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 telangie ctasia type I (HHT1), a dominantly inherited vascular disorder. It shares w ith 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 en doglin led to a decreased TGF-beta response to cellular growth inhibition a nd plasminogen activator inhibitor-1 synthesis, whereas overexpression of b etaglycan resulted in an enhanced response to inhibition of cellular prolif eration and plasminogen activator inhibitor-1 induced expression in the pre sence of TGF-beta. The regulation by endoglin of TGF-beta responses seems t o reside on the extracellular domain, as evidenced by the functional analys is of two chimeric proteins containing different combinations of endoglin a nd betaglycan domains. Binding followed by cross-linking with I-125-TGF-bet a 1 demonstrated that betaglycan expressing cells displayed a clear increas e (about 3.5-fold), whereas endoglin expressing cells only displayed an sli ght increment (about 1.6-fold) in ligand binding with respect to mock trans fectants. SDS-polyacrylamide gel electrophoresis analysis of radiolabeled r eceptors demonstrated that expression of endoglin or betaglycan is associat ed with an increased TGF-beta binding to the signaling receptor complex; ho wever, while endoglin increased binding to types I and II receptors, betagl ycan increased the binding to the type II receptor. Conversely, we found th at TGF-beta binding to endoglin required the presence of receptor type II a s evidenced by transient transfections experiments in COS cells, These find ings suggest a role for endoglin in TGF-beta responses distinct from that o f betaglycan.