Regulation of TGF-ß Signal Transduction

Zhao, Bing; Chen, Ye-Guang

TGF-receptors are partitioned between the lipid rafts and nonraft areas on the plasma membrane [27] [28] [29] [30] [31] [32] . Ligand binding to its receptor at the cell surface not only initiates signaling events but also triggers internalization of both ligand and receptors. We and others have demonstrated that TGF-receptors can be endocytosed via clathrin-coated vesicles as TGF-endocytosis can be blocked by potassium depletion and the GTPase deficient dynamin K44A mutant [33] [34] [35] . Internalization of TGF-receptors through clathrindependent endocytosis to EEA1-positive endosomes is more likely to promote signaling as the FYVE domain-containing protein SARA are enriched in EEA1-positive endosomes and can facilitate R-Smads activation [36] [37] [38] . To support this idea, we found that endofin, which share a homology with SARA, can interact with TGF-receptors and Smad4 and promote TGF--induced Smad complex formation [39] . The internalized receptors can be recycled to the membrane in a Rab11-dependent manner [40] . TGF-receptors located in lipid raft regions enter cells via lipid raft/caveolae and are found in caveolin-positive vesicles [36] . Lipid raft/caveolae is indicated to facilitate the degradation of TGF-receptors and therefore turnoff of TGF-signaling ( Figure 1 ).