Endoglin (CD105) is a cell membrane glycoprotein over-expressed on highly proliferating endothelial cells in culture, and on endothelial cells of angiogenetic blood vessels within benign and malignant tissues. CD105 binds several factors of the Transforming Growth Factor (TGF)-beta superfamily, and its over-expression modulates cellular responses to TGF-beta1. The complex of experimental findings accumulated in the last few years strongly indicate that CD105 is a powerful marker of angiogenesis, and that it might play a critical role in the pathogenesis of vascular diseases and in tumor progression. In this paper, we will review the structural, biological and functional features of CD105, as well as its distribution within normal and neoplastic tissues, emphasizing its foreseeable role as a molecular target for new diagnostic and bioimmunotherapeutic approaches in human malignancies.
The 44G4 antigen is expressed in high amounts on human endothelial cells and at low levels on leukemic cells of pre-B and myelomonocytic origin. Its level of expression on the pre-B leukemic HOON cell line used for derivation of the corresponding mAb is intermediate but sufficient to permit the purification of the Ag. The molecule isolated by immunoaffinity from HOON is a glycoprotein since it bound to Ricinus communis agglutinin, wheat germ agglutinin, and peanut agglutinin lectins. The Ag was purified 2400-fold from a soluble taurocholate extract of HOON cells by affinity to wheat germ agglutinin-agarose and 44G4-IgG-Sepharose. The purified glycoprotein is likely a homodimer as it migrated on SDS-PAGE with an apparent m.w. of 170,000, nonreduced, and 95,000, reduced. Removal of N-linked oligosaccharides by endoglycosidase F led to a decrease in m.w. of 25,000; if neuraminidase and O-glycanase were also present, the total decrease in m.w. was 33,000 suggesting a polypeptide chain of 62,000 and 8,000 in O-linked substitutions. The glycoprotein digested with N-glycanase, neuraminidase, or O-glycanase could still be immunoprecipitated with the 44G4 mAb indicating that the antigenic epitope resides in the polypeptide. By Western blot analysis, the dissociated but nonreduced protein was reactive with 44G4, whereas the reduced and alkylated protein was not. Therefore, the epitope is dependent on the presence of intact disulfide bond(s). Sequential immunoprecipitation with OKT9 and 44G4 antibodies indicated that these epitopes are present on two distinct molecules and that 44G4 is distinct from the transferrin receptor despite a similar subunit structure.
The 44G4 antigen is expressed in high amounts on human endothelial cells and at low levels on leukemic cells of pre-B and myelomonocytic origin. Its level of expression on the pre-B leukemic HOON cell line used for derivation of the corresponding mAb is intermediate but sufficient to permit the purification of the Ag. The molecule isolated by immunoaffinity from HOON is a glycoprotein since it bound to Ricinus communis agglutinin, wheat germ agglutinin, and peanut agglutinin lectins. The Ag was purified 2400-fold from a soluble taurocholate extract of HOON cells by affinity to wheat germ agglutinin-agarose and 44G4-IgG-Sepharose. The purified glycoprotein is likely a homodimer as it migrated on SDS-PAGE with an apparent m.w. of 170,000, nonreduced, and 95,000, reduced. Removal of N-linked oligosaccharides by endoglycosidase F led to a decrease in m.w. of 25,000; if neuraminidase and O-glycanase were also present, the total decrease in m.w. was 33,000 suggesting a polypeptide chain of 62,000 and 8,000 in O-linked substitutions. The glycoprotein digested with N-glycanase, neuraminidase, or O-glycanase could still be immunoprecipitated with the 44G4 mAb indicating that the antigenic epitope resides in the polypeptide. By Western blot analysis, the dissociated but nonreduced protein was reactive with 44G4, whereas the reduced and alkylated protein was not. Therefore, the epitope is dependent on the presence of intact disulfide bond(s). Sequential immunoprecipitation with OKT9 and 44G4 antibodies indicated that these epitopes are present on two distinct molecules and that 44G4 is distinct from the transferrin receptor despite a similar subunit structure.
Evidence
2:
Inferred from Sequence or Structural SimilarityBHF-UCL
J. Biol. Chem. 269, 1995-2001 (1994)[PubMed:8294451]
Human endoglin is a dimeric protein that binds transforming growth factor-beta (TGF-beta). A porcine cDNA clone for endoglin was obtained from a porcine uterus cDNA library. The deduced sequence of the primary translated product of endoglin consists of 643 amino acids with a high sequence identity (96%) to human endoglin in the transmembrane and intracellular domains, but with a lower sequence similarity (66%) in the extracellular domain. In contrast to human endoglin, porcine endoglin has no Arg-Gly-Asp tripeptide in its sequence. Antibodies, raised against a peptide corresponding to the intracellular domain of porcine endoglin, immunoprecipitated an 84-kDa protein under reducing condition and a 130-kDa protein under nonreducing condition in porcine aortic endothelial cells. Porcine endoglin bound TGF-beta 1 and -beta 3 efficiently, but TGF-beta 2 less efficiently. Endoglin was found to be coimmunoprecipitated with TGF-beta receptors type I and/or II by the endoglin antibodies or by TGF-beta receptor II antibodies in the presence of ligand. Thus, endoglin and TGF-beta receptors I and/or II most likely formed a heteromeric receptor complex. Endoglin was phosphorylated on serine residue(s), which did not change after stimulation by TGF-beta 1. These results revealed that endoglin is a phosphorylated protein which forms a heteromeric complex with signaling receptors for TGF-beta.
Interacting selectively and non-covalently with any protein or protein complex (a complex of two or more proteins that may include other nonprotein molecules).
Evidence
1:
Inferred from Physical InteractionIntAct
Tumor cell plasticity enables certain types of highly malignant tumor cells to dedifferentiate and engage a plastic multipotent embryonic-like phenotype, which enables them to 'adapt' during tumor progression and escape conventional therapeutic strategies. This plastic phenotype of aggressive cancer cells enables them to express endothelial cell-specific markers and form tube-like structures, a phenotype that has been linked to aggressive behavior and poor prognosis. We demonstrate here that the transforming growth factor (TGF)-β co-receptor endoglin, an endothelial cell marker, is expressed by tumor cells and its expression correlates with tumor cell plasticity in two types of human cancer, Ewing sarcoma and melanoma. Moreover, endoglin expression was significantly associated with worse survival of Ewing sarcoma patients. Endoglin knockdown in tumor cells interferes with tumor cell plasticity and reduces invasiveness and anchorage-independent growth in vitro. Ewing sarcoma and melanoma cells with reduced endoglin levels showed reduced tumor growth in vivo. Mechanistically, we provide evidence that endoglin, while interfering with TGF-β signaling, is required for efficient bone morphogenetic protein, integrin, focal adhesion kinase and phosphoinositide-3-kinase signaling in order to maintain tumor cell plasticity. The present study delineates an important role of endoglin in tumor cell plasticity and progression of aggressive tumors.
Evidence
2:
Inferred from Physical InteractionHGNC
J. Biol. Chem. 274, 584-594 (1999)[PubMed:9872992]
Endoglin (CD105) is a transmembrane glycoprotein that binds transforming growth factor (TGF)-beta1 and -beta3, and coprecipitates with the Ser/Thr kinase signaling receptor complex by affinity labeling of endothelial and leukemic cells. The present study shows that in addition to TGF-beta1 and -beta3, endoglin interacts with activin-A, bone morphogenetic protein (BMP)-7, and BMP-2 but requires coexpression of the respective ligand binding kinase receptor for this association. Endoglin cannot bind ligands on its own and does not alter binding to the kinase receptors. It binds TGF-beta1 and -beta3 by associating with the TGF-beta type II receptor and interacts with activin-A and BMP-7 via activin type II receptors, ActRII and ActRIIB, regardless of which type I receptor partner is coexpressed. However, endoglin binds BMP-2 by interacting with the ligand binding type I receptors, ALK3 and ALK6. The formation of heteromeric signaling complexes was not altered by the presence of endoglin, although it was coprecipitated with these complexes. Endoglin did not interact with BMP-7 through complexes containing the BMP type II receptor, demonstrating specificity of its action. Our data suggest that endoglin is an accessory protein of multiple kinase receptor complexes of the TGF-beta superfamily.
Evidence
3:
Inferred from Physical InteractionHGNC
Transforming growth factor-beta (TGF-beta) signaling in endothelial cells is able to modulate angiogenesis and vascular remodeling, although the underlying molecular mechanisms remain poorly understood. Endoglin and ALK-1 are components of the TGF-beta receptor complex, predominantly expressed in endothelial cells, and mutations in either endoglin or ALK-1 genes are responsible for the vascular dysplasia known as hereditary hemorrhagic telangiectasia. Here we find that the extracellular and cytoplasmic domains of the auxiliary TGF-beta receptor endoglin interact with ALK-1 (a type I TGF-beta receptor). In addition, endoglin potentiates TGF-beta/ALK1 signaling, with the extracellular domain of endoglin contributing to this functional cooperation between endoglin and ALK-1. By contrast, endoglin appears to interfere with TGF-beta/ALK-5 signaling. These results suggest that the functional association of endoglin with ALK-1 is critical for the endothelial responses to TGF-beta.
Endoglin is an homodimeric membrane antigen with capacity to bind transforming growth factor-beta (TGF-beta) and whose expression is up-regulated on myeloid cells upon differentiation to macrophages. We have isolated full-length cDNA clones from a lambda gt 10 library, prepared from phorbol 12-myristate 13-acetate-differentiated HL60 cells by screening with an endoglin-specific cDNA probe from endothelial cells. Sequencing of the largest clone (3073 bp), revealed that the leader sequence contains 25 residues and that the 586 amino acids of the extracellular and transmembrane domains were identical to those described for endothelial endoglin. However, the cytoplasmic tail encoded by this cDNA clone contains only 14 amino acids as opposed to the 47 residues previously reported, suggesting the existence of two alternative endoglin variants. The expression of these isoforms was demonstrated by polymerase chain reaction analyses on endothelial cells, myelomonocytic cell lines HL-60 and U-937, and placenta. Independent cDNA constructs corresponding to both forms were transfected into mouse fibroblasts leading to the expression of two distinct endoglin molecules. Both forms were shown to bind TGF-beta 1 and, when overexpressed in transfected mouse fibroblasts, to form disulfide-linked homodimers, indicating that the cysteine residues present in the extracellular domain are responsible for the dimerization.
Interacting selectively and non-covalently with TGF-beta, transforming growth factor beta, a multifunctional peptide that controls proliferation, differentiation and other functions in many cell types.
Evidence
1:
Inferred from Physical InteractionBHF-UCL
J. Biol. Chem. 267, 19027-19030 (1992)[PubMed:1326540]
Endoglin, a dimeric membrane glycoprotein expressed at high levels on human vascular endothelial cells, shares regions of sequence identity with betaglycan, a major binding protein for transforming growth factor-beta (TGF-beta) that co-exists with TGF-beta receptors I and II in a variety of cell lines but is low or absent in endothelial cells. We have examined whether endoglin also binds TGF-beta and demonstrate here that the major TGF-beta 1-binding protein co-existing with TGF-beta receptors I and II on human umbilical vein endothelial cells is endoglin, as determined by specific immunoprecipitation of endoglin affinity-labeled with 125I-TGF-beta. Furthermore, endoglin ectopically expressed in COS cells binds TGF-beta 1. Competition affinity-labeling experiments showed that endoglin binds TGF-beta 1 (KD approximately 50 pM) and TGF-beta 3 with high affinity but fails to bind TGF-beta 2. This difference in affinity of endoglin for the TGF-beta isoforms is in contrast to beta-glycan which recognizes all three isoforms. TGF-beta however is binding with high affinity to only a small fraction of the available endoglin molecules, suggesting that some rate-limiting event is required to sustain TGF-beta binding to endoglin.
Evidence
2:
Inferred from Physical InteractionBHF-UCL
Endoglin is an homodimeric membrane antigen with capacity to bind transforming growth factor-beta (TGF-beta) and whose expression is up-regulated on myeloid cells upon differentiation to macrophages. We have isolated full-length cDNA clones from a lambda gt 10 library, prepared from phorbol 12-myristate 13-acetate-differentiated HL60 cells by screening with an endoglin-specific cDNA probe from endothelial cells. Sequencing of the largest clone (3073 bp), revealed that the leader sequence contains 25 residues and that the 586 amino acids of the extracellular and transmembrane domains were identical to those described for endothelial endoglin. However, the cytoplasmic tail encoded by this cDNA clone contains only 14 amino acids as opposed to the 47 residues previously reported, suggesting the existence of two alternative endoglin variants. The expression of these isoforms was demonstrated by polymerase chain reaction analyses on endothelial cells, myelomonocytic cell lines HL-60 and U-937, and placenta. Independent cDNA constructs corresponding to both forms were transfected into mouse fibroblasts leading to the expression of two distinct endoglin molecules. Both forms were shown to bind TGF-beta 1 and, when overexpressed in transfected mouse fibroblasts, to form disulfide-linked homodimers, indicating that the cysteine residues present in the extracellular domain are responsible for the dimerization.
Endoglin is an auxiliary component of the transforming growth factor-beta (TGF-beta) receptor system, able to associate with the signaling receptor types I (TbetaRI) and II (TbetaRII) in the presence of ligand and to modulate the cellular responses to TGF-beta1. Endoglin cannot bind ligand on its own but requires the presence of the signaling receptors, supporting a critical role for the interaction between endoglin and TbetaRI or TbetaRII. This study shows that full-length endoglin interacts with both TbetaRI and TbetaRII, independently of their kinase activation state or the presence of exogenous TGF-beta1. Truncated constructs encoding either the extracellular or the cytoplasmic domains of endoglin demonstrated that the association with the signaling receptors occurs through both extracellular and cytoplasmic domains. However, a more specific mapping revealed that the endoglin/TbetaRI interaction was different from that of endoglin/TbetaRII. TbetaRII interacts with the amino acid region 437-558 of the extracellular domain of endoglin, whereas TbetaRI interacts not only with the region 437-558 but also with the protein region located between amino acid 437 and the N terminus. Both TbetaRI and TbetaRII interact with the cytoplasmic domain of endoglin, but TbetaRI only interacts when the kinase domain is inactive, whereas TbetaRII remains associated in its active and inactive forms. Upon association, TbetaRI and TbetaRII phosphorylate the endoglin cytoplasmic domain, and then TbetaRI, but not TbetaRII, kinase dissociates from the complex. Conversely, endoglin expression results in an altered phosphorylation state of TbetaRII, TbetaRI, and downstream Smad proteins as well as a modulation of TGF-beta signaling, as measured by the reporter gene expression. These results suggest that by interacting through its extracellular and cytoplasmic domains with the signaling receptors, endoglin might affect TGF-beta responses.
Combining with a transforming growth factor beta (TGFbeta) and transmitting the signal from one side of the membrane to the other to initiate a change in cell activity by catalysis of the reaction: ATP protein serine = ADP + protein serine phosphate, and ATP + protein threonine = ADP + protein threonine phosphate.
Endoglin is a cell-surface adhesion protein as well as a coreceptor for transforming growth factor-beta (TGF-beta). It is located on endothelial and few other cells, but also found on certain tumor cells. Brain metastatic breast tumor cells derived from the MDA-MB-231 cell line heavily express endoglin in contrast to the corresponding parental ones. To clarify whether this determines their invasive phenotype, we compared their biological properties with endoglin-silenced brain-metastatic cells, low-expressing parental cells and these transfected with L- and S-endoglins, isoforms transducing or lacking TGF-beta signals. All L-endoglin-overexpressing cells were characterized by numerous invadopodia where endoglin was preferentially localized. Endoglin-expression resulted in elevated levels of the matrix metalloproteinases (MMP-1 and MMP-19) and downregulation of the plasminogen activator inhibitor-1. In Boyden-chamber and wound-healing assays, endoglin-overexpressing cells showed a considerably higher migration and chemotaxis to TGF-beta. In 3D spheroid confrontation assays between breast tumor cells and TGF-beta-secreting glioma cells, high L-endoglin-expressing cells invaded into the glioma-spheroids whereas low-endoglin-expressing cells dissociated in the culture; invasion was blocked by TGF-beta antibodies. In contrast to parental cells, endoglin-overexpressing cells invaded deeply into mouse brain slices. Thus, endoglin expression on tumor cells enhances their invasive character by formation of invadopodia, extracellular proteolysis, chemotaxis and migration.
Combining with an extracellular or intracellular signal and transmitting the signal from one side of the membrane to the other to initiate a change in cell activity.
Senescence of endothelial cells (ECs) may contribute to age-associated cardiovascular diseases, including atherosclerosis and hypertension. The functional and gene expression changes associated with cellular senescence are poorly understood. Here, we have analyzed the expression, during EC senescence, of 2 different isoforms (L, long; S, short) of endoglin, an auxiliary transforming growth factor (TGF)-beta receptor involved in vascular remodeling and angiogenesis. As evidenced by RT-PCR, the S/L ratio of endoglin isoforms was increased during senescence of human ECs in vitro, as well as during aging of mice in vascularized tissues. Next, the effect of S-endoglin protein on the TGF-beta receptor complex was studied. As revealed by coimmunoprecipitation assays, S-endoglin was able to interact with both TGF-beta type I receptors, ALK5 and ALK1, although the interaction with ALK5 was stronger than with ALK1. S-endoglin conferred a lower proliferation rate to ECs and behaved differently from L-endoglin in relation to TGF-beta-responsive reporters with ALK1 or ALK5 specificities, mimicking the behavior of the endothelial senescence markers Id1 and plasminogen activator inhibitor-1. In situ hybridization studies demonstrated the expression of S-endoglin in the endothelium from human arteries. Transgenic mice overexpressing S-endoglin in ECs showed hypertension, decreased hypertensive response to NO inhibition, decreased vasodilatory response to TGF-beta(1) administration, and decreased endothelial nitric oxide synthase expression in lungs and kidneys, supporting the involvement of S-endoglin in the NO-dependent vascular homeostasis. Taken together, these results suggest that S-endoglin is induced during endothelial senescence and may contribute to age-dependent vascular pathology.
Senescence of endothelial cells (ECs) may contribute to age-associated cardiovascular diseases, including atherosclerosis and hypertension. The functional and gene expression changes associated with cellular senescence are poorly understood. Here, we have analyzed the expression, during EC senescence, of 2 different isoforms (L, long; S, short) of endoglin, an auxiliary transforming growth factor (TGF)-beta receptor involved in vascular remodeling and angiogenesis. As evidenced by RT-PCR, the S/L ratio of endoglin isoforms was increased during senescence of human ECs in vitro, as well as during aging of mice in vascularized tissues. Next, the effect of S-endoglin protein on the TGF-beta receptor complex was studied. As revealed by coimmunoprecipitation assays, S-endoglin was able to interact with both TGF-beta type I receptors, ALK5 and ALK1, although the interaction with ALK5 was stronger than with ALK1. S-endoglin conferred a lower proliferation rate to ECs and behaved differently from L-endoglin in relation to TGF-beta-responsive reporters with ALK1 or ALK5 specificities, mimicking the behavior of the endothelial senescence markers Id1 and plasminogen activator inhibitor-1. In situ hybridization studies demonstrated the expression of S-endoglin in the endothelium from human arteries. Transgenic mice overexpressing S-endoglin in ECs showed hypertension, decreased hypertensive response to NO inhibition, decreased vasodilatory response to TGF-beta(1) administration, and decreased endothelial nitric oxide synthase expression in lungs and kidneys, supporting the involvement of S-endoglin in the NO-dependent vascular homeostasis. Taken together, these results suggest that S-endoglin is induced during endothelial senescence and may contribute to age-dependent vascular pathology.
Evidence
2:
Inferred from Sequence or Structural SimilarityBHF-UCL
J. Biol. Chem. 269, 1995-2001 (1994)[PubMed:8294451]
Human endoglin is a dimeric protein that binds transforming growth factor-beta (TGF-beta). A porcine cDNA clone for endoglin was obtained from a porcine uterus cDNA library. The deduced sequence of the primary translated product of endoglin consists of 643 amino acids with a high sequence identity (96%) to human endoglin in the transmembrane and intracellular domains, but with a lower sequence similarity (66%) in the extracellular domain. In contrast to human endoglin, porcine endoglin has no Arg-Gly-Asp tripeptide in its sequence. Antibodies, raised against a peptide corresponding to the intracellular domain of porcine endoglin, immunoprecipitated an 84-kDa protein under reducing condition and a 130-kDa protein under nonreducing condition in porcine aortic endothelial cells. Porcine endoglin bound TGF-beta 1 and -beta 3 efficiently, but TGF-beta 2 less efficiently. Endoglin was found to be coimmunoprecipitated with TGF-beta receptors type I and/or II by the endoglin antibodies or by TGF-beta receptor II antibodies in the presence of ligand. Thus, endoglin and TGF-beta receptors I and/or II most likely formed a heteromeric receptor complex. Endoglin was phosphorylated on serine residue(s), which did not change after stimulation by TGF-beta 1. These results revealed that endoglin is a phosphorylated protein which forms a heteromeric complex with signaling receptors for TGF-beta.
Evidence
3:
Inferred from Physical InteractionBHF-UCL
Endoglin is an auxiliary component of the transforming growth factor-beta (TGF-beta) receptor system, able to associate with the signaling receptor types I (TbetaRI) and II (TbetaRII) in the presence of ligand and to modulate the cellular responses to TGF-beta1. Endoglin cannot bind ligand on its own but requires the presence of the signaling receptors, supporting a critical role for the interaction between endoglin and TbetaRI or TbetaRII. This study shows that full-length endoglin interacts with both TbetaRI and TbetaRII, independently of their kinase activation state or the presence of exogenous TGF-beta1. Truncated constructs encoding either the extracellular or the cytoplasmic domains of endoglin demonstrated that the association with the signaling receptors occurs through both extracellular and cytoplasmic domains. However, a more specific mapping revealed that the endoglin/TbetaRI interaction was different from that of endoglin/TbetaRII. TbetaRII interacts with the amino acid region 437-558 of the extracellular domain of endoglin, whereas TbetaRI interacts not only with the region 437-558 but also with the protein region located between amino acid 437 and the N terminus. Both TbetaRI and TbetaRII interact with the cytoplasmic domain of endoglin, but TbetaRI only interacts when the kinase domain is inactive, whereas TbetaRII remains associated in its active and inactive forms. Upon association, TbetaRI and TbetaRII phosphorylate the endoglin cytoplasmic domain, and then TbetaRI, but not TbetaRII, kinase dissociates from the complex. Conversely, endoglin expression results in an altered phosphorylation state of TbetaRII, TbetaRI, and downstream Smad proteins as well as a modulation of TGF-beta signaling, as measured by the reporter gene expression. These results suggest that by interacting through its extracellular and cytoplasmic domains with the signaling receptors, endoglin might affect TGF-beta responses.
Endoglin is an auxiliary component of the transforming growth factor-beta (TGF-beta) receptor system, able to associate with the signaling receptor types I (TbetaRI) and II (TbetaRII) in the presence of ligand and to modulate the cellular responses to TGF-beta1. Endoglin cannot bind ligand on its own but requires the presence of the signaling receptors, supporting a critical role for the interaction between endoglin and TbetaRI or TbetaRII. This study shows that full-length endoglin interacts with both TbetaRI and TbetaRII, independently of their kinase activation state or the presence of exogenous TGF-beta1. Truncated constructs encoding either the extracellular or the cytoplasmic domains of endoglin demonstrated that the association with the signaling receptors occurs through both extracellular and cytoplasmic domains. However, a more specific mapping revealed that the endoglin/TbetaRI interaction was different from that of endoglin/TbetaRII. TbetaRII interacts with the amino acid region 437-558 of the extracellular domain of endoglin, whereas TbetaRI interacts not only with the region 437-558 but also with the protein region located between amino acid 437 and the N terminus. Both TbetaRI and TbetaRII interact with the cytoplasmic domain of endoglin, but TbetaRI only interacts when the kinase domain is inactive, whereas TbetaRII remains associated in its active and inactive forms. Upon association, TbetaRI and TbetaRII phosphorylate the endoglin cytoplasmic domain, and then TbetaRI, but not TbetaRII, kinase dissociates from the complex. Conversely, endoglin expression results in an altered phosphorylation state of TbetaRII, TbetaRI, and downstream Smad proteins as well as a modulation of TGF-beta signaling, as measured by the reporter gene expression. These results suggest that by interacting through its extracellular and cytoplasmic domains with the signaling receptors, endoglin might affect TGF-beta responses.
Evidence
2:
Inferred from Sequence or Structural SimilarityBHF-UCL
J. Biol. Chem. 269, 1995-2001 (1994)[PubMed:8294451]
Human endoglin is a dimeric protein that binds transforming growth factor-beta (TGF-beta). A porcine cDNA clone for endoglin was obtained from a porcine uterus cDNA library. The deduced sequence of the primary translated product of endoglin consists of 643 amino acids with a high sequence identity (96%) to human endoglin in the transmembrane and intracellular domains, but with a lower sequence similarity (66%) in the extracellular domain. In contrast to human endoglin, porcine endoglin has no Arg-Gly-Asp tripeptide in its sequence. Antibodies, raised against a peptide corresponding to the intracellular domain of porcine endoglin, immunoprecipitated an 84-kDa protein under reducing condition and a 130-kDa protein under nonreducing condition in porcine aortic endothelial cells. Porcine endoglin bound TGF-beta 1 and -beta 3 efficiently, but TGF-beta 2 less efficiently. Endoglin was found to be coimmunoprecipitated with TGF-beta receptors type I and/or II by the endoglin antibodies or by TGF-beta receptor II antibodies in the presence of ligand. Thus, endoglin and TGF-beta receptors I and/or II most likely formed a heteromeric receptor complex. Endoglin was phosphorylated on serine residue(s), which did not change after stimulation by TGF-beta 1. These results revealed that endoglin is a phosphorylated protein which forms a heteromeric complex with signaling receptors for TGF-beta.
The process in which the anatomical structures of arterial blood vessels are generated and organized. Arteries are blood vessels that transport blood from the heart to the body and its organs.
Evidence
1:
Inferred from Sequence or Structural SimilarityBHF-UCL
Endoglin is an integral membrane glycoprotein predominantly expressed on human endothelial cells and recently shown to bind transforming growth factor-beta 1 (TGF beta 1) with high affinity. We now report the cloning and sequencing of a full-length murine endoglin complementary DNA of 2902 base pairs which hybridizes specifically with a single messenger RNA (mRNA) species. The polypeptide of 653 amino acids has an overall identity of 72% with human and porcine endoglin. The transmembrane and cytoplasmic domains of all three proteins differ by two to four amino acids and are 70% identical to the corresponding regions of the TGF beta binding protein, betaglycan. Relative levels of murine endoglin mRNA were estimated by polymerase chain reaction and found to be high in ovary and uterus, intermediate in heart and muscle, and low in placenta and spleen. In situ hybridization and immunofluorescence confirmed that murine endoglin, like its human counterpart, is present in blood vessels and capillaries in all tissues examined. In addition, the stromal cells in the connective tissue of intestine, stomach, heart, muscle, uterus, ovary, and testis were strongly and specifically reactive with complementary RNA probes and with a polyclonal antibody to endoglin; epithelial cell layers were distinctly unreactive. This distribution is similar to that of extracellular TGF beta 1, particularly in heart and uterus, and suggests that endoglin on stromal fibroblast-like cells might be regulating access of TGF beta 1 to the signaling receptor complex. NCTC-2071 fibroblasts in culture were shown to express high levels of endoglin mRNA by polymerase chain reaction. After chemical cross-linking with [125I]TGF beta 1 and immunoprecipitation with the polyclonal antihuman endoglin serum, a radiolabeled band of mol wt 180,000 corresponding to dimeric endoglin was observed under nonreducing conditions, whereas a single band of mol wt 90,000 was seen under reducing conditions. Thus murine fibroblast endoglin is capable of binding TGF beta 1. Future studies should establish the specialized role of endoglin in the TGF beta receptor complex of endothelial and stromal cells.
A series of molecular signals initiated by the binding of a member of the BMP (bone morphogenetic protein) family to a receptor on the surface of a target cell, and ending with regulation of a downstream cellular process, e.g. transcription.
Endoglin (CD105) is a cell membrane glycoprotein over-expressed on highly proliferating endothelial cells in culture, and on endothelial cells of angiogenetic blood vessels within benign and malignant tissues. CD105 binds several factors of the Transforming Growth Factor (TGF)-beta superfamily, and its over-expression modulates cellular responses to TGF-beta1. The complex of experimental findings accumulated in the last few years strongly indicate that CD105 is a powerful marker of angiogenesis, and that it might play a critical role in the pathogenesis of vascular diseases and in tumor progression. In this paper, we will review the structural, biological and functional features of CD105, as well as its distribution within normal and neoplastic tissues, emphasizing its foreseeable role as a molecular target for new diagnostic and bioimmunotherapeutic approaches in human malignancies.
The directed movement of a motile cell guided by a specific chemical concentration gradient. Movement may be towards a higher concentration (positive chemotaxis) or towards a lower concentration (negative chemotaxis).
Endoglin is a cell-surface adhesion protein as well as a coreceptor for transforming growth factor-beta (TGF-beta). It is located on endothelial and few other cells, but also found on certain tumor cells. Brain metastatic breast tumor cells derived from the MDA-MB-231 cell line heavily express endoglin in contrast to the corresponding parental ones. To clarify whether this determines their invasive phenotype, we compared their biological properties with endoglin-silenced brain-metastatic cells, low-expressing parental cells and these transfected with L- and S-endoglins, isoforms transducing or lacking TGF-beta signals. All L-endoglin-overexpressing cells were characterized by numerous invadopodia where endoglin was preferentially localized. Endoglin-expression resulted in elevated levels of the matrix metalloproteinases (MMP-1 and MMP-19) and downregulation of the plasminogen activator inhibitor-1. In Boyden-chamber and wound-healing assays, endoglin-overexpressing cells showed a considerably higher migration and chemotaxis to TGF-beta. In 3D spheroid confrontation assays between breast tumor cells and TGF-beta-secreting glioma cells, high L-endoglin-expressing cells invaded into the glioma-spheroids whereas low-endoglin-expressing cells dissociated in the culture; invasion was blocked by TGF-beta antibodies. In contrast to parental cells, endoglin-overexpressing cells invaded deeply into mouse brain slices. Thus, endoglin expression on tumor cells enhances their invasive character by formation of invadopodia, extracellular proteolysis, chemotaxis and migration.
Endoglin is a cell-surface adhesion protein as well as a coreceptor for transforming growth factor-beta (TGF-beta). It is located on endothelial and few other cells, but also found on certain tumor cells. Brain metastatic breast tumor cells derived from the MDA-MB-231 cell line heavily express endoglin in contrast to the corresponding parental ones. To clarify whether this determines their invasive phenotype, we compared their biological properties with endoglin-silenced brain-metastatic cells, low-expressing parental cells and these transfected with L- and S-endoglins, isoforms transducing or lacking TGF-beta signals. All L-endoglin-overexpressing cells were characterized by numerous invadopodia where endoglin was preferentially localized. Endoglin-expression resulted in elevated levels of the matrix metalloproteinases (MMP-1 and MMP-19) and downregulation of the plasminogen activator inhibitor-1. In Boyden-chamber and wound-healing assays, endoglin-overexpressing cells showed a considerably higher migration and chemotaxis to TGF-beta. In 3D spheroid confrontation assays between breast tumor cells and TGF-beta-secreting glioma cells, high L-endoglin-expressing cells invaded into the glioma-spheroids whereas low-endoglin-expressing cells dissociated in the culture; invasion was blocked by TGF-beta antibodies. In contrast to parental cells, endoglin-overexpressing cells invaded deeply into mouse brain slices. Thus, endoglin expression on tumor cells enhances their invasive character by formation of invadopodia, extracellular proteolysis, chemotaxis and migration.
The orderly movement of a cell from one site to another that will contribute to the formation of an endocardial cushion. The endocardial cushion is a specialized region of mesenchymal cells that will give rise to the heart septa and valves.
Endoglin is a cell-surface adhesion protein as well as a coreceptor for transforming growth factor-beta (TGF-beta). It is located on endothelial and few other cells, but also found on certain tumor cells. Brain metastatic breast tumor cells derived from the MDA-MB-231 cell line heavily express endoglin in contrast to the corresponding parental ones. To clarify whether this determines their invasive phenotype, we compared their biological properties with endoglin-silenced brain-metastatic cells, low-expressing parental cells and these transfected with L- and S-endoglins, isoforms transducing or lacking TGF-beta signals. All L-endoglin-overexpressing cells were characterized by numerous invadopodia where endoglin was preferentially localized. Endoglin-expression resulted in elevated levels of the matrix metalloproteinases (MMP-1 and MMP-19) and downregulation of the plasminogen activator inhibitor-1. In Boyden-chamber and wound-healing assays, endoglin-overexpressing cells showed a considerably higher migration and chemotaxis to TGF-beta. In 3D spheroid confrontation assays between breast tumor cells and TGF-beta-secreting glioma cells, high L-endoglin-expressing cells invaded into the glioma-spheroids whereas low-endoglin-expressing cells dissociated in the culture; invasion was blocked by TGF-beta antibodies. In contrast to parental cells, endoglin-overexpressing cells invaded deeply into mouse brain slices. Thus, endoglin expression on tumor cells enhances their invasive character by formation of invadopodia, extracellular proteolysis, chemotaxis and migration.
The differentiation of endothelial cells from progenitor cells during blood vessel development, and the de novo formation of blood vessels and tubes in the central nervous system. The capillary endothelial cells in the brain are specialized to form the blood-brain barrier.
Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by multisystemic vascular dysplasia and recurrent haemorrhage. Linkage for some families has been established to chromosome 9q33-q34. In the present study, endoglin, a transforming growth factor beta (TGF-beta) binding protein, was analysed as a candidate gene for the disorder based on chromosomal location, expression pattern and function. We have identified mutations in three affected individuals: a C to G substitution converting a tyrosine to a termination codon, a 39 base pair deletion and a 2 basepair deletion which creates a premature termination codon. We have identified endoglin as the HHT gene mapping to 9q3 and have established HHT as the first human disease defined by a mutation in a member of the TGF-beta receptor complex.
The process associated with progression of the cell from its inception to the end of its lifespan that occurs when the cell is in a non-dividing, or quiescent, state.
Evidence
1:
Inferred from Expression PatternBHF-UCL
Evidence for Short
Senescence of endothelial cells (ECs) may contribute to age-associated cardiovascular diseases, including atherosclerosis and hypertension. The functional and gene expression changes associated with cellular senescence are poorly understood. Here, we have analyzed the expression, during EC senescence, of 2 different isoforms (L, long; S, short) of endoglin, an auxiliary transforming growth factor (TGF)-beta receptor involved in vascular remodeling and angiogenesis. As evidenced by RT-PCR, the S/L ratio of endoglin isoforms was increased during senescence of human ECs in vitro, as well as during aging of mice in vascularized tissues. Next, the effect of S-endoglin protein on the TGF-beta receptor complex was studied. As revealed by coimmunoprecipitation assays, S-endoglin was able to interact with both TGF-beta type I receptors, ALK5 and ALK1, although the interaction with ALK5 was stronger than with ALK1. S-endoglin conferred a lower proliferation rate to ECs and behaved differently from L-endoglin in relation to TGF-beta-responsive reporters with ALK1 or ALK5 specificities, mimicking the behavior of the endothelial senescence markers Id1 and plasminogen activator inhibitor-1. In situ hybridization studies demonstrated the expression of S-endoglin in the endothelium from human arteries. Transgenic mice overexpressing S-endoglin in ECs showed hypertension, decreased hypertensive response to NO inhibition, decreased vasodilatory response to TGF-beta(1) administration, and decreased endothelial nitric oxide synthase expression in lungs and kidneys, supporting the involvement of S-endoglin in the NO-dependent vascular homeostasis. Taken together, these results suggest that S-endoglin is induced during endothelial senescence and may contribute to age-dependent vascular pathology.
The series of events in which a stimulus indicating lowered oxygen tension is received by a cell and converted into a molecular signal. Hypoxia, defined as a decline in O2 levels below normoxic levels of 20.8 - 20.95%, results in metabolic adaptation at both the cellular and organismal level.
Endoglin, a co-receptor for transforming growth factor (TGF)-beta 1 and -beta 3 is expressed in the human placenta and plays an important role in the pathogenesis of preeclampsia. Because preeclampsia is associated with hypoxia, and because TGF-beta 3 is overexpressed in preeclamptic pregnancies, we examined the effect of oxygen and TGF-beta 3 on placental endoglin expression and investigated its expression in pathological models of placental hypoxia such as intrauterine growth restriction (IUGR) pregnancies. Endoglin expression was high at 4 to 9 weeks of gestation, when oxygen tension is low, and decreased after 10 weeks, when oxygen tension increases. Exposure of villous explants to low oxygen (3% O2) resulted in elevated expression of both membrane and soluble endoglin compared to standard conditions (20% O2). Moreover, addition of TGF-beta 3 to villous explants under low oxygen conditions increased the expression of endoglin compared to nontreated explants whereas addition of TGF-beta 3-neutralizing antibodies inhibited the low oxygen stimulatory effect on endoglin expression. Endoglin and soluble endoglin expression were significantly increased in placentas of IUGR singletons compared to controls and in the IUGR twin placentas relative to both the control co-twin and the normal twins. These data demonstrate that oxygen regulates the placental expression of endoglin via TGF-beta 3. Reduced placental perfusion leading to placental hypoxia might contribute to the increased expression of endoglin in IUGR pregnancies.
Endoglin is a cell-surface adhesion protein as well as a coreceptor for transforming growth factor-beta (TGF-beta). It is located on endothelial and few other cells, but also found on certain tumor cells. Brain metastatic breast tumor cells derived from the MDA-MB-231 cell line heavily express endoglin in contrast to the corresponding parental ones. To clarify whether this determines their invasive phenotype, we compared their biological properties with endoglin-silenced brain-metastatic cells, low-expressing parental cells and these transfected with L- and S-endoglins, isoforms transducing or lacking TGF-beta signals. All L-endoglin-overexpressing cells were characterized by numerous invadopodia where endoglin was preferentially localized. Endoglin-expression resulted in elevated levels of the matrix metalloproteinases (MMP-1 and MMP-19) and downregulation of the plasminogen activator inhibitor-1. In Boyden-chamber and wound-healing assays, endoglin-overexpressing cells showed a considerably higher migration and chemotaxis to TGF-beta. In 3D spheroid confrontation assays between breast tumor cells and TGF-beta-secreting glioma cells, high L-endoglin-expressing cells invaded into the glioma-spheroids whereas low-endoglin-expressing cells dissociated in the culture; invasion was blocked by TGF-beta antibodies. In contrast to parental cells, endoglin-overexpressing cells invaded deeply into mouse brain slices. Thus, endoglin expression on tumor cells enhances their invasive character by formation of invadopodia, extracellular proteolysis, chemotaxis and migration.
The characteristic morphogenetic movements where the primitive heart tube loops asymmetrically. This looping brings the primitive heart chambers into alignment preceding their future integration.
Evidence
1:
Inferred from Sequence or Structural SimilarityBHF-UCL
Endoglin is an integral membrane glycoprotein predominantly expressed on human endothelial cells and recently shown to bind transforming growth factor-beta 1 (TGF beta 1) with high affinity. We now report the cloning and sequencing of a full-length murine endoglin complementary DNA of 2902 base pairs which hybridizes specifically with a single messenger RNA (mRNA) species. The polypeptide of 653 amino acids has an overall identity of 72% with human and porcine endoglin. The transmembrane and cytoplasmic domains of all three proteins differ by two to four amino acids and are 70% identical to the corresponding regions of the TGF beta binding protein, betaglycan. Relative levels of murine endoglin mRNA were estimated by polymerase chain reaction and found to be high in ovary and uterus, intermediate in heart and muscle, and low in placenta and spleen. In situ hybridization and immunofluorescence confirmed that murine endoglin, like its human counterpart, is present in blood vessels and capillaries in all tissues examined. In addition, the stromal cells in the connective tissue of intestine, stomach, heart, muscle, uterus, ovary, and testis were strongly and specifically reactive with complementary RNA probes and with a polyclonal antibody to endoglin; epithelial cell layers were distinctly unreactive. This distribution is similar to that of extracellular TGF beta 1, particularly in heart and uterus, and suggests that endoglin on stromal fibroblast-like cells might be regulating access of TGF beta 1 to the signaling receptor complex. NCTC-2071 fibroblasts in culture were shown to express high levels of endoglin mRNA by polymerase chain reaction. After chemical cross-linking with [125I]TGF beta 1 and immunoprecipitation with the polyclonal antihuman endoglin serum, a radiolabeled band of mol wt 180,000 corresponding to dimeric endoglin was observed under nonreducing conditions, whereas a single band of mol wt 90,000 was seen under reducing conditions. Thus murine fibroblast endoglin is capable of binding TGF beta 1. Future studies should establish the specialized role of endoglin in the TGF beta receptor complex of endothelial and stromal cells.
Endoglin, a transmembrane glycoprotein that acts as a transforming growth factor-beta (TGF-beta) coreceptor, is downregulated in PC3-M metastatic prostate cancer cells. When restored, endoglin expression in PC3-M cells inhibits cell migration in vitro and attenuates the tumorigenicity of PC3-M cells in SCID mice, though the mechanism of endoglin regulation of migration in prostate cancer cells is not known. The current study indicates that endoglin is phosphorylated on cytosolic domain threonine residues by the TGF-beta type I receptors ALK2 and ALK5 in prostate cancer cells. Importantly, in the presence of constitutively active ALK2, endoglin did not inhibit cell migration, suggesting that endoglin phosphorylation regulated PC3-M cell migration. Therefore, our results suggest that endoglin phosphorylation is a mechanism with relevant functional consequences in prostate cancer cells. These data demonstrate for the first time that TGF-beta receptor-mediated phosphorylation of endoglin is a Smad-independent mechanism involved in the regulation of prostate cancer cell migration.
Senescence of endothelial cells (ECs) may contribute to age-associated cardiovascular diseases, including atherosclerosis and hypertension. The functional and gene expression changes associated with cellular senescence are poorly understood. Here, we have analyzed the expression, during EC senescence, of 2 different isoforms (L, long; S, short) of endoglin, an auxiliary transforming growth factor (TGF)-beta receptor involved in vascular remodeling and angiogenesis. As evidenced by RT-PCR, the S/L ratio of endoglin isoforms was increased during senescence of human ECs in vitro, as well as during aging of mice in vascularized tissues. Next, the effect of S-endoglin protein on the TGF-beta receptor complex was studied. As revealed by coimmunoprecipitation assays, S-endoglin was able to interact with both TGF-beta type I receptors, ALK5 and ALK1, although the interaction with ALK5 was stronger than with ALK1. S-endoglin conferred a lower proliferation rate to ECs and behaved differently from L-endoglin in relation to TGF-beta-responsive reporters with ALK1 or ALK5 specificities, mimicking the behavior of the endothelial senescence markers Id1 and plasminogen activator inhibitor-1. In situ hybridization studies demonstrated the expression of S-endoglin in the endothelium from human arteries. Transgenic mice overexpressing S-endoglin in ECs showed hypertension, decreased hypertensive response to NO inhibition, decreased vasodilatory response to TGF-beta(1) administration, and decreased endothelial nitric oxide synthase expression in lungs and kidneys, supporting the involvement of S-endoglin in the NO-dependent vascular homeostasis. Taken together, these results suggest that S-endoglin is induced during endothelial senescence and may contribute to age-dependent vascular pathology.
Senescence of endothelial cells (ECs) may contribute to age-associated cardiovascular diseases, including atherosclerosis and hypertension. The functional and gene expression changes associated with cellular senescence are poorly understood. Here, we have analyzed the expression, during EC senescence, of 2 different isoforms (L, long; S, short) of endoglin, an auxiliary transforming growth factor (TGF)-beta receptor involved in vascular remodeling and angiogenesis. As evidenced by RT-PCR, the S/L ratio of endoglin isoforms was increased during senescence of human ECs in vitro, as well as during aging of mice in vascularized tissues. Next, the effect of S-endoglin protein on the TGF-beta receptor complex was studied. As revealed by coimmunoprecipitation assays, S-endoglin was able to interact with both TGF-beta type I receptors, ALK5 and ALK1, although the interaction with ALK5 was stronger than with ALK1. S-endoglin conferred a lower proliferation rate to ECs and behaved differently from L-endoglin in relation to TGF-beta-responsive reporters with ALK1 or ALK5 specificities, mimicking the behavior of the endothelial senescence markers Id1 and plasminogen activator inhibitor-1. In situ hybridization studies demonstrated the expression of S-endoglin in the endothelium from human arteries. Transgenic mice overexpressing S-endoglin in ECs showed hypertension, decreased hypertensive response to NO inhibition, decreased vasodilatory response to TGF-beta(1) administration, and decreased endothelial nitric oxide synthase expression in lungs and kidneys, supporting the involvement of S-endoglin in the NO-dependent vascular homeostasis. Taken together, these results suggest that S-endoglin is induced during endothelial senescence and may contribute to age-dependent vascular pathology.
Isoform
Long
Negative regulation of pathway-restricted SMAD protein phosphorylationdefinition[GO:0060394]
Any process that decreases the rate, frequency or extent of pathway-restricted SMAD protein phosphorylation. Pathway-restricted SMAD proteins and common-partner SMAD proteins are involved in the transforming growth factor beta receptor signaling pathways.
Senescence of endothelial cells (ECs) may contribute to age-associated cardiovascular diseases, including atherosclerosis and hypertension. The functional and gene expression changes associated with cellular senescence are poorly understood. Here, we have analyzed the expression, during EC senescence, of 2 different isoforms (L, long; S, short) of endoglin, an auxiliary transforming growth factor (TGF)-beta receptor involved in vascular remodeling and angiogenesis. As evidenced by RT-PCR, the S/L ratio of endoglin isoforms was increased during senescence of human ECs in vitro, as well as during aging of mice in vascularized tissues. Next, the effect of S-endoglin protein on the TGF-beta receptor complex was studied. As revealed by coimmunoprecipitation assays, S-endoglin was able to interact with both TGF-beta type I receptors, ALK5 and ALK1, although the interaction with ALK5 was stronger than with ALK1. S-endoglin conferred a lower proliferation rate to ECs and behaved differently from L-endoglin in relation to TGF-beta-responsive reporters with ALK1 or ALK5 specificities, mimicking the behavior of the endothelial senescence markers Id1 and plasminogen activator inhibitor-1. In situ hybridization studies demonstrated the expression of S-endoglin in the endothelium from human arteries. Transgenic mice overexpressing S-endoglin in ECs showed hypertension, decreased hypertensive response to NO inhibition, decreased vasodilatory response to TGF-beta(1) administration, and decreased endothelial nitric oxide synthase expression in lungs and kidneys, supporting the involvement of S-endoglin in the NO-dependent vascular homeostasis. Taken together, these results suggest that S-endoglin is induced during endothelial senescence and may contribute to age-dependent vascular pathology.
Endoglin is an auxiliary component of the transforming growth factor-beta (TGF-beta) receptor system, able to associate with the signaling receptor types I (TbetaRI) and II (TbetaRII) in the presence of ligand and to modulate the cellular responses to TGF-beta1. Endoglin cannot bind ligand on its own but requires the presence of the signaling receptors, supporting a critical role for the interaction between endoglin and TbetaRI or TbetaRII. This study shows that full-length endoglin interacts with both TbetaRI and TbetaRII, independently of their kinase activation state or the presence of exogenous TGF-beta1. Truncated constructs encoding either the extracellular or the cytoplasmic domains of endoglin demonstrated that the association with the signaling receptors occurs through both extracellular and cytoplasmic domains. However, a more specific mapping revealed that the endoglin/TbetaRI interaction was different from that of endoglin/TbetaRII. TbetaRII interacts with the amino acid region 437-558 of the extracellular domain of endoglin, whereas TbetaRI interacts not only with the region 437-558 but also with the protein region located between amino acid 437 and the N terminus. Both TbetaRI and TbetaRII interact with the cytoplasmic domain of endoglin, but TbetaRI only interacts when the kinase domain is inactive, whereas TbetaRII remains associated in its active and inactive forms. Upon association, TbetaRI and TbetaRII phosphorylate the endoglin cytoplasmic domain, and then TbetaRI, but not TbetaRII, kinase dissociates from the complex. Conversely, endoglin expression results in an altered phosphorylation state of TbetaRII, TbetaRI, and downstream Smad proteins as well as a modulation of TGF-beta signaling, as measured by the reporter gene expression. These results suggest that by interacting through its extracellular and cytoplasmic domains with the signaling receptors, endoglin might affect TGF-beta responses.
Senescence of endothelial cells (ECs) may contribute to age-associated cardiovascular diseases, including atherosclerosis and hypertension. The functional and gene expression changes associated with cellular senescence are poorly understood. Here, we have analyzed the expression, during EC senescence, of 2 different isoforms (L, long; S, short) of endoglin, an auxiliary transforming growth factor (TGF)-beta receptor involved in vascular remodeling and angiogenesis. As evidenced by RT-PCR, the S/L ratio of endoglin isoforms was increased during senescence of human ECs in vitro, as well as during aging of mice in vascularized tissues. Next, the effect of S-endoglin protein on the TGF-beta receptor complex was studied. As revealed by coimmunoprecipitation assays, S-endoglin was able to interact with both TGF-beta type I receptors, ALK5 and ALK1, although the interaction with ALK5 was stronger than with ALK1. S-endoglin conferred a lower proliferation rate to ECs and behaved differently from L-endoglin in relation to TGF-beta-responsive reporters with ALK1 or ALK5 specificities, mimicking the behavior of the endothelial senescence markers Id1 and plasminogen activator inhibitor-1. In situ hybridization studies demonstrated the expression of S-endoglin in the endothelium from human arteries. Transgenic mice overexpressing S-endoglin in ECs showed hypertension, decreased hypertensive response to NO inhibition, decreased vasodilatory response to TGF-beta(1) administration, and decreased endothelial nitric oxide synthase expression in lungs and kidneys, supporting the involvement of S-endoglin in the NO-dependent vascular homeostasis. Taken together, these results suggest that S-endoglin is induced during endothelial senescence and may contribute to age-dependent vascular pathology.
Endoglin (CD105) is a cell membrane glycoprotein over-expressed on highly proliferating endothelial cells in culture, and on endothelial cells of angiogenetic blood vessels within benign and malignant tissues. CD105 binds several factors of the Transforming Growth Factor (TGF)-beta superfamily, and its over-expression modulates cellular responses to TGF-beta1. The complex of experimental findings accumulated in the last few years strongly indicate that CD105 is a powerful marker of angiogenesis, and that it might play a critical role in the pathogenesis of vascular diseases and in tumor progression. In this paper, we will review the structural, biological and functional features of CD105, as well as its distribution within normal and neoplastic tissues, emphasizing its foreseeable role as a molecular target for new diagnostic and bioimmunotherapeutic approaches in human malignancies.
Endoglin is an integral membrane glycoprotein predominantly expressed on human endothelial cells and recently shown to bind transforming growth factor-beta 1 (TGF beta 1) with high affinity. We now report the cloning and sequencing of a full-length murine endoglin complementary DNA of 2902 base pairs which hybridizes specifically with a single messenger RNA (mRNA) species. The polypeptide of 653 amino acids has an overall identity of 72% with human and porcine endoglin. The transmembrane and cytoplasmic domains of all three proteins differ by two to four amino acids and are 70% identical to the corresponding regions of the TGF beta binding protein, betaglycan. Relative levels of murine endoglin mRNA were estimated by polymerase chain reaction and found to be high in ovary and uterus, intermediate in heart and muscle, and low in placenta and spleen. In situ hybridization and immunofluorescence confirmed that murine endoglin, like its human counterpart, is present in blood vessels and capillaries in all tissues examined. In addition, the stromal cells in the connective tissue of intestine, stomach, heart, muscle, uterus, ovary, and testis were strongly and specifically reactive with complementary RNA probes and with a polyclonal antibody to endoglin; epithelial cell layers were distinctly unreactive. This distribution is similar to that of extracellular TGF beta 1, particularly in heart and uterus, and suggests that endoglin on stromal fibroblast-like cells might be regulating access of TGF beta 1 to the signaling receptor complex. NCTC-2071 fibroblasts in culture were shown to express high levels of endoglin mRNA by polymerase chain reaction. After chemical cross-linking with [125I]TGF beta 1 and immunoprecipitation with the polyclonal antihuman endoglin serum, a radiolabeled band of mol wt 180,000 corresponding to dimeric endoglin was observed under nonreducing conditions, whereas a single band of mol wt 90,000 was seen under reducing conditions. Thus murine fibroblast endoglin is capable of binding TGF beta 1. Future studies should establish the specialized role of endoglin in the TGF beta receptor complex of endothelial and stromal cells.
ALK1 is an endothelial-specific type I receptor of the TGFbeta receptor family whose heterozygous mutations cause hereditary hemorrhagic telangiectasia type 2. Although TGFbeta1 and TGFbeta3 have been shown to bind ALK1 under specific experimental conditions, they may not represent the physiological ligands for this receptor. In the present study, we demonstrate that BMP9 induces the phosphorylation of Smad1/5/8 in microvascular endothelial cells, and this phosphorylation lasts over a period of 24 hours. BMP9 also activates the ID1 promoter-derived BMP response element (BRE) in a dose-dependent manner (EC50 = 45 +/- 27 pg/mL), and this activation is abolished by silencing ALK1 expression or addition of ALK1 extracellular domain. Overexpression of endoglin increases the BMP9 response, whereas silencing of both BMPRII and ActRIIA expressions completely abolishes it. BMP10, which is structurally close to BMP9, is also a potent ALK1 ligand. Finally, we demonstrate that BMP9 and BMP10 potently inhibit endothelial cell migration and growth, and stimulate endothelial expression of a panel of genes that was previously reported to be activated by the constitutively active form of ALK1. Taken together, our results suggest that BMP9 and BMP10 are two specific ALK1 ligands that may physiologically trigger the effects of ALK1 on angiogenesis.
Positive regulation of pathway-restricted SMAD protein phosphorylationdefinition[GO:0010862]
Any process that increases the rate, frequency or extent of pathway-restricted SMAD protein phosphorylation. Pathway-restricted SMAD proteins and common-partner SMAD proteins are involved in the transforming growth factor beta receptor signaling pathways.
Endoglin is an auxiliary component of the transforming growth factor-beta (TGF-beta) receptor system, able to associate with the signaling receptor types I (TbetaRI) and II (TbetaRII) in the presence of ligand and to modulate the cellular responses to TGF-beta1. Endoglin cannot bind ligand on its own but requires the presence of the signaling receptors, supporting a critical role for the interaction between endoglin and TbetaRI or TbetaRII. This study shows that full-length endoglin interacts with both TbetaRI and TbetaRII, independently of their kinase activation state or the presence of exogenous TGF-beta1. Truncated constructs encoding either the extracellular or the cytoplasmic domains of endoglin demonstrated that the association with the signaling receptors occurs through both extracellular and cytoplasmic domains. However, a more specific mapping revealed that the endoglin/TbetaRI interaction was different from that of endoglin/TbetaRII. TbetaRII interacts with the amino acid region 437-558 of the extracellular domain of endoglin, whereas TbetaRI interacts not only with the region 437-558 but also with the protein region located between amino acid 437 and the N terminus. Both TbetaRI and TbetaRII interact with the cytoplasmic domain of endoglin, but TbetaRI only interacts when the kinase domain is inactive, whereas TbetaRII remains associated in its active and inactive forms. Upon association, TbetaRI and TbetaRII phosphorylate the endoglin cytoplasmic domain, and then TbetaRI, but not TbetaRII, kinase dissociates from the complex. Conversely, endoglin expression results in an altered phosphorylation state of TbetaRII, TbetaRI, and downstream Smad proteins as well as a modulation of TGF-beta signaling, as measured by the reporter gene expression. These results suggest that by interacting through its extracellular and cytoplasmic domains with the signaling receptors, endoglin might affect TGF-beta responses.
Senescence of endothelial cells (ECs) may contribute to age-associated cardiovascular diseases, including atherosclerosis and hypertension. The functional and gene expression changes associated with cellular senescence are poorly understood. Here, we have analyzed the expression, during EC senescence, of 2 different isoforms (L, long; S, short) of endoglin, an auxiliary transforming growth factor (TGF)-beta receptor involved in vascular remodeling and angiogenesis. As evidenced by RT-PCR, the S/L ratio of endoglin isoforms was increased during senescence of human ECs in vitro, as well as during aging of mice in vascularized tissues. Next, the effect of S-endoglin protein on the TGF-beta receptor complex was studied. As revealed by coimmunoprecipitation assays, S-endoglin was able to interact with both TGF-beta type I receptors, ALK5 and ALK1, although the interaction with ALK5 was stronger than with ALK1. S-endoglin conferred a lower proliferation rate to ECs and behaved differently from L-endoglin in relation to TGF-beta-responsive reporters with ALK1 or ALK5 specificities, mimicking the behavior of the endothelial senescence markers Id1 and plasminogen activator inhibitor-1. In situ hybridization studies demonstrated the expression of S-endoglin in the endothelium from human arteries. Transgenic mice overexpressing S-endoglin in ECs showed hypertension, decreased hypertensive response to NO inhibition, decreased vasodilatory response to TGF-beta(1) administration, and decreased endothelial nitric oxide synthase expression in lungs and kidneys, supporting the involvement of S-endoglin in the NO-dependent vascular homeostasis. Taken together, these results suggest that S-endoglin is induced during endothelial senescence and may contribute to age-dependent vascular pathology.
Endoglin is an auxiliary component of the transforming growth factor-beta (TGF-beta) receptor system, able to associate with the signaling receptor types I (TbetaRI) and II (TbetaRII) in the presence of ligand and to modulate the cellular responses to TGF-beta1. Endoglin cannot bind ligand on its own but requires the presence of the signaling receptors, supporting a critical role for the interaction between endoglin and TbetaRI or TbetaRII. This study shows that full-length endoglin interacts with both TbetaRI and TbetaRII, independently of their kinase activation state or the presence of exogenous TGF-beta1. Truncated constructs encoding either the extracellular or the cytoplasmic domains of endoglin demonstrated that the association with the signaling receptors occurs through both extracellular and cytoplasmic domains. However, a more specific mapping revealed that the endoglin/TbetaRI interaction was different from that of endoglin/TbetaRII. TbetaRII interacts with the amino acid region 437-558 of the extracellular domain of endoglin, whereas TbetaRI interacts not only with the region 437-558 but also with the protein region located between amino acid 437 and the N terminus. Both TbetaRI and TbetaRII interact with the cytoplasmic domain of endoglin, but TbetaRI only interacts when the kinase domain is inactive, whereas TbetaRII remains associated in its active and inactive forms. Upon association, TbetaRI and TbetaRII phosphorylate the endoglin cytoplasmic domain, and then TbetaRI, but not TbetaRII, kinase dissociates from the complex. Conversely, endoglin expression results in an altered phosphorylation state of TbetaRII, TbetaRI, and downstream Smad proteins as well as a modulation of TGF-beta signaling, as measured by the reporter gene expression. These results suggest that by interacting through its extracellular and cytoplasmic domains with the signaling receptors, endoglin might affect TGF-beta responses.
Senescence of endothelial cells (ECs) may contribute to age-associated cardiovascular diseases, including atherosclerosis and hypertension. The functional and gene expression changes associated with cellular senescence are poorly understood. Here, we have analyzed the expression, during EC senescence, of 2 different isoforms (L, long; S, short) of endoglin, an auxiliary transforming growth factor (TGF)-beta receptor involved in vascular remodeling and angiogenesis. As evidenced by RT-PCR, the S/L ratio of endoglin isoforms was increased during senescence of human ECs in vitro, as well as during aging of mice in vascularized tissues. Next, the effect of S-endoglin protein on the TGF-beta receptor complex was studied. As revealed by coimmunoprecipitation assays, S-endoglin was able to interact with both TGF-beta type I receptors, ALK5 and ALK1, although the interaction with ALK5 was stronger than with ALK1. S-endoglin conferred a lower proliferation rate to ECs and behaved differently from L-endoglin in relation to TGF-beta-responsive reporters with ALK1 or ALK5 specificities, mimicking the behavior of the endothelial senescence markers Id1 and plasminogen activator inhibitor-1. In situ hybridization studies demonstrated the expression of S-endoglin in the endothelium from human arteries. Transgenic mice overexpressing S-endoglin in ECs showed hypertension, decreased hypertensive response to NO inhibition, decreased vasodilatory response to TGF-beta(1) administration, and decreased endothelial nitric oxide synthase expression in lungs and kidneys, supporting the involvement of S-endoglin in the NO-dependent vascular homeostasis. Taken together, these results suggest that S-endoglin is induced during endothelial senescence and may contribute to age-dependent vascular pathology.
Senescence of endothelial cells (ECs) may contribute to age-associated cardiovascular diseases, including atherosclerosis and hypertension. The functional and gene expression changes associated with cellular senescence are poorly understood. Here, we have analyzed the expression, during EC senescence, of 2 different isoforms (L, long; S, short) of endoglin, an auxiliary transforming growth factor (TGF)-beta receptor involved in vascular remodeling and angiogenesis. As evidenced by RT-PCR, the S/L ratio of endoglin isoforms was increased during senescence of human ECs in vitro, as well as during aging of mice in vascularized tissues. Next, the effect of S-endoglin protein on the TGF-beta receptor complex was studied. As revealed by coimmunoprecipitation assays, S-endoglin was able to interact with both TGF-beta type I receptors, ALK5 and ALK1, although the interaction with ALK5 was stronger than with ALK1. S-endoglin conferred a lower proliferation rate to ECs and behaved differently from L-endoglin in relation to TGF-beta-responsive reporters with ALK1 or ALK5 specificities, mimicking the behavior of the endothelial senescence markers Id1 and plasminogen activator inhibitor-1. In situ hybridization studies demonstrated the expression of S-endoglin in the endothelium from human arteries. Transgenic mice overexpressing S-endoglin in ECs showed hypertension, decreased hypertensive response to NO inhibition, decreased vasodilatory response to TGF-beta(1) administration, and decreased endothelial nitric oxide synthase expression in lungs and kidneys, supporting the involvement of S-endoglin in the NO-dependent vascular homeostasis. Taken together, these results suggest that S-endoglin is induced during endothelial senescence and may contribute to age-dependent vascular pathology.
Endoglin (CD105) is a cell membrane glycoprotein over-expressed on highly proliferating endothelial cells in culture, and on endothelial cells of angiogenetic blood vessels within benign and malignant tissues. CD105 binds several factors of the Transforming Growth Factor (TGF)-beta superfamily, and its over-expression modulates cellular responses to TGF-beta1. The complex of experimental findings accumulated in the last few years strongly indicate that CD105 is a powerful marker of angiogenesis, and that it might play a critical role in the pathogenesis of vascular diseases and in tumor progression. In this paper, we will review the structural, biological and functional features of CD105, as well as its distribution within normal and neoplastic tissues, emphasizing its foreseeable role as a molecular target for new diagnostic and bioimmunotherapeutic approaches in human malignancies.
Endoglin (CD105) is a cell membrane glycoprotein over-expressed on highly proliferating endothelial cells in culture, and on endothelial cells of angiogenetic blood vessels within benign and malignant tissues. CD105 binds several factors of the Transforming Growth Factor (TGF)-beta superfamily, and its over-expression modulates cellular responses to TGF-beta1. The complex of experimental findings accumulated in the last few years strongly indicate that CD105 is a powerful marker of angiogenesis, and that it might play a critical role in the pathogenesis of vascular diseases and in tumor progression. In this paper, we will review the structural, biological and functional features of CD105, as well as its distribution within normal and neoplastic tissues, emphasizing its foreseeable role as a molecular target for new diagnostic and bioimmunotherapeutic approaches in human malignancies.
Endoglin (CD105) is a cell membrane glycoprotein over-expressed on highly proliferating endothelial cells in culture, and on endothelial cells of angiogenetic blood vessels within benign and malignant tissues. CD105 binds several factors of the Transforming Growth Factor (TGF)-beta superfamily, and its over-expression modulates cellular responses to TGF-beta1. The complex of experimental findings accumulated in the last few years strongly indicate that CD105 is a powerful marker of angiogenesis, and that it might play a critical role in the pathogenesis of vascular diseases and in tumor progression. In this paper, we will review the structural, biological and functional features of CD105, as well as its distribution within normal and neoplastic tissues, emphasizing its foreseeable role as a molecular target for new diagnostic and bioimmunotherapeutic approaches in human malignancies.
Transforming growth factor-beta (TGF-beta) signaling in endothelial cells is able to modulate angiogenesis and vascular remodeling, although the underlying molecular mechanisms remain poorly understood. Endoglin and ALK-1 are components of the TGF-beta receptor complex, predominantly expressed in endothelial cells, and mutations in either endoglin or ALK-1 genes are responsible for the vascular dysplasia known as hereditary hemorrhagic telangiectasia. Here we find that the extracellular and cytoplasmic domains of the auxiliary TGF-beta receptor endoglin interact with ALK-1 (a type I TGF-beta receptor). In addition, endoglin potentiates TGF-beta/ALK1 signaling, with the extracellular domain of endoglin contributing to this functional cooperation between endoglin and ALK-1. By contrast, endoglin appears to interfere with TGF-beta/ALK-5 signaling. These results suggest that the functional association of endoglin with ALK-1 is critical for the endothelial responses to TGF-beta.
Transforming growth factor-beta (TGF-beta) signaling in endothelial cells is able to modulate angiogenesis and vascular remodeling, although the underlying molecular mechanisms remain poorly understood. Endoglin and ALK-1 are components of the TGF-beta receptor complex, predominantly expressed in endothelial cells, and mutations in either endoglin or ALK-1 genes are responsible for the vascular dysplasia known as hereditary hemorrhagic telangiectasia. Here we find that the extracellular and cytoplasmic domains of the auxiliary TGF-beta receptor endoglin interact with ALK-1 (a type I TGF-beta receptor). In addition, endoglin potentiates TGF-beta/ALK1 signaling, with the extracellular domain of endoglin contributing to this functional cooperation between endoglin and ALK-1. By contrast, endoglin appears to interfere with TGF-beta/ALK-5 signaling. These results suggest that the functional association of endoglin with ALK-1 is critical for the endothelial responses to TGF-beta.
Any process that results in a change in state or activity of a cell or an organism (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stimulus indicating lowered oxygen tension. Hypoxia, defined as a decline in O2 levels below normoxic levels of 20.8 - 20.95%, results in metabolic adaptation at both the cellular and organismal level.
Endoglin, a co-receptor for transforming growth factor (TGF)-beta 1 and -beta 3 is expressed in the human placenta and plays an important role in the pathogenesis of preeclampsia. Because preeclampsia is associated with hypoxia, and because TGF-beta 3 is overexpressed in preeclamptic pregnancies, we examined the effect of oxygen and TGF-beta 3 on placental endoglin expression and investigated its expression in pathological models of placental hypoxia such as intrauterine growth restriction (IUGR) pregnancies. Endoglin expression was high at 4 to 9 weeks of gestation, when oxygen tension is low, and decreased after 10 weeks, when oxygen tension increases. Exposure of villous explants to low oxygen (3% O2) resulted in elevated expression of both membrane and soluble endoglin compared to standard conditions (20% O2). Moreover, addition of TGF-beta 3 to villous explants under low oxygen conditions increased the expression of endoglin compared to nontreated explants whereas addition of TGF-beta 3-neutralizing antibodies inhibited the low oxygen stimulatory effect on endoglin expression. Endoglin and soluble endoglin expression were significantly increased in placentas of IUGR singletons compared to controls and in the IUGR twin placentas relative to both the control co-twin and the normal twins. These data demonstrate that oxygen regulates the placental expression of endoglin via TGF-beta 3. Reduced placental perfusion leading to placental hypoxia might contribute to the increased expression of endoglin in IUGR pregnancies.
Endoglin is an integral membrane glycoprotein predominantly expressed on human endothelial cells and recently shown to bind transforming growth factor-beta 1 (TGF beta 1) with high affinity. We now report the cloning and sequencing of a full-length murine endoglin complementary DNA of 2902 base pairs which hybridizes specifically with a single messenger RNA (mRNA) species. The polypeptide of 653 amino acids has an overall identity of 72% with human and porcine endoglin. The transmembrane and cytoplasmic domains of all three proteins differ by two to four amino acids and are 70% identical to the corresponding regions of the TGF beta binding protein, betaglycan. Relative levels of murine endoglin mRNA were estimated by polymerase chain reaction and found to be high in ovary and uterus, intermediate in heart and muscle, and low in placenta and spleen. In situ hybridization and immunofluorescence confirmed that murine endoglin, like its human counterpart, is present in blood vessels and capillaries in all tissues examined. In addition, the stromal cells in the connective tissue of intestine, stomach, heart, muscle, uterus, ovary, and testis were strongly and specifically reactive with complementary RNA probes and with a polyclonal antibody to endoglin; epithelial cell layers were distinctly unreactive. This distribution is similar to that of extracellular TGF beta 1, particularly in heart and uterus, and suggests that endoglin on stromal fibroblast-like cells might be regulating access of TGF beta 1 to the signaling receptor complex. NCTC-2071 fibroblasts in culture were shown to express high levels of endoglin mRNA by polymerase chain reaction. After chemical cross-linking with [125I]TGF beta 1 and immunoprecipitation with the polyclonal antihuman endoglin serum, a radiolabeled band of mol wt 180,000 corresponding to dimeric endoglin was observed under nonreducing conditions, whereas a single band of mol wt 90,000 was seen under reducing conditions. Thus murine fibroblast endoglin is capable of binding TGF beta 1. Future studies should establish the specialized role of endoglin in the TGF beta receptor complex of endothelial and stromal cells.
A series of molecular signals initiated by the binding of an extracellular ligand to a transforming growth factor beta receptor on the surface of a target cell, and ending with regulation of a downstream cellular process, e.g. transcription.
Endoglin is a cell-surface adhesion protein as well as a coreceptor for transforming growth factor-beta (TGF-beta). It is located on endothelial and few other cells, but also found on certain tumor cells. Brain metastatic breast tumor cells derived from the MDA-MB-231 cell line heavily express endoglin in contrast to the corresponding parental ones. To clarify whether this determines their invasive phenotype, we compared their biological properties with endoglin-silenced brain-metastatic cells, low-expressing parental cells and these transfected with L- and S-endoglins, isoforms transducing or lacking TGF-beta signals. All L-endoglin-overexpressing cells were characterized by numerous invadopodia where endoglin was preferentially localized. Endoglin-expression resulted in elevated levels of the matrix metalloproteinases (MMP-1 and MMP-19) and downregulation of the plasminogen activator inhibitor-1. In Boyden-chamber and wound-healing assays, endoglin-overexpressing cells showed a considerably higher migration and chemotaxis to TGF-beta. In 3D spheroid confrontation assays between breast tumor cells and TGF-beta-secreting glioma cells, high L-endoglin-expressing cells invaded into the glioma-spheroids whereas low-endoglin-expressing cells dissociated in the culture; invasion was blocked by TGF-beta antibodies. In contrast to parental cells, endoglin-overexpressing cells invaded deeply into mouse brain slices. Thus, endoglin expression on tumor cells enhances their invasive character by formation of invadopodia, extracellular proteolysis, chemotaxis and migration.
Hereditary haemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by multisystemic vascular dysplasia and recurrent haemorrhage. Linkage for some families has been established to chromosome 9q33-q34. In the present study, endoglin, a transforming growth factor beta (TGF-beta) binding protein, was analysed as a candidate gene for the disorder based on chromosomal location, expression pattern and function. We have identified mutations in three affected individuals: a C to G substitution converting a tyrosine to a termination codon, a 39 base pair deletion and a 2 basepair deletion which creates a premature termination codon. We have identified endoglin as the HHT gene mapping to 9q3 and have established HHT as the first human disease defined by a mutation in a member of the TGF-beta receptor complex.
The process in which the anatomical structures of venous blood vessels are generated and organized. Veins are blood vessels that transport blood from the body and its organs to the heart.
Evidence
1:
Inferred from Sequence or Structural SimilarityBHF-UCL
Endoglin is an integral membrane glycoprotein predominantly expressed on human endothelial cells and recently shown to bind transforming growth factor-beta 1 (TGF beta 1) with high affinity. We now report the cloning and sequencing of a full-length murine endoglin complementary DNA of 2902 base pairs which hybridizes specifically with a single messenger RNA (mRNA) species. The polypeptide of 653 amino acids has an overall identity of 72% with human and porcine endoglin. The transmembrane and cytoplasmic domains of all three proteins differ by two to four amino acids and are 70% identical to the corresponding regions of the TGF beta binding protein, betaglycan. Relative levels of murine endoglin mRNA were estimated by polymerase chain reaction and found to be high in ovary and uterus, intermediate in heart and muscle, and low in placenta and spleen. In situ hybridization and immunofluorescence confirmed that murine endoglin, like its human counterpart, is present in blood vessels and capillaries in all tissues examined. In addition, the stromal cells in the connective tissue of intestine, stomach, heart, muscle, uterus, ovary, and testis were strongly and specifically reactive with complementary RNA probes and with a polyclonal antibody to endoglin; epithelial cell layers were distinctly unreactive. This distribution is similar to that of extracellular TGF beta 1, particularly in heart and uterus, and suggests that endoglin on stromal fibroblast-like cells might be regulating access of TGF beta 1 to the signaling receptor complex. NCTC-2071 fibroblasts in culture were shown to express high levels of endoglin mRNA by polymerase chain reaction. After chemical cross-linking with [125I]TGF beta 1 and immunoprecipitation with the polyclonal antihuman endoglin serum, a radiolabeled band of mol wt 180,000 corresponding to dimeric endoglin was observed under nonreducing conditions, whereas a single band of mol wt 90,000 was seen under reducing conditions. Thus murine fibroblast endoglin is capable of binding TGF beta 1. Future studies should establish the specialized role of endoglin in the TGF beta receptor complex of endothelial and stromal cells.
Endoglin is a cell-surface adhesion protein as well as a coreceptor for transforming growth factor-beta (TGF-beta). It is located on endothelial and few other cells, but also found on certain tumor cells. Brain metastatic breast tumor cells derived from the MDA-MB-231 cell line heavily express endoglin in contrast to the corresponding parental ones. To clarify whether this determines their invasive phenotype, we compared their biological properties with endoglin-silenced brain-metastatic cells, low-expressing parental cells and these transfected with L- and S-endoglins, isoforms transducing or lacking TGF-beta signals. All L-endoglin-overexpressing cells were characterized by numerous invadopodia where endoglin was preferentially localized. Endoglin-expression resulted in elevated levels of the matrix metalloproteinases (MMP-1 and MMP-19) and downregulation of the plasminogen activator inhibitor-1. In Boyden-chamber and wound-healing assays, endoglin-overexpressing cells showed a considerably higher migration and chemotaxis to TGF-beta. In 3D spheroid confrontation assays between breast tumor cells and TGF-beta-secreting glioma cells, high L-endoglin-expressing cells invaded into the glioma-spheroids whereas low-endoglin-expressing cells dissociated in the culture; invasion was blocked by TGF-beta antibodies. In contrast to parental cells, endoglin-overexpressing cells invaded deeply into mouse brain slices. Thus, endoglin expression on tumor cells enhances their invasive character by formation of invadopodia, extracellular proteolysis, chemotaxis and migration.
A reference proteome is a set of protein sequences derived from a complete proteome which constitutes a defined standard for a particular user community. Reference proteomes are manually defined according to a number of criteria. They cover the proteomes of well- studied model organisms and other proteomes of interest for biomedical and biotechnological research. Reference proteomes have been selected to provide broad coverage of the tree of life, and constitute a representative cross-section of the taxonomic diversity to be found within UniProtKB.
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