Endoglin

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Endoglin
Identifiers
Symbols ENG ; END; HHT1; ORW1
External IDs OMIM131195 MGI95392 HomoloGene92 GeneCards: ENG Gene
RNA expression pattern
PBB GE ENG 201809 s at tn.png
PBB GE ENG 201808 s at tn.png
More reference expression data
Orthologs
Species Human Mouse
Entrez 2022 13805
Ensembl ENSG00000106991 ENSMUSG00000026814
UniProt P17813 Q63961
RefSeq (mRNA) NM_000118 NM_001146348
RefSeq (protein) NP_000109 NP_001139820
Location (UCSC) Chr 9:
130.58 – 130.62 Mb
Chr 2:
32.65 – 32.68 Mb
PubMed search [1] [2]

Endoglin is a type I membrane glycoprotein located on cell surfaces and is part of the TGF beta receptor complex. It is also commonly referred to as CD105, END, FLJ41744, HHT1, ORW and ORW1.[1] It has a crucial role in angiogenesis, therefore, making it an important protein for tumor growth, survival and metastasis of cancer cells to other locations in the body.

Gene and expression[edit]

The human endoglin gene is located on human chromosome 9 with location of the cytogenic band at 9q34.11.[2][3] Endoglin glycoprotein is encoded by 39,757 bp and translates into 658 amino acids.[1]

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.[1] The expression of the vascular system begins at about 4 weeks and continues after that.[1] 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.[1][4]

Structure[edit]

The glycoprotein consists of a homodimer of 180 kDA with disulfide links.[5] It is the cysteines 350 and 582 that are involved with the disulfide linkage in these homodimers.[1] 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.[5] The 260 amino acid domain closest to the extracellular membrane is referred to as zona pelucida (ZP).[1] The outermost extracellular domain is termed as the orphan domain and it is the part that binds ligands such as BMP9.[1] There are two isoforms of endoglin created by alternative splicing: the long isoform (L-endoglin) and the short isoform (S-endoglin).[6] 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.[1] It has been found on endothelial cells in all tissues,[5] activated macrophages, activated monocytes, lymphoblasts fibroblasts, and smooth muscle cells. Endoglin was first identified using monoclonal antibody (mAb) 44G4 but more mAbs against endoglin have been discovered, giving more ways to identify it in tissues.[7]

It is suggested that endoglin has 5 potential N-linked glycosylation sites in the N-terminal domain and an O-glycan domain near the membrane domain that is rich in Serine and Threonine.[5] The cytoplasmic tail contains a PDZ-binding motif that allows it to bind to PDZ containing proteins and interact with them.[8] 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).[5] This RGD sequence on endoglin is the first RGD sequence identified on endothelial tissue.[5]

Interactions[edit]

Endoglin has been shown to interact with high affinity to TGF beta receptor 3[2][9] and TGF beta receptor 1,[8][10] and with lower affinity to TGF beta receptor 2.[2] It has high sequence similarity to another TGF beta binding protein, beta-glycan, which was one of the first cues that indicated that endoglin is a TGF beta binding proteins.[11] 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.[11]

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.[8] 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.[8] 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.[8] Unlike TGF beta receptor I which can only bind the cytoplasmic tail when it's kinase domain is inactive, TGF beta receptor II can bind endoglin with an inactive and active kinase domain.[8] 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.[8] 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.[8]

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.[1] 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.[12]

Function[edit]

Endoglin has been found to be an auxiliary receptor for the TGF-beta receptor complex.[8] It thus is involved in modulating a response to the binding of TGF-beta1, TGF-beta3, activin-A, BMP-2, and BMP-7. Beside TGF-beta signaling endoglin may have other functions. It has been postulated that endoglin is involved in the cytoskeletal organization affecting cell morphology and migration.[13] 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.[13]

Clinical significance[edit]

In humans endoglin may be involved in the autosomal dominant disorder known as hereditary hemorrhagic telangiectasia (HHT) type 1.[5] HHT is actually the first human disease linked to the TGF beta receptor complex.[14] 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[edit]

The mutations that lead to this disorder are:[14]

  1. a Cytosine (C) to Guanine (G) substitution which converts a tyrosine to stop codon
  2. a 39 base pair deletion
  3. 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 preeclampsia.[15]

Role in cancer[edit]

The important role that endoglin plays in angiogenesis[16] 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 metastisis.[17][18] 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.[17] Also, it has been suggested that endoglin can be used for tumor imaging and prognosis.[17]

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.[1] 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.[19] 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.[1] 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 helpo of endoglin), immune system evasion, and their ECM composition, allowing them to become malignant.[1]

Prostate cancer and endoglin expression[edit]

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.[20] 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.[20] 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.[20] 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.[20] This study emphasizes the importance of endoglin in TGF-beta signaling pathways in other cell types other than endothelial cells.

See also[edit]

References[edit]

  1. ^ a b c d e f g h i j k l m Lopez-Novoa JM, Bernabeu C (January 2012). "ENG (endoglin)". Atlas of Genetics and Cytogenetics in Oncology and Haematology. 
  2. ^ a b c "ENG Gene - | EGLN Protein | EGLN Antibody". GeneCards. 
  3. ^ Fernández-Ruiz E, St-Jacques S, Bellón T, Letarte M, Bernabéu C (1993). "Assignment of the human endoglin gene (END) to 9q34-->qter". Cytogenet. Cell Genet. 64 (3–4): 204–7. doi:10.1159/000133576. PMID 8404038. 
  4. ^ Rodríguez-Peña A, Prieto M, Duwel A, Rivas JV, Eleno N, Pérez-Barriocanal F, Arévalo M, Smith JD, Vary CP, Bernabeu C, López-Novoa JM (2001). "Up-regulation of endoglin, a TGF-beta-binding protein, in rats with experimental renal fibrosis induced by renal mass reduction". Nephrol. Dial. Transplant. 16 Suppl 1: 34–9. doi:10.1093/ndt/16.suppl_1.34. PMID 11369818. 
  5. ^ 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. Archived from the original on 2006-09-29. Retrieved 2006-08-28. 
  6. ^ Velasco, S; et al (15 March 2008). "L- and S-endoglin differentially modulate TGFbeta1 signaling mediated by ALK1 and ALK5 in L6E9 myoblasts.". J Cell Sci 15 (121(Pt 6)): 913–9. doi:10.1242/jcs.023283. PMID 18303046. 
  7. ^ Gougos A, St Jacques S, Greaves A, O'Connell PJ, d'Apice AJ, Bühring HJ, Bernabeu C, van Mourik JA, Letarte M (January 1992). "Identification of distinct epitopes of endoglin, an RGD-containing glycoprotein of endothelial cells, leukemic cells, and syncytiotrophoblasts". Int. Immunol. 4 (1): 83–92. doi:10.1093/intimm/4.1.83. PMID 1371694. 
  8. ^ a b c d e f g h i Guerrero-Esteo M, Sanchez-Elsner T, Letamendia A, Bernabeu C (August 2002). "Extracellular and cytoplasmic domains of endoglin interact with the transforming growth factor-beta receptors I and II". J. Biol. Chem. 277 (32): 29197–209. doi:10.1074/jbc.M111991200. PMID 12015308. 
  9. ^ Altomonte M, Montagner R, Fonsatti E, Colizzi F, Cattarossi I, Brasoveanu LI, Nicotra MR, Cattelan A, Natali PG, Maio M (November 1996). "Expression and structural features of endoglin (CD105), a transforming growth factor beta1 and beta3 binding protein, in human melanoma". Br. J. Cancer 74 (10): 1586–91. doi:10.1038/bjc.1996.593. PMC 2074853. PMID 8932339. 
  10. ^ Barbara NP, Wrana JL, Letarte M (January 1999). "Endoglin is an accessory protein that interacts with the signaling receptor complex of multiple members of the transforming growth factor-beta superfamily". J. Biol. Chem. 274 (2): 584–94. doi:10.1074/jbc.274.2.584. PMID 9872992. 
  11. ^ a b Cheifetz S, Bellón T, Calés C, Vera S, Bernabeu C, Massagué J, Letarte M (September 1992). "Endoglin is a component of the transforming growth factor-beta receptor system in human endothelial cells". J. Biol. Chem. 267 (27): 19027–30. PMID 1326540. 
  12. ^ Guerrero-Esteo M, Lastres P, Letamendía A, Pérez-Alvarez MJ, Langa C, López LA, Fabra A, García-Pardo A, Vera S, Letarte M, Bernabéu C (September 1999). "Endoglin overexpression modulates cellular morphology, migration, and adhesion of mouse fibroblasts". Eur. J. Cell Biol. 78 (9): 614–23. doi:10.1016/S0171-9335(99)80046-6. PMID 10535303. 
  13. ^ a b Sanz-Rodriguez F, Guerrero-Esteo M, Botella LM, Banville D, Vary CP, Bernabéu C (July 2004). "Endoglin regulates cytoskeletal organization through binding to ZRP-1, a member of the Lim family of proteins". J. Biol. Chem. 279 (31): 32858–68. doi:10.1074/jbc.M400843200. PMID 15148318. 
  14. ^ a b McAllister KA, Grogg KM, Johnson DW, Gallione CJ, Baldwin MA, Jackson CE, Helmbold EA, Markel DS, McKinnon WC, Murrell J (December 1994). "Endoglin, a TGF-beta binding protein of endothelial cells, is the gene for hereditary haemorrhagic telangiectasia type 1". Nat. Genet. 8 (4): 345–51. doi:10.1038/ng1294-345. PMID 7894484. 
  15. ^ Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, Bdolah Y, Lim KH, Yuan HT, Libermann TA, Stillman IE, Roberts D, D'Amore PA, Epstein FH, Sellke FW, Romero R, Sukhatme VP, Letarte M, Karumanchi SA (June 2006). "Soluble endoglin contributes to the pathogenesis of preeclampsia". Nat. Med. 12 (6): 642–9. doi:10.1038/nm1429. PMID 16751767. 
  16. ^ Li DY, Sorensen LK, Brooke BS, Urness LD, Davis EC, Taylor DG, Boak BB, Wendel DP (May 1999). "Defective angiogenesis in mice lacking endoglin". Science 284 (5419): 1534–7. doi:10.1126/science.284.5419.1534. PMID 10348742. 
  17. ^ a b c Duff SE, Li C, Garland JM, Kumar S (June 2003). "CD105 is important for angiogenesis: evidence and potential applications". FASEB J. 17 (9): 984–92. doi:10.1096/fj.02-0634rev. PMID 12773481. 
  18. ^ Takahashi N, Haba A, Matsuno F, Seon BK (November 2001). "Antiangiogenic therapy of established tumors in human skin/severe combined immunodeficiency mouse chimeras by anti-endoglin (CD105) monoclonal antibodies, and synergy between anti-endoglin antibody and cyclophosphamide". Cancer Res. 61 (21): 7846–54. PMID 11691802. 
  19. ^ Li C, Guo B, Wilson PB, Stewart A, Byrne G, Bundred N, Kumar S (March 2000). "Plasma levels of soluble CD105 correlate with metastasis in patients with breast cancer". Int. J. Cancer 89 (2): 122–6. doi:10.1002/(SICI)1097-0215(20000320)89:2<122::AID-IJC4>3.0.CO;2-M. PMID 10754488. 
  20. ^ a b c d O'Connor, John C.; Mary C. Farach-Carson, Charles J. Schneider and Daniel D. Carson (2007). "Coculture with Prostate Cancer Cells Alters Endoglin Expression and Attenuates Transforming Growth Factor-beta Signaling in Reactive Bone Marrow Stromal Cells". Mol Cancer Res 5 (6): 585–603. doi:10.1158/1541-7786.mcr-06-0408. 

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