The oncoprotein c-ski functions as a direct antagonist of the transforming growth factor-{beta} type I receptor.

The oncoprotein c-Ski has been implicated in the negative regulation of transforming growth factor-β (TGF-β) 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-β signaling through alternative mechanisms. Here, we provide evidence that c-Ski can restrict TGF-β signaling by interacting directly with the activated TGF-β type I receptor (TβRI). We explored the physiologic relevance of the c-Ski/TβRI interaction and found that it can culminate in a constitutive association of TβRI with a nonfunctional R-Smad/Smad4 complex. Based on these findings, we hypothesize that the interaction between c-Ski and TβRI might interfere with nuclear translocation of the R-Smad/Smad4 complex, thereby attenuating TGF-β 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.
Mesh Terms:
Adenocarcinoma, Breast Neoplasms, Cell Nucleus, Cytoplasm, DNA-Binding Proteins, Female, Humans, Immunoenzyme Techniques, Intracellular Signaling Peptides and Proteins, Lung Neoplasms, Melanoma, Phosphorylation, Protein Transport, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins, Receptors, Transforming Growth Factor beta, Signal Transduction, Skin, Smad Proteins, Receptor-Regulated, Smad2 Protein, Smad3 Protein, Tissue Array Analysis, Transforming Growth Factor beta, Tumor Cells, Cultured
Cancer Res.
Date: Nov. 01, 2010
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