The FYVE domain of Smad Anchor for Receptor Activation (SARA) is required to prevent skin carcinogenesis, but not in mouse development.

Smad Anchor for Receptor Activation has been reported as a critical role in TGF-β signal transduction by recruiting non-activated Smad2/3 to the TGF-β receptor and ensuring appropriate subcellular localization of the activated receptor-bound complex. However, controversies still exist in previous reports. In this study, we describe the expression of two isoforms, and in mice and report the generation and characterization of duanyu1800 mutant mice with FYVE domain deletion. duanyu1800 mutant mice developed normally and showed no gross abnormalities. Further examination showed that the TGF-β signaling pathway was indeed altered in duanyu1800 mutant mice, with the downregulation of Smad2 protein expression. The decreasing expression of Smad2 was caused by enhancing Smurf2-mediated proteasome degradation pathway. However, the internalization of TGF-β receptors into the early endosome was not affected in duanyu1800 mutant mouse embryonic fibroblasts (MEFs). Moreover, the downregulation of Smad2 in duanyu1800 mutant MEFs was not sufficient to disrupt the diverse cellular biological functions of TGF-β signaling, including growth inhibition, apoptosis, senescence, and the epithelial-to-mesenchymal transition. Our results indicate that duanyu1800 is not involved in the activation process of TGF-β signal transduction. Using a two-stage skin chemical carcinogenesis assay, we found that the loss of duanyu1800 promoted skin tumor formation and malignant progression. Our data suggest a protective role of duanyu1800 in skin carcinogenesis.

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