ENG - endoglin | Elisa - Clia - Antibody - Protein

Background

Endoglin, encoded by the ENG gene, is a key transmembrane glycoprotein in the TGF-β (transforming growth factor-beta) receptor complex, with significant roles in vascular development and endothelial cell biology. Also known as CD105, endoglin is crucial in angiogenesis and vascular homeostasis. It is prominently expressed on the surface of endothelial cells, especially in active angiogenic areas, as well as in other cell types like smooth muscle cells and some immune cells. Endoglin regulates cellular responses to TGF-β signaling, particularly within endothelial cells, which is essential for their proliferation, migration, and survival.

Mutations in the ENG gene are linked to hereditary hemorrhagic telangiectasia type 1 (HHT1), a genetic disorder characterized by abnormal blood vessel formation, causing arteriovenous malformations, frequent nosebleeds, and other bleeding-related symptoms. Endoglin also plays a prominent role in cancer biology, where it can act as a biomarker for tumor angiogenesis. Its dual role in promoting normal vascular health and contributing to disease makes it an essential molecule in vascular biology research.

Protein Structure

Endoglin is a type I transmembrane protein approximately 633 amino acids in length, weighing around 90 kDa. Structurally, endoglin is composed of several domains that contribute to its function and interactions within the TGF-β receptor complex.

Extracellular Domain:

• The extracellular domain of endoglin is large and glycosylated, playing a central role in ligand binding and receptor interactions. It contains multiple N-linked glycosylation sites, which contribute to the protein’s stability and ligand-binding affinity.
• This domain also includes a Zona Pellucida (ZP) domain, a protein-protein interaction motif commonly involved in receptor complex formation. In endoglin, the ZP domain facilitates interactions with other TGF-β receptors (particularly TGF-β receptor I and II), enabling endoglin to modulate TGF-β signaling.
• The extracellular region enables endoglin to interact with TGF-β1 and TGF-β3, acting as an accessory receptor in the TGF-β signaling pathway. This interaction is crucial for modulating endothelial cell responses to TGF-β, such as proliferation and differentiation.

Transmembrane Domain:

• The transmembrane domain of endoglin is a hydrophobic α-helical segment that anchors the protein within the cell membrane. This domain supports the structural stability of endoglin and its positioning as part of the TGF-β receptor complex on the cell surface.

Intracellular Domain:

• The intracellular domain of endoglin is relatively short but plays a crucial role in signal transduction. It contains specific phosphorylation sites, which enable it to interact with intracellular signaling molecules.
• Although not directly involved in ligand binding, the intracellular domain interacts with components of the cytoskeleton, particularly zyxin and other signaling adaptor proteins, to regulate downstream signaling pathways.
• Through these interactions, the intracellular domain can modulate cellular responses to TGF-β, which include changes in gene expression, cellular adhesion, and structural organization within endothelial cells.

Classification and Subtypes

Endoglin (CD105) belongs to the TGF-β receptor family, specifically acting as an accessory receptor in this pathway. Within this family, endoglin does not possess intrinsic kinase activity but modulates TGF-β receptor function through its role as a co-receptor.

There are two main isoforms of endoglin due to alternative splicing:

Long Isoform (L-Endoglin):

• This is the predominant isoform found in endothelial cells and is responsible for promoting endothelial cell proliferation and angiogenesis.

Short Isoform (S-Endoglin):

• This variant lacks parts of the cytoplasmic tail and has distinct signaling properties, sometimes acting as an inhibitor of TGF-β signaling. S-Endoglin can modulate the effects of L-Endoglin, particularly in tissues where tightly regulated angiogenesis and TGF-β signaling are essential.

Function and Biological Significance

Angiogenesis:

• Endoglin is a primary regulator of angiogenesis, supporting endothelial cell proliferation, migration, and new blood vessel formation. It does so by modulating TGF-β signaling, balancing between TGF-β1 and TGF-β3 responses. While TGF-β1 tends to inhibit cell proliferation, TGF-β3, when engaged through endoglin, promotes endothelial proliferation, facilitating new blood vessel formation.
• Its role in angiogenesis is particularly prominent during wound healing and tissue repair, where endoglin expression increases to support vascular remodeling.

Vascular Integrity and Homeostasis:

• Endoglin plays a key role in maintaining vascular integrity by regulating endothelial cell adhesion and structural organization. By modulating the TGF-β pathway, endoglin helps maintain a balance between vascular stability and flexibility.
• It supports the formation of tight junctions between endothelial cells, promoting vessel stability and preventing abnormal blood leakage. This function is particularly vital in maintaining the integrity of small capillaries and preventing arteriovenous malformations.

TGF-β Signaling Modulation:

• Endoglin serves as a co-receptor within the TGF-β receptor complex, regulating how cells respond to TGF-β ligands. This function is vital in endothelial cells, where TGF-β influences cellular behavior, including migration, adhesion, and survival.
• By selectively interacting with TGF-β1 and TGF-β3, endoglin can promote either inhibitory or stimulatory effects on endothelial cell proliferation, making it an essential regulator in vascular biology.

Role in Immune Modulation:

• Endoglin expression is also observed in some immune cells, such as macrophages and certain T cells. In these cells, endoglin modulates the immune response, particularly during inflammation. Its expression may increase in response to inflammatory cytokines, indicating a role in mediating immune cell interactions with endothelial cells during inflammation.

Clinical Issues

Hereditary Hemorrhagic Telangiectasia Type 1 (HHT1):

• Mutations in the ENG gene cause HHT1, a genetic disorder characterized by vascular dysplasia. Patients with HHT1 exhibit fragile blood vessels that are prone to bleeding, resulting in symptoms such as recurrent nosebleeds, telangiectasias (small, dilated blood vessels), and arteriovenous malformations (AVMs) in organs like the lungs, liver, and brain.
• In HHT1, mutated endoglin disrupts TGF-β signaling, impairing proper blood vessel formation and leading to abnormal vascular structures. HHT1 is a significant clinical concern due to its potential for serious complications, including stroke, hemorrhage, and organ failure from AVMs.

Cancer:

• Endoglin expression is elevated in the endothelium of tumor-associated blood vessels due to its angiogenic role. This property has made endoglin a promising biomarker for tumor angiogenesis in cancers such as breast, colorectal, and prostate cancers. Elevated endoglin levels correlate with increased vascularization within tumors, supporting cancer growth and metastasis.
• Therapies targeting endoglin aim to reduce tumor angiogenesis by blocking the pro-angiogenic effects of TGF-β signaling. Anti-endoglin antibodies are being investigated for their potential to inhibit tumor blood vessel formation, thereby restricting tumor growth and metastasis.

Cardiovascular Diseases:

• Endoglin expression has been implicated in cardiovascular diseases, including hypertension, atherosclerosis, and pulmonary arterial hypertension (PAH). Abnormal endoglin expression in endothelial cells can lead to impaired vascular responses to TGF-β, resulting in endothelial dysfunction, a critical factor in cardiovascular disease progression.

Inflammatory Diseases:

• Endoglin’s role in immune cell regulation also implicates it in inflammatory conditions. For example, increased endoglin expression on activated macrophages has been associated with chronic inflammatory diseases such as rheumatoid arthritis and psoriasis.

Summary

Endoglin (ENG), a transmembrane glycoprotein part of the TGF-β receptor complex, is essential in angiogenesis, vascular stability, and endothelial cell function. Structurally, it includes a glycosylated extracellular domain, a transmembrane domain, and a short intracellular domain with phosphorylation sites, allowing it to interact with both the extracellular matrix and intracellular signaling components. Endoglin exists in two isoforms, L-Endoglin and S-Endoglin, which differentially modulate TGF-β signaling.

Endoglin’s primary function is in promoting endothelial cell proliferation and angiogenesis, especially during tissue repair and development. It is also crucial in maintaining vascular integrity and regulating immune responses. Clinically, mutations in ENG cause HHT1, leading to fragile blood vessels and abnormal vessel formation, increasing the risk of hemorrhage and AVMs. Endoglin’s role in angiogenesis makes it a potential therapeutic target in cancer and a biomarker for tumor vascularization. Additionally, endoglin is involved in cardiovascular and inflammatory diseases, making it an important focus for vascular disease research.