Avenue, Room E403, Chicago, IL 60612, USA.
authors.forename: Manish
authors.initials: M
authors.lastname: Mittal
authors.affiliation: Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Pharmacology, University of Illinois, College of Medicine, 835 South Wolcott Avenue, Room E403, Chicago, IL 60612, USA; The Center for Lung and Vascular Biology, University of Illinois, College of Medicine, 835 South Wolcott Avenue, Room E403, Chicago, IL 60612, USA.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Hong
authors.affiliation: Department of Pharmacology, Max-Planck-Institute for Heart and Lung Research, Bad Nauheim 61231, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.affiliation: Department of Pharmacology, University of Illinois, College of Medicine, 835 South Wolcott Avenue, Room E403, Chicago, IL 60612, USA; The Center for Lung and Vascular Biology, University of Illinois, College of Medicine, 835 South Wolcott Avenue, Room E403, Chicago, IL 60612, USA.
authors.forename: Jalees
authors.initials: J
authors.lastname: Rehman
authors.affiliation: Department of Pharmacology, University of Illinois, College of Medicine, 835 South Wolcott Avenue, Room E403, Chicago, IL 60612, USA; The Center for Lung and Vascular Biology, University of Illinois, College of Medicine, 835 South Wolcott Avenue, Room E403, Chicago, IL 60612, USA. Electronic address: abmalik@uic.edu.
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D015536:Down-Regulation; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism*; D017353:Gene Deletion; D051379:Mice; D000066450:Mouse Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D044463:Receptor, PAR-1 / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D044463:Receptor, PAR-1; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: Embryonic stem cells; Endothelial cells; G-protein-coupled receptor; GPCR; PAR1; TGF-β signaling; cell differentiation; scaffolding protein; stem cells