The Oncoprotein c-Ski Functions as a Direct Antagonist of the Transforming Growth Factor-β Type I Receptor

The oncoprotein c-Ski has been implicated in the negative regulation of transforming growth factor-beta (TGF-beta) signaling owing to its ability to repress Smad transcriptional activity via recruitment of a transcriptional corepressor complex containing histone deacetylases. However, c-Ski has also been shown to localize to the cytoplasm, raising the interesting possibility that it might disable TGF-beta signaling through alternative mechanisms. Here, we provide evidence that c-Ski can restrict TGF-beta signaling by interacting directly with the activated TGF-beta type I receptor (T beta RI). We explored the physiologic relevance of the c-Ski/T beta RI interaction and found that it can culminate in a constitutive association of T beta RI with a nonfunctional R-Smad/Smad4 complex. Based on these findings, we hypothesize that the interaction between c-Ski and T beta RI might interfere with nuclear translocation of the R-Smad/Smad4 complex, thereby attenuating TGF-beta signaling. Such a mechanism may play a crucial role in tumor progression, because many tumors that express high levels of c-Ski also display impaired nuclear accumulation of Smads. Cancer Res; 70(21); 8457-66. (C) 2010 AACR.