ENG (endoglin)

2012-01-01   Jose M Lopez-Novoa , Carmelo Bernabeu 





The human ENDOGLIN gene encodes 15 exons.


The human ENDOGLIN gene has a proximal promoter that lacks TATA and CAAT boxes, but contains GC-rich regions that anchor the transcription factor Sp1, which is involved in the basal transcription of ENG. A 3,4-kb transcript of ENG has been described. There are two alternatively spliced isoforms of endoglin, the predominantly expressed long isoform (L-endoglin) and the short isoform (S-endoglin). S-endoglin is generated by intron retention in a process that involves the spliceosome component ASF/SF2. Transforming Growth Factor-beta1 (TGF-β1) via Smad, hypoxia via HIF-1 and vascular injury via KLF6 upregulate ENG transcription.


Atlas Image
Figure 1. Structural representation of Endoglin. Endoglin is a type I membrane protein with a large extracellular domain that contains a zona pelucida (ZP) domain 260 amino acids in the juxtamembrane region and an N-terminal orphan domain with no known homology. Endoglin is a disulfide linked homodimer which form dimers. At least Cys350, located in the linker region spanning residues 338 to 362 between the ZP domain and the orphan domain, together with the juxtamembrane Cys582, are involved in the dimerization of endoglin via disulfide linkages. Consensus motifs to attach N-linked glycans, O-linked glycans and glycosaminoglycans to the extracellular domain have been identified. Both endoglin and betaglycan cytoplasmic domains are phosphorylated at Ser/Thr residues and they contain consensus PDZ-binding motifs present at the carboxyl terminus. The cytoplasmic domain interacts with zyxin, ZRP-1, β-arrestin and Tctex2b proteins. These cytosolic interactions mediate downstream functions, including F-actin dynamics, focal adhesion composition, and protein transport via endocytic vesicles. The cytoplasmic (CYT), transmembrane (TM) and extracellular (EC) domains of the protein are indicated. The scheme is not to scale.


Human endoglin is a type I integral membrane protein with a large extracellular domain (561 amino acids), a single hydrophobic transmembrane domain, and a short cytosolic domain. There are two different alternatively spliced isoforms, L-endoglin and S-endoglin, which have been detected in human and mouse tissues. In humans, S-endoglin and L-endoglin proteins vary from each other in their cytoplasmic tails that contain 14 and 47 amino acids, respectively, with a sequence of only 7 residues being specific for S-endoglin. Because L-endoglin is the predominantly expressed isoform, most of the functional studies are referred to this isoform. Endoglin is a highly glycosylated protein expressed as a 180-kDa disulfide-linked homodimer. The primary structure of endoglin suggests that there are five N-linked glycosylation sites in the NH2-terminal domain and a probable O-glycan domain, which are proximal to the membrane-spanning domain. Human endoglin also contains an Arg-Gly-Asp (RGD) peptide sequence that is known as a cell recognition site for numerous adhesive proteins present in the extracellular matrix (ECM). This RGD motif is also present in orangutan endoglin, but is absent from mouse, porcine, rat and canine endoglin proteins. Structurally, endoglin belongs to the zona pellucida (ZP) family of proteins that share a ZP domain of approximately 260 amino acid residues in their extracellular region. The three-dimensional structure of the extracellular domain of endoglin at 25Å resolution, using single particle electron microscopy, has been elucidated. Endoglin arranges as a dome made of antiparallel-oriented monomers enclosing a cavity at one end. Each subunit comprises one ZP domain in the juxtamembrane region. The NH2-terminal domain does not show any significant homology to any other protein family/domain and thereby has been named an "orphan" domain. This orphan domain is a monomeric structure that is responsible for ligand (BMP9) binding. The cytosolic domain of endoglin is constitutively phosphorylated, and it can be targeted by serine and threonine kinases, including the TGF-beta type I and type II receptors. The endoglin phosphorylation status can influence its subcellular localization and cellular migration. Endoglin cytoplasmic domain contains a consensus postsynaptic density 95/Drosophila disk large/zonula occludens-1 (PDZ)-binding motif (Ser-Ser-Met-Ala) present at the carboxyl terminus that mediates endoglin interaction with several PDZ domain-containing proteins and endoglin phosphorylation of distal threonine residues. In addition to the membrane bound forms of endoglin, the proteolytic action of the metalloproteinase MMP-14 (MT1-MMP) on the full-length membrane-bound endoglin, at the juxtamembrane region of the extracellular domain, can give rise to a soluble form of endoglin.
Atlas Image
Figure 2. Membrane bound and soluble forms of endoglin. Two different membrane bound isoforms are generated by alternative splicing, S-endoglin and L-endoglin. They differ from each other in the length and composition of their cytoplasmic tails. The amino acid sequences from short (S)-endoglin and long (L)-endoglin cytoplasmic tails are indicated. Sequences that differ between L and S isoforms are in blue. The PDZ-binding motif in L-endoglin is underlined. Proteolytic processing of membrane bound endoglin generates soluble endoglin that is upregulated in cancer and preeclampsia. The metalloprotease MMP-14, a major endoglin-shedding protease, acts on the juxtamembrane region leading to the secretion of the large ectodomain of endoglin.


Endoglin is expressed at low levels in resting endothelial cells, but it is highly expressed in vascular endothelial cells at sites of active angiogenesis such as tumor vessels, inflamed tissues, healing wounds, psoriatic skin, inflamed synovial arthritis, upon vascular injury, and during embryogenesis. During the development of the cardiovascular system, endoglin is found on the vascular endothelium of human embryos during all developmental stages from 4 weeks onward, and it is transiently upregulated on cushion tissue mesenchyme during heart septation. Endoglin is also overexpressed in endothelial cells after ischemia and reperfusion in the kidney, hindlimbs and heart. In addition to endothelial cells, endoglin is expressed at high levels in syncytiotrophoblasts. The expression of endoglin is also modulated in other cell types. For example, endoglin is present on monocytes, and it is upregulated during the monocyte-macrophage transition. Also, whereas endoglin expression is low in normal smooth muscle cells, its expression is upregulated in vascular smooth muscle cells of human atherosclerotic plaques. Endoglin is expressed in cardiac fibroblasts and modulates the profibrogenic actions of angiotensin II. Endoglin is also expressed in other tissues undergoing fibrosis such as the kidney and liver.


Endoglin is an auxiliary receptor for the TGF-beta family of proteins. Individual members of this family play key roles in different physiological processes such as development, cellular proliferation, extracellular matrix synthesis, angiogenesis or immune responses and its deregulation may result in tumor development. TGF-β plays a dual and paradoxical role in cancer. On the one hand it acts as a tumor suppressor during the premalignant phase of carcinogenesis, inhibiting cell growth and inducing apoptosis or differentiation. On the other hand, cancer cells that have lost this inhibitory growth response exploit the ability of TGF-β to modulate processes such as cell invasion, angiogenesis, immune regulation, or interactions between tumor cells and their microenvironment that make them more malignant.
Endoglin binds several members of the TGF-beta family including TGF-beta1 and TGF-beta3 (but not TGF-beta2), activin-A, BMP-2, BMP-7, and BMP-9. Among these, BMP-9 is able to bind endoglin in the absence of signaling receptors (types I and II). Endoglin forms a protein complex with the TGF-beta type I (ALK1 and ALK5) and type II receptors and the ligand. Endoglin modulates ligand binding and signaling by an association with ALK1 and ALK5. These type I receptors activate signaling pathways via Smad1, Smad5, and Smad8 (ALK1) or Smad2 and Smad3 (ALK5) to regulate, among others, the proangiogenic inhibitor of DNA binding 1 (Id1) or PAI-1 target genes, respectively. The balance between ALK1 and ALK5 signaling pathways in endothelial cells and vascular smooth muscle cells plays a crucial role during vascular remodeling and angiogenesis, although the exact molecular mechanisms remain to be elucidated. In the ALK1/ALK5 setting, endoglin inhibits the TGF- beta/ALK5/Smad3-mediated cellular responses and enhances ALK5/Smad2-mediated responses. In addition, endoglin promotes TGF-beta1/ALK1 and BMP-9/ALK1 signaling in endothelial cells. Also, endoglin enhances the BMP-7 signal via Smad1/Smad5 pathway in myoblasts. Thus endoglin appears to be a critical modulator of the balance between ALK1 and ALK5 signaling. Although TGF-β is a potent inhibitor of cell proliferation as well as an inducer of apoptosis and extracellular matrix proteins synthesis, endoglin expression may counteract these effects in several cell types. A major role for endoglin in regulating TGF-beta-dependent vascular remodelling and angiogenesis has been demonstrated. Indeed, endoglin knockout mice die at midgestation because of defective angiogenesis. Endoglin also regulates the expression and activity of endothelial nitric oxide synthase, which is involved in angiogenesis and vascular tone. Phosphorylation of the cytoplasmic domain of endoglin influences its subcellular localization, potentially by modulating endoglins interactions with actin adhesive proteins such as zyxin and ZRP-1, thereby modifying the cytoskeleton organization and adhesion properties of endoglin-expressing cells. The conserved distal end of the endoglin cytoplasmic domain interacts with β-arrestin2 and regulates endoglin internalization via endocytic vesicles.
Endoglin is emerging as a modulator of the TGF-β response with important roles in cancer. Endoglin is highly expressed in the tumor-associated vascular endothelium with prognostic significance in selected neoplasias and with potential to be a prime vascular target for antiangiogenic cancer therapy. In addition, the expression of endoglin in tumor cells themselves appears to play an important role in the progression of cancer, influencing cell proliferation, motility, invasiveness and tumorigenicity. The role of endoglin in tumor cells is different from that in the tumor vasculature. Thus, within cancer cells, endoglin acts as a tumor suppressor. By contrast, endoglin shows a proangiogenic role in endothelial cells that facilitates tumor growth of solid vascularized tumors.
Endoglin belongs to the zona pellucida (ZP) family of proteins that share a ZP domain of approximately 260 amino acid residues in their extracellular region. Among the ZP family, endoglin shows the highest homology with betaglycan, a type III TGF-β receptor. Endoglin shares a high degree of amino acid sequence homology with betaglycan in the transmembrane and cytoplasmic domains. Indeed, the cytoplasmic domain of these proteins constitutes the most highly conserved region among homologous members from different mammalian species, as well as between endoglin and betaglycan. Both human endoglin and betaglycan cytoplasmic domains contain consensus PDZ-binding motifs at their carboxyl terminus (SerSerMetAla and SerSerThrAla, respectively).



Mutations in the ENDOGLIN gene result in Hereditary Hemorrhagic Telangiectasia type 1 (HHT1).


No somatic mutations of ENG have been found in human cancer, although a mosaicism of pathogenic mutations in individuals affected of Hereditary Hemorrhagic Telangiectasia type 1 have been described. Also, silencing by both epigenetic inactivation and allelic loss of ENG in esophageal squamous cell carcinoma has been reported.

Implicated in

Entity name
Solid tumours
Endoglin overexpression seems to play a major role in the angiogenesis activation necessary for tumour growth and metastasis. Paradoxically, in tumour cells endoglin seems to play a role in cell migration, invasiveness, and metastasis, acting as a suppressor of invasion and metastasis. Indeed, in prostate cancer, down-regulation of endoglin expression in prostate carcinoma cell lines was found associated with malignant progression, and suppression of endoglin expression enhanced migration and invasion of nontumorigenic prostate cell lines, while overexpression of endoglin had the opposite effect. Moreover, progressive endoglin loss led to progressive increases in the number of circulating prostate carcinoma cells and the formation of metastases, in agreement with the observation that the ENG gene was the only one found to be down-regulated during detachment of metastatic prostate cancer cells.
Endoglin expression is down-regulated in both primary tumors and cell lines of esophageal squamous cell carcinomas (SCCs), and overexpression of endoglin in esophageal SCC cells led to reduced invasiveness and tumorigenicity. The mechanisms for endoglin down-regulation in esophageal tumors include epigenetic silencing by gene methylation and loss of heterozygosity (LOH). In addition, the 9q33-34 region, where the ENG gene maps, is frequently lost in esophageal cancer. The lack of endoglin expression in primary breast cancer correlates with ENG gene methylation and poor clinical outcome, and this loss of endoglin expression cooperates with the activated ErbB2 oncogene to promote migration and invasion of nontumorigenic breast epithelial cells, while endoglin overexpression reduces the metastatic ability of the aggressive MDA-MB-231 carcinoma cell line.
It has been reported that microvascular density (MDV) measurements using anti-endoglin antibodies are more sensitive and have better prognostic value than those using antibodies against other endothelial markers such as CD34, CD31 or vWF. This has been reported for breast carcinoma, and non-small cell lung cancer, esophageal or prostatic adenocarcinoma, early tongue cancer, squamous cell carcinoma of the hypopharynx, head and neck squamous carcinoma, colo-rectal cancer and early oral cancer patients. MVD measured with endoglin antibodies in colorectal mucosa predicted the risk of progressing from dysplasia to carcinoma.
In patients with Barretts esophagus, a pre-tumoral dysplasia, endoglin staining gave a significantly higher MVD in Barretts esophagus with high-grade dysplasia than in Barretts esophagus low-grade dysplasia. Furthermore, in pretreatment biopsies from breast cancer patients, low endoglin expression levels determined by immunohistochemical staining predict a favourable clinical response to chemotherapy. However, the better prognostic value of endoglin than CD34 staining in microvessels has not been confirmed for lymphopoietic tumors, as in patients with multiple myeloma.
As described above, the extracellular domain of membrane-bound endoglin can be proteolytically cleaved, leading to shedding of soluble endoglin (sEng). Increased levels of sEng in plasma have been reported in cancer patients with respect to healthy donors and increased sEng levels correlate with metastasis in breast and colorectal cancers. However, sEng levels were found decreased in patients receiving chemotherapy. This finding reduces the utility of sEng as a prognostic marker for the follow-up of cancer survivors who are treated with chemotherapy. Elevated plasma levels of sEng also predict decreased response and survival to hormone therapy of women with metastatic breast cancer. In prostate cancer, high levels of serum sEng correlate with advanced stages of tumor progression and urinary sEng seems to be also a useful marker for diagnosis. In addition, plasma sEng levels in prostate cancer have a predictive value for metastasis as well as for increased risk recurrence in patients treated with radical prostatectomy and bilateral pelvic lymphadenectomy. High levels of sEng are also present in myeloid malignancies that are characterized by a high cellular proliferation rate, such as acute myeloid leukemia and chronic myeloproliferative disorders. By contrast, there are several reports on gastric, esophageal, and ovarian tumors that failed to find sEng as a valuable marker in the assessment of cancer spread.
Atlas Image
Figure 3. Dual role of endoglin in cancer. Changes in endoglin expression in both the tumor and the vascular endothelium modulate malignancy. A. Increased endoglin expression in endothelial cells correlates with increased tumor growth, probably due to its proangiogenic role. Downregulation of endoglin in endothelial cells is associated with decreased tumor angiogenesis and tumor growth. B. Increased endoglin expression in tumor cells correlates with tumor suppression, whereas downregulation of endoglin leads to tumor progression, allowing migration, invasion and malignancy.
Atlas Image
Figure 4. Endoglin expression in tumor vessels. Endoglin is expressed in endothelial cells and it is highly upregulated during tumor neoangiogenesis. As a marker of neoangiogenesis, endoglin may have diagnostic (tumor imaging), prognostic (anti-endoglin staining of tumor microvessels and levels of soluble endoglin in sera) and therapeutic (anti-endoglin antibodies currently used in clinical trials) value.
Entity name
Hereditary hemorrhagic telangiectasia type 1 (HHT1)
HHT, also called Rendu-Osler-Weber disease, is an autosomal dominant transmitted disease affecting one in 5000 to 8000 people around the world. This pathology is characterized by the presence of epistaxis, skin or mucous telangiectases and less frequently, arteriovenous malformations in the lung, liver or brain. Spontaneous, irregular, recurrent, epistaxis cause anemia and asthenia and they may require a continuous replenishment of iron reserves during the patients life.
HHT1 is caused by mutations in the ENDOGLIN gene (ENG). The three genes identified so far in the several forms of HHT (ENG, ACVRL1, MADH4) encode proteins involved in signaling of the TGF-β family, thus suggesting that HHT is caused by a malfunction of the TGF-β/SMAD-dependent signaling pathway. Pathogenic mutations in ENG result in the absence of endoglin expression at the cell surface, thus leading to haploinsufficiency.
The diagnosis is based on clinical evaluation, following the so called Curaçao criteria. An individual is considered as an HHT patient if she/he has, at least 3 out of the following 4 criteria: (i) spontaneous and recurrent epistaxis; (ii) multiple telangiectases at characteristic locations (lips, oral cavity, fingers, nose); (iii) visceral lesions (gastrointestinal telangiectases, pulmonary, hepatic, cerebral or spinal arteriovenous malformations-AVMs); or (iv) a first degree relative with HHT. The penetrance of the disease increases with age and at 45 years is about 90%. The establishment of an early molecular diagnosis is very useful. Two loci, ENG and ACVRL1, are involved by mutation in more than 90% of HHT cases, giving rise to HHT1 and HHT2 forms of the disease, respectively.
Entity name
Preeclampsia is a systemic syndrome manifested primarily by hypertension and proteinuria after 20 weeks of gestation. It presents mainly in the second half of pregnancy, affecting approximately 3% to 5% of pregnancies worldwide. There is no specific cure, being delivery of the placenta the only definitive treatment. At present, preeclampsia is the leading cause of maternal mortality, preterm birth, and consequent neonatal morbidity and mortality.
A soluble form of endoglin (sEng) has been implicated in the pathogenesis of preeclampsia. During normal pregnancy, the placenta undergoes massive changes in the vascularization status, with specific angiogenesis and vasculogenesis processes that require a precise balance between pro-angiogenic and anti-angiogenic factors. In preeclampsia several anti-angiogenic factors, such as soluble VEGF receptor Flt1 (sFlt1) and sEng are produced by the placenta in higher than amounts leading to an imbalance of pro-angiogenic and anti-angiogenic factors that is thought to be involved in abnormal placental vascularization and disease onset. sEng is a truncated form of endoglin containing only the extracellular domain. This soluble endoglin form is able to bind and antagonize the proangiogenic effects of transforming growth factor-β family members.
Serum levels of sEng currently serve as reliable biomarkers for the clinical diagnosis and prediction of preeclampsia. Maternal levels of sEng before the onset of preeclampsia are significantly higher than in women with normal gestations. Reproducible increases of sEng in the mid- to late-second trimester onward have been observed. Changes in levels of angiogenic factors with advancing gestation may be more predictive of preeclampsia than individual levels at any single time point.
Changes in sEng and other pro- or anti-angiogenic proteins can be useful in establishing the diagnosis of preeclampsia in challenging, ambiguous, or atypical cases. For example, these biomarkers can discriminate preeclampsia from other causes of hypertension in pregnancy, as in patients with pre-existing renal disease, other causes of gestational thrombocytopenia such as idiopathic thrombocytopenic purpura, or in cases of gestational hypertension or proteinuria before 20 weeks gestation. The degree of increase in circulating angiogenic biomarkers appears to correlate with severity of preeclampsia and complications, such as placental abruption and intrauterine growth restriction. sEng and other soluble factors might be also useful for risk stratification.


Pubmed IDLast YearTitleAuthors
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189743882008S-endoglin expression is induced in senescent endothelial cells and contributes to vascular pathology.Blanco FJ et al
157024802005Interaction and functional interplay between endoglin and ALK-1, two components of the endothelial transforming growth factor-beta receptor complex.Blanco FJ et al
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152742932004CD105 inhibits transforming growth factor-beta-Smad3 signalling.Guo B et al
204241162010Matrix metalloproteinase-14 (MT1-MMP)-mediated endoglin shedding inhibits tumor angiogenesis.Hawinkels LJ et al
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Other Information

Locus ID:

NCBI: 2022
MIM: 131195
HGNC: 3349
Ensembl: ENSG00000106991


dbSNP: 2022
ClinVar: 2022
TCGA: ENSG00000106991


Gene IDTranscript IDUniprot

Expression (GTEx)


Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
167517672006Soluble endoglin contributes to the pathogenesis of preeclampsia.458
181752412008A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate.187
122282472002Endoglin expression is regulated by transcriptional cooperation between the hypoxia and transforming growth factor-beta pathways.89
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
217374542011Soluble endoglin specifically binds bone morphogenetic proteins 9 and 10 via its orphan domain, inhibits blood vessel formation, and suppresses tumor growth.76
215468422011Hereditary hemorrhagic telangiectasia: an overview of diagnosis, management, and pathogenesis.69
219491302005Relative antithrombotic effect of soluble GPVI dimer compared with anti-GPVI antibodies in mice.68
120153082002Extracellular and cytoplasmic domains of endoglin interact with the transforming growth factor-beta receptors I and II.64
157024802005Interaction and functional interplay between endoglin and ALK-1, two components of the endothelial transforming growth factor-beta receptor complex.62
192116122009A new nonsense mutation of SMAD8 associated with pulmonary arterial hypertension.62


Jose M Lopez-Novoa ; Carmelo Bernabeu

ENG (endoglin)

Atlas Genet Cytogenet Oncol Haematol. 2012-01-01

Online version: http://atlasgeneticsoncology.org/gene/40452/eng-(endoglin)