The TGFβ (transforming growth factor β) 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 TβRs (TGFβ receptors): TβRI (TβR type I), TGβRII (TβR type II) and TGFβRIII (TβR type III, also known as betaglycan). Whereas the role of TβRII and TβRI in TGFβ signal propagation has been established, the contribution of TβRIII to TGFβ signalling is less well understood. At the cell surface, TβRI and TβRII 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 TGFβ-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 TβRIII to TβRII and TβRI membrane partitioning, receptor half-life and signalling. Using sucrose-density ultracentrifugation to isolate membrane-raft fractions, we show that TβRIII recruits both TβRII and TβRI to non-raft membrane fractions. Immunofluorescence microscopy analysis demonstrated that overexpression of TβRIII affects intracellular trafficking of TβRII by recruiting TβRII to EEA1 (early endosome antigen 1)- and Rab5-positive early endosomes. Using 125I-labelled TGFβ1 to follow cell-surface receptor degradation we show that overexpression of TβRIII also extends the receptor half-life of the TβRII–TβRI complex. Interestingly, we also show, using a luciferase reporter assay, that TβRIII increases basal TGFβ signalling. As numerous pathologies show aberrant activation of TGFβ signalling, the present study illustrates that TβRIII may represent a novel therapeutic target.
TGFβ (transforming growth factor β) receptor type III directs clathrin-mediated endocytosis of TGFβ receptor types I and II
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Sarah McLean, Gianni M. Di Guglielmo; TGFβ (transforming growth factor β) receptor type III directs clathrin-mediated endocytosis of TGFβ receptor types I and II. Biochem J 1 July 2010; 429 (1): 137–145. doi: https://doi.org/10.1042/BJ20091598
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