Endoglin Differentially Modulates Antagonistic Transforming Growth Factor-β1 and BMP-7 Signaling

Scherner, O.; Meurer, Steffen K.; Tihaa, Lidia; Gressner, A. M.; Weiskirchen, Ralf

doi:10.1074/jbc.m611062200

Cited by 93 publications

(84 citation statements)

References 62 publications

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“…TGF‐β signaling is the major pathway promoting EndMT 5, 11, 12. Although endoglin functions as a coreceptor of TGF‐β signaling, this molecule has been shown to inhibit some pathways downstream from TGF‐β receptors 20, 21. Indeed, Anderberg et al recently showed that deficiency in endoglin resulted in tumor vasculature that displayed hallmarks of EndMT 34.…”

Section: Discussionmentioning

confidence: 99%

“…Inhibiting endoglin by gene knockdown in ECs inhibits TGF‐β/ALK1 signaling, and potentiates TGF‐β/ALK5 signaling,16, 17, 18 resulting in reduced proliferation 17, 19. In contrary, endoglin overexpression suppresses TGF‐β/ALK5 signaling 20, 21. Mouse embryos lacking ALK1, ALK5, TGF‐β type 2 receptor, or endoglin die during midgestation because of impaired vascular development,12 further highlighting the significance of TGF‐β signaling in the vascular system.…”

Section: Introductionmentioning

confidence: 99%

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miR‐342‐5p Is a Notch Downstream Molecule and Regulates Multiple Angiogenic Pathways Including Notch, Vascular Endothelial Growth Factor and Transforming Growth Factor β Signaling

Yan

Cao

Liang

et al. 2016

JAHA

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BackgroundEndothelial cells (ECs) form blood vessels through angiogenesis that is regulated by coordination of vascular endothelial growth factor (VEGF), Notch, transforming growth factor β, and other signals, but the detailed molecular mechanisms remain unclear.Methods and ResultsSmall RNA sequencing initially identified miR‐342‐5p as a novel downstream molecule of Notch signaling in ECs. Reporter assay, quantitative reverse transcription polymerase chain reaction and Western blot analysis indicated that miR‐342‐5p targeted endoglin and modulated transforming growth factor β signaling by repressing SMAD1/5 phosphorylation in ECs. Transfection of miR‐342‐5p inhibited EC proliferation and lumen formation and reduced angiogenesis in vitro and in vivo, as assayed by using a fibrin beads–based sprouting assay, mouse aortic ring culture, and intravitreal injection of miR‐342‐5p agomir in P3 pups. Moreover, miR‐342‐5p promoted the migration of ECs, accompanied by reduced endothelial markers and increased mesenchymal markers, indicative of increased endothelial–mesenchymal transition. Transfection of endoglin at least partially reversed endothelial–mesenchymal transition induced by miR‐342‐5p. The expression of miR‐342‐5p was upregulated by transforming growth factor β, and inhibition of miR‐342‐5p attenuated the inhibitory effects of transforming growth factor β on lumen formation and sprouting by ECs. In addition, VEGF repressed miR‐342‐5p expression, and transfection of miR‐342‐5p repressed VEGFR2 and VEGFR3 expression and VEGF‐triggered Akt phosphorylation in ECs. miR‐342‐5p repressed angiogenesis in a laser‐induced choroidal neovascularization model in mice, highlighting its clinical potential.ConclusionsmiR‐342‐5p acts as a multifunctional angiogenic repressor mediating the effects and interaction among angiogenic pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

miR‐342‐5p Is a Notch Downstream Molecule and Regulates Multiple Angiogenic Pathways Including Notch, Vascular Endothelial Growth Factor and Transforming Growth Factor β Signaling

Yan

Cao

Liang

et al. 2016

JAHA

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“…In addition, endoglin has been shown to interact with zyxin-related protein 1 resulting in a dramatic change in the structure of the actin cytoskeleton and the localization of zyxinrelated protein 1 (Sanz-Rodriguez et al, 2004). Second, in addition to TGF-b1, endoglin can bind, in association with different TGF-b superfamily receptors, to BMP2, BMP7, BMP9, activin A and TGF-b3 (Cheifetz et al, 1992;Barbara et al, 1999;Scharpfenecker et al, 2007), and has been reported to have a functional role in modulating responses to BMP2 (Ishibashi et al, 2010) and BMP7 (Scherner et al, 2007) in periodontal ligament cells and myoblasts, respectively. Although there are no published reports of endoglin modulating the response to other TGF-b family ligands in epithelial cells, it will be of interest in the future to determine whether the TGF-b1-independent functions of endoglin expressed on tumor cells may be mediated by binding to alternate ligands and/ or other TGF-b superfamily receptors.…”

Section: Discussionmentioning

confidence: 99%

Endoglin expression in breast tumor cells suppresses invasion and metastasis and correlates with improved clinical outcome

et al. 2010

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Tumor growth factor-b (TGF-b) signaling in cancer has been implicated in growth suppression of early lesions and enhancing tumor cell invasion and metastasis. However, the cellular mechanisms that determine this signaling output in individual tumors are still largely unknown. In endothelial cells, TGF-b signaling is modulated by the TGF-b coreceptor endoglin (CD105). Here we demonstrate that endoglin is expressed in a subset of invasive breast cancers and cell lines and is subject to epigenetic silencing by gene methylation. Endoglin downregulation in non-tumorigenic MCF10A breast cells leads to the formation of abnormal acini in 3D culture, but does not promote cell migration or transformation. In contrast, in the presence of activated ErbB2, endoglin downregulation in MCF10A cells leads to enhanced invasion into a 3D matrix. Consistent with these data, ectopic expression of endoglin in MDA-MB-231 cells blocks TGF-b-enhanced cell motility and invasion and reduces lung colonization in an in vivo metastasis model. Unlike endothelial cells, endoglin does not modulate Smadmediated TGF-b signaling in breast cells but attenuates the cytoskeletal remodeling to impair cell migration and invasion. Importantly, in a large cohort of invasive breast cancers, lack of endoglin expression in the tumor cell compartment correlates with ENG gene methylation and poor clinical outcome.

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“…The transcription factors Snai1 and Id1 have also been implicated in the development of fibrosis. 30,31 Snai1 transcripts increased in fibrotic kidney compared with control kidney and were expressed by pericytes but increased in myofibroblasts compared with pericytes ( Figure 6, B and C). Id1 transcripts were down-regulated in diseased whole kidney compared with healthy kidney, but Id1 transcripts were increased in myofibroblasts compared with pericytes.…”

Section: Snai1 and Id1 Transcription Factors Implicated In Fibrosismentioning

confidence: 94%

Pericytes and Perivascular Fibroblasts Are the Primary Source of Collagen-Producing Cells in Obstructive Fibrosis of the Kidney

Lin

Kisseleva

Brenner

et al. 2008

The American Journal of Pathology

767

856

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Understanding the origin of scar-producing myofibroblasts is vital in discerning the mechanisms by which fibrosis develops in response to inflammatory injury. Using a transgenic reporter mouse model expressing enhanced green fluorescent protein (GFP) under the regulation of the collagen type I, ␣ 1 (coll1a1) promoter and enhancers, we examined the origins of coll1a1-producing cells in the kidney. Here we show that in normal kidney, both podocytes and pericytes generate coll1a1 transcripts as detected by enhanced GFP, and that in fibrotic kidney, coll1a1-GFP expression accurately identifies myofibroblasts. To determine the contribution of circulating immune cells directly to scar production, wild-type mice, chimeric with bone marrow from coll-GFP mice, underwent ureteral obstruction to induce fibrosis. Histological examination of kidneys from these mice showed recruitment of small numbers of fibrocytes to the fibrotic kidney, but these fibrocytes made no significant contribution to interstitial fibrosis. Instead, using kinetic modeling and time course microscopy, we identified coll1a1-GFP-expressing pericytes as the major source of interstitial myofibroblasts in the fibrotic kidney. Our studies suggest that either vascular injury or vascular factors are the most likely triggers for pericyte migration and differentiation into myofibroblasts. Therefore, our results serve to refocus fibrosis research to injury of the vasculature rather than injury to the epithelium.

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Endoglin Differentially Modulates Antagonistic Transforming Growth Factor-β1 and BMP-7 Signaling

Cited by 93 publications

References 62 publications

miR‐342‐5p Is a Notch Downstream Molecule and Regulates Multiple Angiogenic Pathways Including Notch, Vascular Endothelial Growth Factor and Transforming Growth Factor β Signaling

miR‐342‐5p Is a Notch Downstream Molecule and Regulates Multiple Angiogenic Pathways Including Notch, Vascular Endothelial Growth Factor and Transforming Growth Factor β Signaling

Endoglin expression in breast tumor cells suppresses invasion and metastasis and correlates with improved clinical outcome

Pericytes and Perivascular Fibroblasts Are the Primary Source of Collagen-Producing Cells in Obstructive Fibrosis of the Kidney

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