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.
UPMC, Université Paris 06, UMR S 938, CDR Saint-Antoine, Hôpital Saint-Antoine, Paris, France.
Nathalie
N
Ferrand
Azeddine
A
Atfi
Céline
C
Prunier
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology; D002467:Cell Nucleus / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000502:physiology*; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008545:Melanoma / Q000378:metabolism* / Q000556:secondary; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021381:Protein Transport; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D012867:Skin / Q000378:metabolism / Q000473:pathology; D051896:Smad Proteins, Receptor-Regulated / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D046888:Tissue Array Analysis; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014407:Tumor Cells, Cultured
D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; D018125:Receptors, Transforming Growth Factor beta; C060615:SKIL protein, human; D051896:Smad Proteins, Receptor-Regulated; D051899:Smad2 Protein; D051900:Smad3 Protein; D016212:Transforming Growth Factor beta; C060614:SKI protein, human; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I