Ligand-dependent and -independent Transforming Growth Factor-β Receptor Recycling Regulated by Clathrin-mediated Endocytosis and Rab11

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Abstract
Proteins in the transforming growth factor-β (TGF-β) family recognize transmembrane serine/threonine kinases known as type I and type II receptors. Binding of TGF-β to receptors results in receptor down-regulation and signaling. Whereas previous work has focused on activities controlling TGF-β signaling, more recent studies have begun to address the trafficking properties of TGF-β receptors. In this report, it is shown that receptors undergo recycling both in the presence and absence of ligand activation, with the rates of internalization and recycling being unaffected by ligand binding. Recycling occurs as receptors are most likely internalized through clathrin-coated pits, and then returned to the plasma membrane via a rab11-dependent, rab4-independent mechanism. Together, the results suggest a mechanism wherein activated TGF-β receptors are directed to a distinct endocytic pathway for down-regulation and clathrin-dependent degradation after one or more rounds of recycling.