Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors

Goumans, Marie–José; Valdimarsdóttir, Guðrún; Itoh, Susumu; Rosendahl, Alexander; Sideras, Paschalis; Dijke, Peter ten

doi:10.1093/emboj/21.7.1743

Cited by 1,016 publications

(1,131 citation statements)

References 46 publications

(73 reference statements)

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“…TGF-b1 was previously shown to induce both Smad-2 and Smad-1/-5 phosphorylation in wildtype mouse embryonic endothelial cells and bovine aortic endothelial cells (Goumans et al, 2002). Both TGF-b1-and U87MG-CM-induced Smad-2 and Smad-1/-5 phosphorylation were inhibited in the presence of SB431542.…”

Section: Tgf-b1 Induces Igfbp7 Expression In Hbecmentioning

confidence: 87%

“…TGF-b has been implicated in various biological functions including cell cycle control, carcinogenesis, invasion, metastasis (Massague, 1998) and vascular remodeling (Pepper, 1997), acting as either an inhibitor or stimulator of angiogenesis depending on experimental conditions (Goumans et al, 2002). TGF-b signaling is initiated by binding of the ligand to its constitutively active cell surface receptor, TbR-II.…”

Section: Discussionmentioning

confidence: 99%

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Glioblastoma-secreted factors induce IGFBP7 and angiogenesis by modulating Smad-2-dependent TGF-β signaling

et al. 2008

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Section: Tgf-b1 Induces Igfbp7 Expression In Hbecmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Glioblastoma-secreted factors induce IGFBP7 and angiogenesis by modulating Smad-2-dependent TGF-β signaling

et al. 2008

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“…As the TGF␤ concentration is increased, TGF␤ activates only ALK5-mediated pathways to inhibit endothelial cell proliferation and migration. Therefore, by activating ALK1 and ALK5, or ALK5 alone, TGF␤ can both stimulate and inhibit endothelial cell proliferation and migration to balance angiogenesis (Goumans et al, 2002(Goumans et al, , 2003.…”

Section: Discussionmentioning

confidence: 99%

Transforming growth factor‐β stimulates epithelial–mesenchymal transformation in the proepicardium

Olivey

Mundell

Austin

et al. 2005

Developmental Dynamics

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The proepicardium (PE) migrates over the heart and forms the epicardium. A subset of these PE-derived cells undergoes epithelial-mesenchymal transformation (EMT) and gives rise to cardiac fibroblasts and components of the coronary vasculature. We report that transforming growth factor-␤ (TGF␤) 1 and TGF␤2 increase EMT in PE explants as measured by invasion into a collagen gel, loss of cytokeratin expression, and redistribution of ZO1. The type I TGF␤ receptors ALK2 and ALK5 are both expressed in the PE. However, only constitutively active (ca) ALK2 stimulates PE-derived epithelial cell activation, the first step in transformation, whereas caALK5 stimulates neither activation nor transformation in PE explants. Overexpression of Smad6, an inhibitor of ALK2 signaling, inhibits epithelial cell activation, whereas BMP7, a known ligand for ALK2, has no effect. These data demonstrate that TGF␤ stimulates transformation in the PE and suggest that ALK2 partially mediates this effect. Developmental Dynamics 235:50 -59, 2006.

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“…Thus, activation of the Smad1 pathway may contribute to maintaining constitutively elevated expression levels of CCN2 in SSc fibroblasts in vivo and in vitro. TGF␤-dependent activation of the Smad1 pathway was first described in endothelial cells (27). In these cells, TGF␤ signals through a heteromeric receptor complex that includes TGF␤RII, ALK-5, and ALK-1 (28).…”

Section: Smad1 Signaling Pathway In Ssc 2535mentioning

confidence: 99%

Smad1 pathway is activated in systemic sclerosis fibroblasts and is targeted by imatinib mesylate

Pannu¹,

Asano²,

Nakerakanti³

et al. 2008

Arthritis & Rheumatism

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Objective. Activation of Smad1 signaling has recently been implicated in the development of fibrosis. The goal of the present study was to gain further insights into activation of the Smad1 pathway in fibrosis in systemic sclerosis (SSc) and to determine whether this pathway is targeted by the antifibrotic drug imatinib mesylate.Methods. Levels of phosphorylated Smad1 and total Smad1 were examined in SSc and control skin biopsy samples by immunohistochemistry and in cultured fibroblasts by Western blotting. Activity of the CCN2 promoter was examined by a luciferase reporter gene assay. Interactions of Smad1 with the CCN2 promoter were examined by in vitro and in vivo DNA binding assays. Expression of the nonreceptor tyrosine kinase c-Abl and Smad1 was blocked using respective small interfering RNA.Results. Total and phosphorylated Smad1 levels were significantly elevated in SSc skin biopsy samples and in cultured SSc fibroblasts and correlated with elevated CCN2 protein and CCN2 promoter activity. DNA binding assays demonstrated that Smad1 was a direct activator of the CCN2 gene. Small interfering RNA-mediated depletion of Smad1 in SSc fibroblasts normalized the production of CCN2 and collagen. Imatinib mesylate blocked activation of the Smad1 pathway in transforming growth factor ␤-stimulated control fibroblasts and reversed activation of this pathway in SSc fibroblasts. Likewise, blockade of c-Abl abrogated activation of the Smad1 pathway in SSc fibroblasts.Conclusion. Our findings demonstrate that activation of Smad1 signaling occurs in a subset of SSc patients and contributes to persistent activation of SSc fibroblasts. Demonstration that the Smad1/CCN2 pathway is blocked by imatinib mesylate further clarifies the mechanism of the antifibrotic effects of this compound.

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Balancing the activation state of the endothelium via two distinct TGF-beta type I receptors

Cited by 1,016 publications

References 46 publications

Glioblastoma-secreted factors induce IGFBP7 and angiogenesis by modulating Smad-2-dependent TGF-β signaling

Glioblastoma-secreted factors induce IGFBP7 and angiogenesis by modulating Smad-2-dependent TGF-β signaling

Transforming growth factor‐β stimulates epithelial–mesenchymal transformation in the proepicardium

Smad1 pathway is activated in systemic sclerosis fibroblasts and is targeted by imatinib mesylate

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