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.

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.

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.