Figure 4. Potential mechanism for enhancement TGF-β signaling in the presence of receptor mutations.

The endocytosis and subsequent recycling or degradation of TGF-β receptors is an important mechanism for regulating TGF-β signaling. There are two independent endocytic pathways, regulated by accessory protein interactions that exist to regulate TGF-β signaling: A.) the clathrin-mediated pathway leading to receptor recycling, and B.) the caveolin-mediated pathway leading to proteasomal degradation of TGF-β receptors. The TGF-βRII mutations identified in several aneurysm syndromes may contribute to the enhanced TGF-β signaling by facilitating interactions with SARA, or by diminishing association with Smad7, favoring receptor recycling and resulting in prolonged activation of TGF-β signals.