TIF1γ protein regulates epithelial-mesenchymal transition by operating as a Small Ubiquitin-like Modifier (SUMO) E3 ligase for the transcriptional regulator SnoN

Yoshiho Ikeuchi, Shorafidinkhuja Dadakhujaev, Amrita S. Chandhoke, Mai Anh Huynh, Anna Oldenborg, Mikako Ikeuchi, Lili Deng, Eric J. Bennett, J. Wade Harper, Azad Bonni, Shirin Bonni

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Abstract

Epithelial-mesenchymal transition (EMT) is a fundamental cellular process that contributes to epithelial tissue morphogenesis during normal development and in tumor invasiveness and metastasis. The transcriptional regulator SnoN robustly influences EMT in response to the cytokine TGFβ, but the mechanisms that regulate the fundamental role of SnoN in TGFβ-induced EMT are not completely understood. Here we employ interaction proteomics to uncover the signaling protein TIF1γ as a specific interactor of SnoN1 but not the closely related isoform SnoN2. A 16-amino acid peptide within a unique region of SnoN1 mediates the interaction of SnoN1 with TIF1γ. Strikingly, although TIF1γ is thought to act as a ubiquitin E3 ligase, we find that TIF1γ operates as a small ubiquitin-like modifier (SUMO) E3 ligase that promotes the sumoylation of SnoN1 at distinct lysine residues. Importantly, TIF1γ-induced sumoylation is required for the ability of SnoN1 to suppress TGFβ-induced EMT, as assayed by the disruption of the morphogenesis of acini in a physiologically relevant three-dimensional model of normal murine mammary gland (NMuMG) epithelial cells. Collectively, our findings define a novel TIF1γ-SnoN1 sumoylation pathway that plays a critical role in EMT and has important implications for our understanding of TGFβ signaling and diverse biological processes in normal development and cancer biology.

Original languageEnglish
Pages (from-to)25067-25078
Number of pages12
JournalJournal of Biological Chemistry
Volume289
Issue number36
DOIs
StatePublished - Jan 1 2014

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    Ikeuchi, Y., Dadakhujaev, S., Chandhoke, A. S., Huynh, M. A., Oldenborg, A., Ikeuchi, M., Deng, L., Bennett, E. J., Harper, J. W., Bonni, A., & Bonni, S. (2014). TIF1γ protein regulates epithelial-mesenchymal transition by operating as a Small Ubiquitin-like Modifier (SUMO) E3 ligase for the transcriptional regulator SnoN. Journal of Biological Chemistry, 289(36), 25067-25078. https://doi.org/10.1074/jbc.M114.575878