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Keywords:

  • actin cytoskeleton;
  • activin;
  • non-Smad signaling;
  • Rab/Ran/Ral;
  • receptor endocytosis;
  • Rho;
  • Smad signaling;
  • small GTPases;
  • TGFβ;
  • trafficking

The integrated roles of small GTPases in executing the transforming growth factor β (TGFβ) signaling pathway have attracted increasing attention in recent years. In this review, we summarize recent findings on TGFβ signaling during receptor endocytosis, Smad trafficking and actin cytoskeleton remodeling, and emphasize the role of small GTPases in these processes. First, we give an overview of the different endocytic routes taken by TGFβ receptors, their impact on active TGFβ signaling versus degradation and their regulation by the small GTPases Rab, RalA/Ral-binding protein 1 and Rap2. Second, we focus on the mechanisms and regulation of Smad trafficking in the cytoplasm, through the nuclear pores and into the nucleus, and the contribution of Ran GTPase to these events. Third, we summarize the role of Rho small GTPases in early and late cytoskeleton remodeling in various cell models and diseases, and the positive and negative cross-talk between Rho GTPases and the TGFβ/Smad pathway. The biological significance of this exciting research field, the perspectives and critical open questions are discussed.