TIF1γ Protein Regulates Epithelial-Mesenchymal Transition by Operating as a Small Ubiquitin-like Modifier (SUMO) E3 Ligase for the Transcriptional Regulator SnoN1

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 mecha...

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Published in:	The Journal of biological chemistry Vol. 289; no. 36; pp. 25067 - 25078
Main Authors:	Ikeuchi, Yoshiho, Dadakhujaev, Shorafidinkhuja, Chandhoke, Amrita S., Huynh, Mai Anh, Oldenborg, Anna, Ikeuchi, Mikako, Deng, Lili, Bennett, Eric J., Harper, J. Wade, Bonni, Azad, Bonni, Shirin
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 05-09-2014 American Society for Biochemistry and Molecular Biology
Subjects:	Amino Acid Sequence Animals Binding Sites - genetics Blotting, Western Cell Biology Cell Culture Techniques Cell Line Epithelial Cells - drug effects Epithelial Cells - metabolism Epithelial-Mesenchymal Transition - drug effects Epithelial-Mesenchymal Transition - genetics Gene Expression - drug effects HEK293 Cells Hep G2 Cells Humans Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - metabolism Mammary Glands, Animal - cytology Mammary Glands, Animal - metabolism Mice Microscopy, Fluorescence Molecular Sequence Data Protein Binding Proto-Oncogene Proteins - genetics Proto-Oncogene Proteins - metabolism Reverse Transcriptase Polymerase Chain Reaction RNA Interference Sequence Homology, Amino Acid Sumoylation - drug effects Transcription Factors - genetics Transcription Factors - metabolism Transforming Growth Factor beta - pharmacology Ubiquitin-Protein Ligases - genetics Ubiquitin-Protein Ligases - metabolism TIF1γ Protein-Protein Interaction Cell Signaling Sumoylation Transforming Growth Factor β (TGFβ) SnoN Epithelial-Mesenchymal Transition (EMT)
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Summary:	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.
Bibliography:	Both authors contributed equally to this work. Present address: Institute of Industrial Science, The University of Tokyo, Tokyo 153-8505, Japan. Present address: Division of Biological Sciences, University of California San Diego, La Jolla, CA 92093.
ISSN:	0021-9258 1083-351X
DOI:	10.1074/jbc.M114.575878