AbstractBackgroundJeffis a dominant mouse mutant displaying chronic otitis media. The gene underlyingJeffisFbxo11, a member of the large F-box family, which are specificity factors for the SCF E3 ubiquitin ligase complex.Jeffhomozygotes die shortly after birth displaying a number of developmental abnormalities including cleft palate and eyes open at birth. TGF-β signalling is involved in a number of epithelial developmental processes and we have investigated the impact of theJeffmutation on the expression of this pathway.ResultsPhospho-Smad2 (pSmad2) is significantly upregulated in epithelia ofJeffhomozygotes. Moreover, there was a significant increase in nuclear localization of pSmad2 in contrast to wild type. Mice heterozygous for bothJeffandSmad2mutations recapitulate many of the features of theJeffhomozygous phenotype. However, tissue immunoprecipitations failed to detect any interaction betweenFbxo11andSmad2. Fbxo11 is known to neddylate p53, a co-factor of pSmad2, but we did not find any evidence of genetic interactions betweenJeffandp53mutants. Nevertheless, p53 levels are substantially reduced inJeffmice suggesting that Fbxo11 plays a role in stabilizing p53.ConclusionOverall, our findings support a model wherebyFbxo11, possibly via stabilization of p53, is required to limit the accumulation of pSmad2 in the nucleus of epithelial cells of palatal shelves, eyelids and airways of the lungs. The finding thatFbxo11impacts upon TGF-β signalling has important implications for our understanding of the underlying disease mechanisms of middle ear inflammatory disease.