Reduction of transforming growth factor‐β type II receptor is caused by the enhanced ubiquitin‐dependent degradation in human renal cell carcinoma

Abstract Although dysregulation of transforming growth factor‐β (TGF‐β) signaling is implicated in renal carcinogenesis, its precise mechanism is unknown in renal cell carcinoma (RCC). In our study, we investigated Smad‐mediated TGF‐β signaling pathway and its regulatory mechanisms in surgical samples from patients with RCC. We found that immunoreactivity for nuclear phosphorylated Smad2 was significantly decreased in RCC compared to normal renal tissues, thereby TGF‐β signaling was suggested to be attenuated in RCC tissues. In accordance with the result, transcriptional downregulation of Smad4 and post‐transcriptional downregulation of TGF‐β type II receptor (TβR‐II) were frequently found in RCC tissues compared to normal renal tissues. Next, to clarify the reason why the protein level of TβR‐II was decreased in RCC, we investigated the activities of degradation and ubiquitination of TβR‐II. We found that both proteasome‐mediated degradation and ubiquitination of TβR‐II were markedly enhanced in RCC tissues. Moreover, we found that the level of Smad‐ubiquitination regulatory factor 2 (Smurf2), the E3 ligase for TβR‐II, was increased in RCC tissues of the patients with higher clinical stages compared to the normal tissues and was inversely correlated with the level of TβR‐II. Our results suggest that the low TβR‐II protein level is due to augmented ubiquitin‐dependent degradation via Smurf2 and might be involved in the attenuation of TGF‐β signaling pathway in RCC.