Endoglin

The human endoglin gene is located on human chromosome 9 with location of the cytogenic band at 9q34.11. Endoglin glycoprotein is encoded by 39,757 bp and translates into 658 amino acids. == Structure ==

The glycoprotein consists of a homodimer of 180 kDA stabilized by intermolecular disulfide bonds. It has a large extracellular domain of about 561 amino acids, a hydrophobic transmembrane domain and a short cytoplasmic tail domain composed of 45 amino acids. The outermost extracellular region is termed as the orphan domain (or, more correctly, orphan region (OR)) and it is the part that binds ligands such as BMP-9. There are two isoforms of endoglin created by alternative splicing: the long isoform (L-endoglin) and the short isoform (S-endoglin). However, the L-isoform is expressed to a greater extent than the S-isoform. A soluble form of endoglin can be produced by the proteolytic cleaving action of metalloproteinase MMP-14 in the extracellular domain near the membrane. It is suggested that endoglin has 5 potential N-linked glycosylation sites in the N-terminal domain (of which N102 was experimentally observed in the crystal structure of the orphan region ()) and an O-glycan domain near the membrane domain that is rich in Serine and Threonine. The ZP module (residues P338-G581), whose ZP-N and ZP-C moieties (residues T349-L443 and N444-S576, respectively) are closely packed against each other, mediates the homodimerization of endoglin by forming an intermolecular disulfide bond that involves cysteine 516. Together with a second intermolecular disulfide, involving cysteine 582, this generates a molecular clamp that secures the ligand via interaction of two copies of OR1 with the knuckle regions of homodimeric BMP-9. In addition to rationalizing a large number of HHT1 mutations, the crystal structure of endoglin shows that the epitope of anti-ENG monoclonal antibody TRC105 overlaps with the binding site for BMP-9. == Interactions ==

Endoglin has been shown to interact with high affinity to TGF beta receptor 3 and TGF beta receptor 1, and with lower affinity to TGF beta receptor 2. It has high sequence similarity to another TGF beta binding protein, betaglycan, which was one of the first cues that indicated that endoglin is a TGF beta binding proteins. However, it has been shown that TGF beta binds with high affinity to only a small amount of the available endoglin, which suggests that there is another factor regulating this binding. == Function ==

Endoglin has been found to be an auxiliary receptor for the TGF-beta receptor complex. Endoglin has a role in the development of the cardiovascular system and in vascular remodeling. Its expression is regulated during heart development . Experimental mice without the endoglin gene die due to cardiovascular abnormalities. == Clinical significance ==

In humans endoglin may be involved in the autosomal dominant disorder known as hereditary hemorrhagic telangiectasia (HHT) type 1. This condition leads to frequent nose bleeds, telangiectases on skin and mucosa and may cause arteriovenous malformations in different organs including brain, lung, and liver. Mutations causing HHT Some mutations that lead to this disorder are: Role in cancer The role of endoglin plays in angiogenesis and the modulation of TGF beta receptor signaling, which mediates cellular localization, cellular migration, cellular morphology, cell proliferation, cluster formation, etc., makes endoglin an important player in tumor growth and metastasis. Being able to target and efficiently reduce or halt neoangiogenesis in tumors would prevent metastasis of primary cancer cells into other areas of the body. The TGF beta receptor-endoglin complex relay contradicting signals from TGF beta as well. TGF beta can act as a tumor suppressor in the premalignant stage of the benign neoplasm by inhibiting its growth and inducing apoptosis. Also, the downstream TGF-beta/bone morphogenic protein (BMP) signaling pathway, which includes Smad1 and Smad2/3, were attenuated along with Smad-dependent gene transcription. == See also ==