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Endoglin involvement in integrin-mediated cell adhesion as a putative pathogenic mechanism in hereditary hemorrhagic telangiectasia type 1 (HHT1).

Rossi E, Lopez-Novoa JM, Bernabeu C - Front Genet (2015)

Bottom Line: Because of the absence of effective treatments for HHT symptoms, studies aimed at identifying novel biological functions of endoglin which could serve as therapeutic targets of the disease are needed.Endoglin displays, within its zona pellucida domain, an RGD motif, which is a prototypic sequence involved in integrin-based interactions with other proteins.In addition, functional, as well as protein and gene expression analysis have shown that ectopic endoglin represses the synthesis of several members of the integrin family and modulates integrin-mediated cell adhesions.

View Article: PubMed Central - PubMed

Affiliation: INSERM, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, UMR-S 1140 Paris, France.

ABSTRACT
Mutations in the endoglin gene (ENG) are responsible for ∼50% of all cases with hereditary hemorrhagic telangiectasia (HHT). Because of the absence of effective treatments for HHT symptoms, studies aimed at identifying novel biological functions of endoglin which could serve as therapeutic targets of the disease are needed. Endoglin is an endothelial membrane protein, whose most studied function has been its role as an auxiliary receptor in the TGF-β receptor complex. However, several lines of evidence suggest the involvement of endoglin in TGF-β-independent functions. Endoglin displays, within its zona pellucida domain, an RGD motif, which is a prototypic sequence involved in integrin-based interactions with other proteins. Indeed, we have recently described a novel role for endothelial endoglin in leukocyte trafficking and extravasation via its interaction with leukocyte integrins. In addition, functional, as well as protein and gene expression analysis have shown that ectopic endoglin represses the synthesis of several members of the integrin family and modulates integrin-mediated cell adhesions. This review focuses on the tight link between endoglin and integrins and how the role of endothelial endoglin in integrin-dependent cell adhesion processes can provide a better understanding of the pathogenic mechanisms leading to vascular lesions in endoglin haploinsufficient HHT1 patients.

No MeSH data available.


Related in: MedlinePlus

Structure and cell adhesion function of endoglin. (A) Structural representation of endoglin. Endoglin is a type I membrane protein with a large extracellular (EC) domain that contains a zona pellucida (ZP) domain in the juxtamembrane region and an NH2-terminal orphan domain. The ZP domain encodes an Arg-Gly-Asp (RGD) tripeptide that is involved in integrin binding, whereas de orphan domain is involved in binding to members of the TGF-β superfamily. Endoglin forms dimers and the corresponding monomers are disulphide linked (S-S). The cytoplasmic (CYT) domain can be phosphorylated (P) at Ser/Thr/Tyr residues. The transmembrane (TM), and EC domains of the protein are indicated. The scheme is not to scale. (B) Role of endothelial endoglin in leukocyte adhesion and transmigration. A schematic diagram shows a hypothetical model for leukocyte transmigration through the vessel endothelium. In an inflammatory focus, different soluble factors are released, including the chemokine CXCL12, leading to activation and endoglin-dependent extravasation of leukocytes. The transmigration process of the leukocyte involves the binding of CXCL12 to its receptor CXCR4, which in turn activates β1 integrins. Once activated, β1 integrin binds to the RGD motif of endoglin present on the endothelial cell surface, allowing the extravasation and migration of leukocytes to the inflammatory site.
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Figure 1: Structure and cell adhesion function of endoglin. (A) Structural representation of endoglin. Endoglin is a type I membrane protein with a large extracellular (EC) domain that contains a zona pellucida (ZP) domain in the juxtamembrane region and an NH2-terminal orphan domain. The ZP domain encodes an Arg-Gly-Asp (RGD) tripeptide that is involved in integrin binding, whereas de orphan domain is involved in binding to members of the TGF-β superfamily. Endoglin forms dimers and the corresponding monomers are disulphide linked (S-S). The cytoplasmic (CYT) domain can be phosphorylated (P) at Ser/Thr/Tyr residues. The transmembrane (TM), and EC domains of the protein are indicated. The scheme is not to scale. (B) Role of endothelial endoglin in leukocyte adhesion and transmigration. A schematic diagram shows a hypothetical model for leukocyte transmigration through the vessel endothelium. In an inflammatory focus, different soluble factors are released, including the chemokine CXCL12, leading to activation and endoglin-dependent extravasation of leukocytes. The transmigration process of the leukocyte involves the binding of CXCL12 to its receptor CXCR4, which in turn activates β1 integrins. Once activated, β1 integrin binds to the RGD motif of endoglin present on the endothelial cell surface, allowing the extravasation and migration of leukocytes to the inflammatory site.

Mentions: Human endoglin is a type I integral membrane protein with a large extracellular (EC) domain (561 amino acids), a single hydrophobic transmembrane (TM) domain, and a short cytosolic tail (Figure 1A). Endoglin is a glycosylated protein expressed as a 180-kDa disulfide-linked homodimer in endothelial cells (Gougos and Letarte, 1990). The predominant expression of endoglin in endothelial cells suggests that these are the target cells in HHT, where endoglin haploinsufficiency reveals its pathogenicity. Structurally, endoglin belongs to the zona pellucida (ZP) family of proteins that share a juxtamembrane ZP domain of 260 amino acid residues in their EC region (Llorca et al., 2007). This ZP domain encodes an RGD tripeptide that is a prototypic member of a family of motifs involved in integrin-based interactions with EC matrix and certain cell surface proteins (Takada et al., 2007). Recently, it has been demonstrated that endothelial endoglin interacts with leukocyte integrin α5β1 via its RGD motif, suggesting a regulatory role for endoglin in transendothelial leukocyte trafficking (Rossi et al., 2013). The RGD motif is present in endoglin from primates, while functionally related RGD-like motifs are found in endoglin from rodents and other mammals, stressing the physiological importance and high conservation of this motif (Gougos and Letarte, 1990; Rossi et al., 2013). Next to the ZP domain is the orphan domain, which is located in the NH2-terminus of the protein (Llorca et al., 2007). The orphan domain is involved in the binding to members of the TGF-β superfamily (activin, TGF-β, and BMP families) in accordance with the role of endoglin as an auxiliary TGF-β receptor (Alt et al., 2012). Thus, endoglin modulates the endothelial response to TGF-β-related ligands, including cell proliferation, apoptosis, vascular remodeling, angiogenesis, wound healing, or fibrosis (López-Novoa and Bernabeu, 2010). Of note, most of ENG mutations associated with HHT1 map to the EC domain, suggesting that the biological function of this domain is critical for the disease (Bernabeu et al., 2010). The cytosolic domain of endoglin is phosphorylated at Ser/Thr/Tyr residues and it can be targeted by serine/threonine (Lastres et al., 1994) and tyrosine (Pan et al., 2014) kinases. It has been shown that the endoglin phosphorylation status can influence its subcellular localization (Koleva et al., 2006) and degradation (Pan et al., 2014). The cytoplasmic domain of endoglin also regulates actin cytoskeletal organization, microtubule-based transport machinery, and cell migration (Ray et al., 2010; Romero et al., 2010), through its specific binding to different cytosolic proteins (López-Novoa and Bernabeu, 2010).


Endoglin involvement in integrin-mediated cell adhesion as a putative pathogenic mechanism in hereditary hemorrhagic telangiectasia type 1 (HHT1).

Rossi E, Lopez-Novoa JM, Bernabeu C - Front Genet (2015)

Structure and cell adhesion function of endoglin. (A) Structural representation of endoglin. Endoglin is a type I membrane protein with a large extracellular (EC) domain that contains a zona pellucida (ZP) domain in the juxtamembrane region and an NH2-terminal orphan domain. The ZP domain encodes an Arg-Gly-Asp (RGD) tripeptide that is involved in integrin binding, whereas de orphan domain is involved in binding to members of the TGF-β superfamily. Endoglin forms dimers and the corresponding monomers are disulphide linked (S-S). The cytoplasmic (CYT) domain can be phosphorylated (P) at Ser/Thr/Tyr residues. The transmembrane (TM), and EC domains of the protein are indicated. The scheme is not to scale. (B) Role of endothelial endoglin in leukocyte adhesion and transmigration. A schematic diagram shows a hypothetical model for leukocyte transmigration through the vessel endothelium. In an inflammatory focus, different soluble factors are released, including the chemokine CXCL12, leading to activation and endoglin-dependent extravasation of leukocytes. The transmigration process of the leukocyte involves the binding of CXCL12 to its receptor CXCR4, which in turn activates β1 integrins. Once activated, β1 integrin binds to the RGD motif of endoglin present on the endothelial cell surface, allowing the extravasation and migration of leukocytes to the inflammatory site.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4285797&req=5

Figure 1: Structure and cell adhesion function of endoglin. (A) Structural representation of endoglin. Endoglin is a type I membrane protein with a large extracellular (EC) domain that contains a zona pellucida (ZP) domain in the juxtamembrane region and an NH2-terminal orphan domain. The ZP domain encodes an Arg-Gly-Asp (RGD) tripeptide that is involved in integrin binding, whereas de orphan domain is involved in binding to members of the TGF-β superfamily. Endoglin forms dimers and the corresponding monomers are disulphide linked (S-S). The cytoplasmic (CYT) domain can be phosphorylated (P) at Ser/Thr/Tyr residues. The transmembrane (TM), and EC domains of the protein are indicated. The scheme is not to scale. (B) Role of endothelial endoglin in leukocyte adhesion and transmigration. A schematic diagram shows a hypothetical model for leukocyte transmigration through the vessel endothelium. In an inflammatory focus, different soluble factors are released, including the chemokine CXCL12, leading to activation and endoglin-dependent extravasation of leukocytes. The transmigration process of the leukocyte involves the binding of CXCL12 to its receptor CXCR4, which in turn activates β1 integrins. Once activated, β1 integrin binds to the RGD motif of endoglin present on the endothelial cell surface, allowing the extravasation and migration of leukocytes to the inflammatory site.
Mentions: Human endoglin is a type I integral membrane protein with a large extracellular (EC) domain (561 amino acids), a single hydrophobic transmembrane (TM) domain, and a short cytosolic tail (Figure 1A). Endoglin is a glycosylated protein expressed as a 180-kDa disulfide-linked homodimer in endothelial cells (Gougos and Letarte, 1990). The predominant expression of endoglin in endothelial cells suggests that these are the target cells in HHT, where endoglin haploinsufficiency reveals its pathogenicity. Structurally, endoglin belongs to the zona pellucida (ZP) family of proteins that share a juxtamembrane ZP domain of 260 amino acid residues in their EC region (Llorca et al., 2007). This ZP domain encodes an RGD tripeptide that is a prototypic member of a family of motifs involved in integrin-based interactions with EC matrix and certain cell surface proteins (Takada et al., 2007). Recently, it has been demonstrated that endothelial endoglin interacts with leukocyte integrin α5β1 via its RGD motif, suggesting a regulatory role for endoglin in transendothelial leukocyte trafficking (Rossi et al., 2013). The RGD motif is present in endoglin from primates, while functionally related RGD-like motifs are found in endoglin from rodents and other mammals, stressing the physiological importance and high conservation of this motif (Gougos and Letarte, 1990; Rossi et al., 2013). Next to the ZP domain is the orphan domain, which is located in the NH2-terminus of the protein (Llorca et al., 2007). The orphan domain is involved in the binding to members of the TGF-β superfamily (activin, TGF-β, and BMP families) in accordance with the role of endoglin as an auxiliary TGF-β receptor (Alt et al., 2012). Thus, endoglin modulates the endothelial response to TGF-β-related ligands, including cell proliferation, apoptosis, vascular remodeling, angiogenesis, wound healing, or fibrosis (López-Novoa and Bernabeu, 2010). Of note, most of ENG mutations associated with HHT1 map to the EC domain, suggesting that the biological function of this domain is critical for the disease (Bernabeu et al., 2010). The cytosolic domain of endoglin is phosphorylated at Ser/Thr/Tyr residues and it can be targeted by serine/threonine (Lastres et al., 1994) and tyrosine (Pan et al., 2014) kinases. It has been shown that the endoglin phosphorylation status can influence its subcellular localization (Koleva et al., 2006) and degradation (Pan et al., 2014). The cytoplasmic domain of endoglin also regulates actin cytoskeletal organization, microtubule-based transport machinery, and cell migration (Ray et al., 2010; Romero et al., 2010), through its specific binding to different cytosolic proteins (López-Novoa and Bernabeu, 2010).

Bottom Line: Because of the absence of effective treatments for HHT symptoms, studies aimed at identifying novel biological functions of endoglin which could serve as therapeutic targets of the disease are needed.Endoglin displays, within its zona pellucida domain, an RGD motif, which is a prototypic sequence involved in integrin-based interactions with other proteins.In addition, functional, as well as protein and gene expression analysis have shown that ectopic endoglin represses the synthesis of several members of the integrin family and modulates integrin-mediated cell adhesions.

View Article: PubMed Central - PubMed

Affiliation: INSERM, Faculté des Sciences Pharmaceutiques et Biologiques, Université Paris Descartes, UMR-S 1140 Paris, France.

ABSTRACT
Mutations in the endoglin gene (ENG) are responsible for ∼50% of all cases with hereditary hemorrhagic telangiectasia (HHT). Because of the absence of effective treatments for HHT symptoms, studies aimed at identifying novel biological functions of endoglin which could serve as therapeutic targets of the disease are needed. Endoglin is an endothelial membrane protein, whose most studied function has been its role as an auxiliary receptor in the TGF-β receptor complex. However, several lines of evidence suggest the involvement of endoglin in TGF-β-independent functions. Endoglin displays, within its zona pellucida domain, an RGD motif, which is a prototypic sequence involved in integrin-based interactions with other proteins. Indeed, we have recently described a novel role for endothelial endoglin in leukocyte trafficking and extravasation via its interaction with leukocyte integrins. In addition, functional, as well as protein and gene expression analysis have shown that ectopic endoglin represses the synthesis of several members of the integrin family and modulates integrin-mediated cell adhesions. This review focuses on the tight link between endoglin and integrins and how the role of endothelial endoglin in integrin-dependent cell adhesion processes can provide a better understanding of the pathogenic mechanisms leading to vascular lesions in endoglin haploinsufficient HHT1 patients.

No MeSH data available.


Related in: MedlinePlus