CD105

Official Full Name

endoglin

Organism

Homo sapiens

GeneID

2022

Background

This gene encodes a homodimeric transmembrane protein which is a major glycoprotein of the vascular endothelium. This protein is a component of the transforming growth factor beta receptor complex and it binds to the beta1 and beta3 peptides with high affinity. Mutations in this gene cause hereditary hemorrhagic telangiectasia, also known as Osler-Rendu-Weber syndrome 1, an autosomal dominant multisystemic vascular dysplasia. This gene may also be involved in preeclampsia and several types of cancer. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2013]

Synonyms

END; HHT1; ORW1;

Protein Sequence

MDRGTLPLAVALLLASCSLSPTSLAETVHCDLQPVGPERGEVTYTTSQVSKGCVAQAPNAILEVHVLFLEFPTGPSQLELTLQASKQNGTWPREVLLVLSVNSSVFLHLQALGIPLHLAYNSSLVTFQEPPGVNTTELPSFPKTQILEWAAERGPITSAAELNDPQSILLRLGQAQGSLSFCMLEASQDMGRTLEWRPRTPALVRGCHLEGVAGHKEAHILRVLPGHSAGPRTVTVKVELSCAPGDLDAVLILQGPPYVSWLIDANHNMQIWTTGEYSFKIFPEKNIRGFKLPDTPQGLLGEARMLNASIVASFVELPLASIVSLHASSCGGRLQTSPAPIQTTPPKDTCSPELLMSLIQTKCADDAMTLVLKKELVAHLKCTITGLTFWDPSCEAEDRGDKFVLRSAYSSCGMQVSASMISNEAVVNILSSSSPQRKKVHCLNMDSLSFQLGLYLSPHFLQASNTIEPGQQSFVQVRVSPSVSEFLLQLDSCHLDLGPEGGTVELIQGRAAKGNCVSLLSPSPEGDPRFSFLLHFYTVPIPKTGTLSCTVALRPKTGSQDQEVHRTVFMRLNIISPDLSGCTSKGLVLPAVLGITFGAFLIGALLTAALWYIYSHTRSPSKREPVVAVAAPASSESSSTNHSIGSTQSTPCSTSSMA

Open

Disease

Angiosarcoma, Brain cancer, Breast cancer, Fallopian tube cancer, Gynecologic cancer, Kaposi sarcoma, Liver cancer, Lung cancer, Non-small-cell lung cancer, Ovarian cancer, Peritoneal cancer, Renal cell carcinoma, Retinopathy

Approved Drug

Clinical Trial Drug

2 +

Discontinued Drug

Protein
Clones

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Detailed Information

The ENG gene encodes endoglin (CD105), a homodimeric transmembrane glycoprotein predominantly expressed on vascular endothelial cells. Binding TGF-β1, TGF-β2, and additional TGF-β superfamily members including Activin A, BMP2, BMP7, and BMP9, CD105 is an auxiliary receptor within the TGF-β receptor complex. It is essential for the control of angiogenesis, cellular migration, and vascular remodeling. Vascular abnormalities define the disorder known as autosomal dominant hereditary hemorrhagic telangiectasia type 1 (HHT1), which has mutations in ENG. Furthermore, a major therapeutic target is CD105 as it is implicated in various types of cancer, hypertension, and preeclampsia.

Structure and Isoforms of CD105

Two main types of CD105 are soluble CD105 (sEng) and membrane-bound CD105. Cleavage driven by the metalloprotein MT1-MMP generates soluble CD105. Pathological states like preeclampsia, atherosclerosis, and hypertension show high sEng levels, suggesting its possible involvement in thrombosis and other vascular problems.

CD105 is structurally a 180-kDa homodimer joined by disulfide linkages. It comprises a transmembrane segment, a C-terminal zona pellucida (ZP) domain, an N-terminal orphan domain (OR), and a short intracellular tail. Features preserved disulfide linkages, the OR domain creates a β-helical shape necessary for its binding characteristics. By use of conserved residues including Q270 and I271, CD105's OR1 subdomain interacts especially with BMP9 to promote high-affinity ligand binding. Underlining their functional relevance, mutations in these residues reduce BMP9 binding and downstream signaling.

CD105 in TGF-β and BMP Signaling

Within the TGF-β signaling system, CD105 is a co-receptor that modulates activity by two main TGF-β type I receptors, ALK1 and ALK5. While ALK5 activates Smad2/3, ALK1 engages Smad1/5/8 and these receptors activate different Smad pathways. Angiogenesis and vascular remodeling in endothelial cells depend on a balance between ALK1 and ALK5 signaling. Overexpression of CD105 in endothelial cells highlights its protective function against hypoxia-induced mortality and TGF-β1-induced endothelial cell death by counteracting its antiproliferative properties. Through the BMPR2 receptor complex, CD105 also enables BMP9/10 signaling, therefore controlling vascular stability and development.

Figure 1 illustrates endoglin-mediated signaling pathways in endothelial cells, highlighting their roles in regulating proliferation, apoptosis, and cell migration through interactions with TGF-β and BMP signaling components. Figure 1. Schematic representation of endoglin-mediated signaling in endothelial cells (ECs).( Litwiniuk-Kosmala M, et al., 2023)

Role of CD105 in Diseases

CD105 is implicated in several diseases, either as a membrane-bound receptor or in its soluble form. Key conditions include:

1. Hereditary Hemorrhagic Telangiectasia (HHT1): HHT1 is characterized by frequent epistaxis, mucocutaneous telangiectasias, and arteriovenous malformations in organs like the brain, lungs, and liver. ENG mutations disrupt vascular integrity, contributing to the pathogenesis of HHT1.

2. Preeclampsia and Cardiovascular Disorders: Elevated sEng levels are associated with the severity of preeclampsia and complications like HELLP syndrome. sEng disrupts endothelial function, contributing to vascular complications in pregnancy-related conditions.

3. Cancer: CD105 expression correlates with tumor angiogenesis and metastasis, making it a potential marker for cancer progression. It serves as a promising therapeutic target for anti-angiogenic therapies in oncology.

4. Hypertension and Atherosclerosis: Soluble CD105 levels are elevated in hypertension and atherosclerosis, suggesting its involvement in endothelial dysfunction and vascular inflammation.

5. Other Conditions: Mutations or altered expression of CD105 have been linked to systemic sclerosis, pulmonary arterial hypertension (PAH), and other vascular diseases.

Biological and Clinical Significance of CD105

CD105 plays a vital role in endothelial cell proliferation, migration, and differentiation. Its expression is controlled throughout cardiovascular development; deletion of it causes embryonic death from cardiovascular abnormalities. Under stress or damage, especially in adult tissues, CD105 is crucial for vascular integrity and remodeling. Emphasizing CD105's adaptability in controlling different biological processes, its role also spans additional cell types including mesenchymal stem cells, trophoblasts, and immune cells.

Therapeutic Implications

CD105's involvement in vascular pathologies makes it a critical target for therapeutic intervention. Under research for their ability to stop tumor angiogenesis are anti-CD105 treatments include small compounds and monoclonal antibodies. Moreover, its part in cardiovascular diseases and preeclampsia emphasizes the necessity of focused strategies to control sEng levels.

Conclusion

CD105 (ENG gene) is a pivotal glycoprotein with diverse roles in vascular biology and disease. Its relevance in angiogenesis, vascular remodeling, and endothelial cell function is highlighted by its structural elements, binding selectivity, and signaling pathways. From inherited vascular problems to cancer and cardiovascular difficulties, dysregulation of CD105 fuels many illnesses. New treatments aiming at CD105's pathways may be developed from advances in knowledge of its molecular processes.

References:

Oladejo M, Nguyen HM, Wood L. CD105 in the progression and therapy of renal cell carcinoma. Cancer Lett. 2023;570:216327.
Sur D, Havasi A, Lungulescu CV, et al. Endoglin (CD105) as a putative prognostic biomarker for colorectal cancer: a systematic review. Med Pharm Rep. 2022;95(3):251-259.
Litwiniuk-Kosmala M, Makuszewska M, Czesak M. Endoglin in head and neck neoplasms. Front Med (Lausanne). 2023 Feb 10;10:1115212.

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