Elevated expression of endoglin, a component of the TGF‐β‐receptor complex, correlates with proliferation of tumor endothelial cells

Miller, Daniel W.; Graulich, Wolff; Karges, Bernadett; Stahl, Sabine; Ernst, M.; Ramaswamy, Annette; Sedlacek, H.‐Harald; Müller, Rolf; Adamkiewicz, Jürgen

doi:10.1002/(sici)1097-0215(19990517)81:4<568::aid-ijc11>3.3.co;2-o

Cited by 25 publications

(32 citation statements)

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“…Multiple lines of evidence suggested that endoglin plays a crucial role in angiogenesis (1, 2), cancer (12,17), and preeclampsia (13). In this paper we have systematically studied the structurefunction relationships and interaction of the endoglin ECD with its ligands and receptors.…”

Section: Discussionmentioning

confidence: 99%

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Soluble Endoglin Specifically Binds Bone Morphogenetic Proteins 9 and 10 via Its Orphan Domain, Inhibits Blood Vessel Formation, and Suppresses Tumor Growth

Castonguay¹,

Werner²,

Matthews

et al. 2011

Journal of Biological Chemistry

196

229

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Endoglin (CD105), a transmembrane protein of the transforming growth factor ␤ superfamily, plays a crucial role in angiogenesis. Mutations in endoglin result in the vascular defect known as hereditary hemorrhagic telangiectasia (HHT1). The soluble form of endoglin was suggested to contribute to the pathogenesis of preeclampsia. To obtain further insight into its function, we cloned, expressed, purified, and characterized the extracellular domain (ECD) of mouse and human endoglin fused to an immunoglobulin Fc domain. We found that mouse and human endoglin ECD-Fc bound directly, specifically, and with high affinity to bone morphogenetic proteins 9 and 10 (BMP9 and BMP10) in surface plasmon resonance (Biacore) and cell-based assays. We performed a function mapping analysis of the different domains of endoglin by examining their contributions to the selectivity and biological activity of the protein. Endoglin (CD105) is a homodimeric glycosylated cell-surface protein of 180 kDa previously identified as a co-receptor belonging to the TGF␤ superfamily (1). Several lines of evidence support an important role of endoglin in cardiovascular development and vascular remodeling (2). Loss-of-function mutations in endoglin are implicated in the vascular disorder hereditary hemorrhagic telangiectasia type 1 (HHT1), 3 which is a bleeding disorder characterized by arteriovenous malformations in the brain, lungs, and liver and is attributed to haploinsufficiency (3-5). Homozygous endoglin knock-out mice die during early gestation due to the lack of development of normal mature blood vessels (6). Adult endoglin heterozygous mice (7-8) or mice with a conditional mutation in the endoglin gene (9) exhibited similar angiogenic abnormalities and were used as animal models for HHT1. Mutations in the endoglin gene found in numerous HHT1 patients are localized most exclusively in the extracellular domain (4). The specific role of endoglin in the vascular dysplasia observed in HHT patients is not known, but it is likely to be related to the role of TGF␤ family signaling in angiogenesis (2, 10). Interestingly, another form of HHT, known as HHT2, which is also characterized by the presence of telangiectases as well as arteriovenous malformations in brain, lungs and liver, results from the loss of TGF␤ type I receptor ALK1 (11), which suggests an interrelatedness between endoglin and ALK1 and possibly involvement of the same ligand(s) in the mechanism of action of both molecules.A soluble form of endoglin has been observed in the serum of patients with different types of solid malignancies (12) and of pregnant women suffering from preeclampsia, a disease leading to vascular permeability (13), hypertension, and placental abruption (14). This soluble form, which reportedly results from partial shedding of the membrane-bound form of endoglin by the matrix metalloproteinase 14 (MT1-MMP) (15), a phenomenon also observed for the other type III receptor betaglycan (16), has been proposed to act as a scavenger or trap for circulating TGF␤ family liga...

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Section: Discussionmentioning

confidence: 99%

“…Despite strong evidence highlighting the role of endoglin in angiogenesis, cancer (12,17), and preeclampsia, the molecular mechanism of its action remains unclear as the data are somewhat contradictory. Originally, it was demonstrated that endoglin binds to TGF␤1 and TGF␤3 but fails to bind to TGF␤2 in cross-linking experiments performed on HUVEC…”

mentioning

confidence: 99%

Soluble Endoglin Specifically Binds Bone Morphogenetic Proteins 9 and 10 via Its Orphan Domain, Inhibits Blood Vessel Formation, and Suppresses Tumor Growth

Castonguay¹,

Werner²,

Matthews

et al. 2011

Journal of Biological Chemistry

196

229

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“…Compared with vascular endothelial cells in normal tissues, a stronger staining for endoglin was detected in vascular endothelial cells in tissues undergoing active angiogenesis, such as in regenerating and inflamed tissues or tumours (Bodey et al, 1998a;Bodey et al, 1998b;Miller et al, 1999;Seon et al, 1997;Wang et al, 1994). Increased endoglin expression was also observed in ECs of microvessels from pathological skin lesions and in established atherosclerotic lesions (Burrows et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Defective paracrine signalling by TGFβ in yolk sac vasculature of endoglin mutant mice: a paradigm for hereditary haemorrhagic telangiectasia

et al. 2004

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Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder in humans that is characterised by multisystemic vascular dyplasia and recurrent haemorrhage. Germline mutations in one of two different genes,endoglin or ALK1 can cause HHT. Both are members of the transforming growth factor (TGF) β receptor family of proteins, and are expressed primarily on the surface of endothelial cells (ECs). Mice that lack endoglin or activin receptor like kinase (ALK) 1 die at mid-gestation as a result of defects in the yolk sac vasculature. Here, we have analyzed TGFβsignalling in yolk sacs from endoglin knockout mice and from mice with endothelial-specific deletion of the TGFβ type II receptor (TβRII)or ALK5. We show that TGFβ/ALK5 signalling from endothelial cells to adjacent mesothelial cells is defective in these mice, as evidenced by reduced phosphorylation of Smad2. This results in the failure of vascular smooth muscle cells to differentiate and associate with endothelial cells so that blood vessels remain fragile and become dilated. Phosphorylation of Smad2 and differentiation of smooth muscle can be rescued by culture of the yolk sac with exogenous TGFβ1. Our data show that disruption of TGFβsignalling in vascular endothelial cells results in reduced availability of TGFβ1 protein to promote recruitment and differentiation of smooth muscle cells, and provide a possible explanation for weak vessel walls associated with HHT.

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“…Therefore, the present study may help in designing new therapeutic strategies to treat HHT1 by increasing expression of the normal endoglin allele. On the other hand, endoglin has been found to be up-regulated in the tumor neovasculature (45)(46)(47)(48)(49)77), and several anti-endoglin antibodymediated immunotherapies have been shown to suppress the growth of human tumor xenografts in severe combined immunodeficient (SCID) mice (48,78,79). Thus, the results from the endoglin regulation studies shown here might be useful to optimize the expression and recognition of endoglin as a marker of the tumor vasculature in the anti-angiogenic therapy of cancer.…”

Section: Hif-1␣ Smad3 and Sp1 Form A Multiprotein Complex On The Enmentioning

confidence: 99%

Endoglin Expression Is Regulated by Transcriptional Cooperation between the Hypoxia and Transforming Growth Factor-β Pathways

Sánchez-Elsner¹,

Botella²,

Velasco

et al. 2002

Journal of Biological Chemistry

289

214

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Endoglin is a transforming growth factor-␤ (TGF-␤) co-receptor expressed mainly on endothelial cells and involved in cardiovascular development, angiogenesis, and vascular remodeling. This is illustrated by the fact that mutations in the endoglin gene give rise to hereditary hemorrhagic telangiectasia type 1, a dominant vascular disease with clinical manifestations that originate by a mechanism of haploinsufficiency. Thus, studies on the regulated expression of endoglin are crucial to devising therapeutic strategies for hereditary hemorrhagic telangiectasia type 1. Endoglin is highly expressed in the neovasculature associated with hypoxia such as ischemic tissues and tumors, but the molecular mechanism of this up-regulation is unknown. Here, we have investigated the possible regulation of endoglin expression by hypoxia. Surface protein, transcript, and promoter activity levels of endoglin were found to be up-regulated by hypoxia, indicating that the regulation takes place at the transcriptional level. A hypoxia-responsive element downstream of the main transcription start site of the endoglin gene was functionally characterized. Whereas hypoxia alone moderately stimulated endoglin transcription, addition of TGF-␤ under hypoxic conditions resulted in transcriptional cooperation between both signaling pathways, leading to marked stimulation of endoglin expression. Because basal endoglin transcription is sustained by Sp1, and TGF-␤ and hypoxia signaling pathways are mediated by Smad proteins and hypoxia-inducible factor-1 (HIF-1), respectively, the involvement of these transcription factors was analyzed. Functional and co-immunoprecipitation experiments demonstrated the existence of a multiprotein complex (Sp1⅐Smad3⅐HIF-1) on the endoglin promoter, mediating the cooperation between the hypoxia and TGF-␤ pathways. Within this multiprotein complex, Smad3 appears to function not only as a coactivator factor, but also as an adaptor between HIF-1 and Sp1. We propose that basal endoglin transcription (highly dependent on Sp1) may switch from a constitutive to an inducible state through Sp1 interaction with HIF-1 and Smad transcription factors, induced by hypoxia and TGF-␤, respectively.

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Elevated expression of endoglin, a component of the TGF‐β‐receptor complex, correlates with proliferation of tumor endothelial cells

Cited by 25 publications

References 0 publications

Soluble Endoglin Specifically Binds Bone Morphogenetic Proteins 9 and 10 via Its Orphan Domain, Inhibits Blood Vessel Formation, and Suppresses Tumor Growth

Soluble Endoglin Specifically Binds Bone Morphogenetic Proteins 9 and 10 via Its Orphan Domain, Inhibits Blood Vessel Formation, and Suppresses Tumor Growth

Defective paracrine signalling by TGFβ in yolk sac vasculature of endoglin mutant mice: a paradigm for hereditary haemorrhagic telangiectasia

Endoglin Expression Is Regulated by Transcriptional Cooperation between the Hypoxia and Transforming Growth Factor-β Pathways

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