TGF beta (transforming growth factor beta) receptor type III directs clathrin-mediated endocytosis of TGF beta receptor types I and II.

The TGFbeta (transforming growth factor beta) pathway is an essential cell signalling pathway that is implicated in both normal developmental processes, such as organogenesis, and pathological disorders, such as cancer and fibrosis. There are three prototypical TbetaRs (TGFbeta receptors): TbetaRI (TbetaR type I), TGbetaRII (TbetaR type II) and TGFbetaRIII (TbetaR type III, also known as betaglycan). Whereas the role of TbetaRII and TbetaRI in TGFbeta signal propagation has been established, the contribution of TbetaRIII to TGFbeta signalling is less well understood. At the cell surface, TbetaRI and TbetaRII receptors can be internalized by clathrin-mediated endocytosis and clathrin-independent membrane-raft-dependent endocytosis. Interestingly, the endocytic route of the receptors plays a direct role in TGFbeta-dependent Smad signal transduction; receptors endocytosed via clathrin-mediated endocytosis activate Smad signalling, whereas receptors endocytosed via membrane rafts are targeted for degradation. The objective of the present study was to evaluate the contribution of TbetaRIII to TbetaRII and TbetaRI membrane partitioning, receptor half-life and signalling. Using sucrose-density ultracentrifugation to isolate membrane-raft fractions, we show that TbetaRIII recruits both TbetaRII and TbetaRI to non-raft membrane fractions. Immunofluorescence microscopy analysis demonstrated that overexpression of TbetaRIII affects intracellular trafficking of TbetaRII by recruiting TbetaRII to EEA1 (early endosome antigen 1)- and Rab5-positive early endosomes. Using 125I-labelled TGFbeta1 to follow cell-surface receptor degradation we show that overexpression of TbetaRIII also extends the receptor half-life of the TbetaRII-TbetaRI complex. Interestingly, we also show, using a luciferase reporter assay, that TbetaRIII increases basal TGFbeta signalling. As numerous pathologies show aberrant activation of TGFbeta signalling, the present study illustrates that TbetaRIII may represent a novel therapeutic target.