Endocytic regulation of TGF-beta signaling

Transforming growth factor-beta (TGF-beta) signaling is tightly regulated to ensure its proper physiological functions in different cells and tissues. Like other cell surface receptors, TGF-beta receptors are internalized into the cell, and this process plays an important regulatory role in TGF-beta signaling. It is well documented that TGF-beta receptors are endocytosed via clathrin-coated vesicles as TGF-beta endocytosis can be blocked by potassium depletion and the GTPase-deficient dynamin K44A mutant. TGF-beta receptors may also enter cells via cholesterol-rich membrane microdomain lipid rafts/caveolae and are found in caveolin-1-positive vesicles. Although receptor endocytosis is not essential for TGF-beta signaling, clathrin-mediated endocytosis has been shown to promote TGF-beta-induced Smad activation and transcriptional responses. Lipid rafts/caveolae are widely regarded as signaling centers for G protein-coupled receptors and tyrosine kinase receptors, but they are indicated to facilitate the degradation of TGF-beta receptors and therefore turnoff of TGF-beta signaling. This review summarizes current understanding of TGF-beta receptor endocytosis, the possible mechanisms underlying this process, and the role of endocytosis in modulation of TGF-beta signaling.