Membrane trafficking regulates the activity and stability of TGF-β receptors. Internalization of TGF-β receptors through clathrin-dependent endocytosis enhances TGF-β-Smad signaling, whereas caveolin-mediated endocytosis promotes the ubiquitination and degradation of the receptors and thus the turnoff of signaling. c-Cbl neddylates TβRII and facilitates its clathrin-dependent endocytosis, while PICK1 promotes lipid raft/caveolae localization and caveolin-mediated endocytosis of TβRI. Dapper2 locates in late endosomes and accelerates the lysosomal degradation of TβRI. The lipid raft localization of TGF-β receptors is critical for TGF-β-mediated MAPK activation.
