Endoglin
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Location (UCSC) | Chr 9: 127.82 – 127.85 Mb | Chr 2: 32.54 – 32.57 Mb | |||||||
PubMed search | [3] | [4] |
View/Edit Human | View/Edit Mouse |
Endoglin (ENG) is a type I membrane
Gene and expression
The human endoglin gene is located on human chromosome 9 with location of the cytogenic band at 9q34.11.[6][7] Endoglin glycoprotein is encoded by 39,757 bp and translates into 658 amino acids.[5]
The expression of the endoglin gene is usually low in resting endothelial cells. This, however, changes once neoangiogenesis begins and endothelial cells become active in places like tumor vessels, inflamed tissues, skin with psoriasis, vascular injury and during embryogenesis.[5] The expression of the vascular system begins at about 4 weeks and continues after that.[5] Other cells in which endoglin is expressed consist of monocytes, especially those transitioning into macrophages, low expression in normal smooth muscle cells, high expression vascular smooth muscle cells and in kidney and liver tissues undergoing fibrosis.[5][8]
Structure
The glycoprotein consists of a homo
There are two isoforms of endoglin created by alternative splicing: the long isoform (L-endoglin) and the short isoform (S-endoglin).[14] 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.[5] It has been found on
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 (PDB: 5I04)) and an O-glycan domain near the membrane domain that is rich in Serine and Threonine.[9] The cytoplasmic tail contains a PDZ-binding motif that allows it to bind to PDZ containing proteins and interact with them.[16] It contains an Arginine-Glycine-Aspartic Acid (RGD) tripeptide sequence that enables cellular adhesion, through the binding of integrins or other RGD binding receptors that are present in the extracellular matrix (ECM).[9] This RGD sequence on endoglin is the first RGD sequence identified on endothelial tissue.[9]
X-ray crystallographic structures of human endoglin (
Interactions
Endoglin has been shown to
Endoglin itself doesn't bind the TGF beta ligands, but is present with the TGF beta receptors when the ligand is bound, indicating an important role for endoglin.[16] The full length endoglin will bind to the TGF beta receptor complex whether TGF beta is bound or not, but the truncated forms of endoglin have more specific binding.[16] The amino acid (aa) region 437–558 in the extracellular domain of endoglin will bind to TGF beta receptor II. TGF beta receptor I binds to the 437-588 aa region and to the aa region between 437 and the N-terminus.[16] Unlike TGF beta receptor I which can only bind the cytoplasmic tail when its kinase domain is inactive, TGF beta receptor II can bind endoglin with an inactive and active kinase domain.[16] The kinase is active when it is phosphorylated. Furthermore, TGF beta receptor I will dissociate from endoglin soon after it phosphorylates its cytoplasmic tail, leaving TGF beta receptor I inactive.[16] Endoglin is constituitively phosphorylated at the serine and threonine residues in the cytoplasmic domain. The high interaction between endoglin's cytoplasmic and extracellular tail with the TGF beta receptor complexes indicates an important role for endoglin in the modulation of the TGF beta responses, such as cellular localization and cellular migration.[16]
Endoglin can also mediate F-actin dynamics, focal adhesions, microtubular structures, endocytic vesicular transport through its interaction with zyxin, ZRP-1, beta-arrestin and Tctex2beta, LK1, ALK5, TGF beta receptor II, and GIPC.[5] In one study with mouse fibroblasts, the overexpression of endoglin resulted in a reduction of some ECM components, decreased cellular migration, a change in cellular morphology and intercellular cluster formation.[20]
Function
Endoglin has been found to be an auxiliary receptor for the TGF-beta receptor complex.
Clinical significance
In humans endoglin may be involved in the
Mutations causing HHT
Some mutations that lead to this disorder are:[22]
- a Cytosine (C) to Guanine (G) substitution which converts a tyrosine to stop codon
- a 39 base pair deletion
- a 2 base pair deletion which creates an early stop codon
Endoglin levels have been found to be elevated in pregnant women who subsequently develop
Role in cancer
The role of endoglin plays in angiogenesis[24] 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.[25][26] 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.[25] Also, it has been suggested that endoglin can be used for tumor imaging and prognosis.[25]
The role of endoglin in cancer can be contradicting at times since it is needed for neoangiogenesis in tumors, which is needed for tumor growth and survival, yet the reduction in expression of endoglin has in many cancers correlated with a negative outcome of that cancer.[5] In breast cancer, for example, the reduction of the full form of endoglin, and the increase of the soluble form of endoglin correlate with metastasis of cancer cells.[27] 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.[5] However, once the cancer cells have gone through the Hallmarks of Cancer and lost inhibitory growth responses, TGF beta mediates cell invasion, angiogenesis (with the help of endoglin), immune system evasion, and their ECM composition, allowing them to become malignant.[5]
Prostate cancer and endoglin expression
It has been shown that endoglin expression and TGF-beta secretion are attenuated in bone marrow stromal cells when they are cocultured with prostate cancer cells.[28] 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.[28] Another result in this study was that both Smad1/5/8-dependent inhibitor of DNA binding 1 expression and Smad2/3-dependent plasminogen activator inhibitor I had a reduction in expression and cell proliferation.[28] Ultimately, the cocultured prostate cancer cells altered the TGF-beta signaling in the bone stromal cells, which suggests this modulation is a mechanism of prostate cancer metastases facilitating their growth and survival in the reactive bone stroma.[28] This study emphasizes the importance of endoglin in TGF-beta signaling pathways in other cell types other than endothelial cells.
As a drug target
TRC105 is an experimental
See also
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000106991 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000026814 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ a b c d e f g h i j Lopez-Novoa JM, Bernabeu C (January 2012). "ENG (endoglin)". Atlas of Genetics and Cytogenetics in Oncology and Haematology.
- ^ a b c "ENG Gene - | EGLN Protein | EGLN Antibody". GeneCards.
- PMID 8404038.
- PMID 11369818.
- ^ a b c d e f g Michelle Letarte. "Structure and function of endoglin, a component of the TGF- beta receptor, etc". University of Toronto. Retrieved 2006-08-28.[dead link]
- S2CID 38778076.
- PMID 29853186.
- PMID 21737454.
- ^
- PMID 18303046.
- PMID 1371694.
- ^ PMID 12015308.
- PMID 8932339.
- PMID 9872992.
- ^ PMID 1326540.
- PMID 10535303.
- ^ PMID 15148318.
- ^ S2CID 21623340.
- S2CID 23471093.
- PMID 10348742.
- ^ S2CID 16282675.
- PMID 11691802.
- S2CID 24538739.
- ^ PMID 17579118.
- ^ "TRC105 Gets Orphan Drug Status for Soft-Tissue Sarcoma. Feb 2016". cancernetwork.com. 2016-02-04. Retrieved 8 January 2019.
External links
- GeneReviews/NCBI/NIH/UW entry on Hereditary Hemorrhagic Telangiectasia
- CD105+Antigen at the U.S. National Library of Medicine Medical Subject Headings (MeSH)