The RING finger protein11 binds to Smad4 and enhances Smad4-dependant TGF-beta signalling.
BACKGROUND
In breast carcinomas, prolonged signalling through the TGF-beta receptor promotes latent tumour progression, metastasis and the epithelial-to-mesenchymal transition of tumour cells. Previously, it has been found that the 154 amino acid RING finger protein, RNF11, was overexpressed in high-grade breast tumours and was capable of modulating TGF-beta signalling.


METHODS
Utilizing cellular and biochemical assays, key interactions and molecular roles for the RNF11 protein in the TGF-beta pathway were explored.


RESULTS
It is shown that RNF11 is required for TGF-beta signalling and is capable of enhancing the Smad-TGF-beta signalling pathway directly. Further, that endogenous RNF11 and Smad4 proteins associate and co-localize in a TGF-beta-enhanced manner. This study indicates that RNF11 induces an increase in Smad4 protein levels. In functional assays, it is observed that RNF11 enhances Smad4-dependant TGF-beta signalling and that RNF11 alone can recapitulate Smad4-dependant apoptosis in cellular assays.


CONCLUSIONS
RNF11 acts directly on Smad4 to enhance Smad4 function, and plays a role in prolonged TGF-beta signalling and possibly in latent tumour progression.
Azmi
Peter B
PB
Department of Molecular and Cellular Biology, Sunnybrook Research Institute, and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, M4N 3M5, Canada.
Seth
Arun K
AK
D017209:Apoptosis; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D005455:Fluorescent Antibody Technique; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism
D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C404508:RNF11 protein, human; C497796:SMAD4 protein, human; D051901:Smad4 Protein; D016212:Transforming Growth Factor beta; D025801:Ubiquitin