Role of endoglin in cellular responses to transforming growth factor-beta. A comparative study with betaglycan.
Endoglin (CD105) is the target gene for the hereditary hemorrhagic telangiectasia type I (HHT1), a dominantly inherited vascular disorder. It shares with betaglycan a limited amino acid sequence homology and being components of the membrane transforming growth factor-beta (TGF-beta) receptor complex. Using rat myoblasts as a model system, we found that overexpression of endoglin led to a decreased TGF-beta response to cellular growth inhibition and plasminogen activator inhibitor-1 synthesis, whereas overexpression of betaglycan resulted in an enhanced response to inhibition of cellular proliferation and plasminogen activator inhibitor-1 induced expression in the presence of TGF-beta. The regulation by endoglin of TGF-beta responses seems to reside on the extracellular domain, as evidenced by the functional analysis of two chimeric proteins containing different combinations of endoglin and betaglycan domains. Binding followed by cross-linking with 125I-TGF-beta1 demonstrated that betaglycan expressing cells displayed a clear increase (about 3. 5-fold), whereas endoglin expressing cells only displayed an slight increment (about 1.6-fold) in ligand binding with respect to mock transfectants. SDS-polyacrylamide gel electrophoresis analysis of radiolabeled receptors demonstrated that expression of endoglin or betaglycan is associated with an increased TGF-beta binding to the signaling receptor complex; however, while endoglin increased binding to types I and II receptors, betaglycan increased the binding to the type II receptor. Conversely, we found that TGF-beta binding to endoglin required the presence of receptor type II as evidenced by transient transfections experiments in COS cells. These findings suggest a role for endoglin in TGF-beta responses distinct from that of betaglycan.
Letamendía
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Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas (CSIC), Velazquez 144, 28006 Madrid, Spain.
Lastres
P
P
Botella
L M
LM
Raab
U
U
Langa
C
C
Velasco
B
B
Attisano
L
L
Bernabeu
C
C
D000818:Animals; D015703:Antigens, CD; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D000071063:Endoglin; D009132:Muscles / Q000166:cytology / Q000378:metabolism; D011509:Proteoglycans / Q000502:physiology*; D051381:Rats; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta / Q000502:physiology*; D015398:Signal Transduction; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000502:physiology*
D015703:Antigens, CD; D017931:DNA Primers; C064206:ENG protein, human; D000071063:Endoglin; D011509:Proteoglycans; D011956:Receptors, Cell Surface; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D019010:Vascular Cell Adhesion Molecule-1; C071736:betaglycan