Internalization of the TGF-β type I receptor into caveolin-1 and EEA1 double-positive early endosomes

Cell Res. 2015 Jun;25(6):738-52. doi: 10.1038/cr.2015.60. Epub 2015 May 22.


Endocytosis and intracellular sorting of transforming growth factor-β (TGF-β) receptors play an important regulatory role in TGF-β signaling. Two major endocytic pathways, clathrin- and caveolae-mediated endocytosis, have been reported to independently mediate the internalization of TGF-β receptors. In this study, we demonstrate that the clathrin- and caveolae-mediated endocytic pathways can converge during TGF-β receptor endocytic trafficking. By tracking the intracellular dynamics of fluorescently-labeled TGF-β type I receptor (TβRI), we found that after mediating TβRI internalization, certain clathrin-coated vesicles and caveolar vesicles are fused underneath the plasma membrane, forming a novel type of caveolin-1 and clathrin double-positive vesicles. Under the regulation of Rab5, the fused vesicles are targeted to early endosomes and thus deliver the internalized TβRI to the caveolin-1 and EEA1 double-positive early endosomes (caveolin-1-positive early endosomes). We further showed that the caveolin-1-positive early endosomes are positive for Smad3/SARA, Rab11 and Smad7/Smurf2, and may act as a multifunctional device for TGF-β signaling and TGF-β receptor recycling and degradation. Therefore, these findings uncover a novel scenario of endocytosis, the direct fusion of clathrin-coated and caveolae vesicles during TGF-β receptor endocytic trafficking, which leads to the formation of the multifunctional sorting device, caveolin-1-positive early endosomes, for TGF-β receptors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Caveolin 1 / metabolism*
  • Cells, Cultured
  • Endosomes / metabolism*
  • HeLa Cells
  • Humans
  • Microscopy, Electron
  • Protein-Serine-Threonine Kinases / metabolism*
  • Receptor, Transforming Growth Factor-beta Type I
  • Receptors, Transforming Growth Factor beta / metabolism*
  • Vesicular Transport Proteins / metabolism*


  • CAV1 protein, human
  • Caveolin 1
  • Receptors, Transforming Growth Factor beta
  • Vesicular Transport Proteins
  • early endosome antigen 1
  • Protein-Serine-Threonine Kinases
  • Receptor, Transforming Growth Factor-beta Type I