CIN85 modulates TGFβ signaling by promoting the presentation of TGFβ receptors on the cell surface

Members of the transforming growth factor beta (TGF beta) family initiate cellular responses by binding to TGF beta receptor type II (Tf3R11) and type I (TpRI) serine/threonine kinases, whereby Srnad2 and Smad3 are phosphorylated and activated, promoting their association with Smadzi. We report here that T beta RI interacts with the SH3 domains of the adaptor protein CIN85 in response to TGF beta stimulation in a TRAF6-dependent manner. Small interfering RNA mediated knockdown of CIN85 resulted in accumulation of T beta RI in intracellular compartments and diminished TGF beta-stimulated Sniad2 phosphorylation. Overexpression of CIN85 instead increased the amount of T beta RI at the cell surface. This effect was inhibited by a dominant-negative mutant of Rab11, suggesting that CIN85 promoted recycling of TGF beta receptors. CIN85 enhanced TGF beta-stimulated Smad2 phosphorylation, transcriptional responses, and cell migration. CIN85 expression correlated with the degree of malignancy of prostate cancers. Collectively, our results reveal that CIN85 promotes recycling of TGF beta receptors and thereby positively regulates TGF beta signaling.