title: TIF1γ protein regulates epithelial-mesenchymal transition by operating as a small ubiquitin-like modifier (SUMO) E3 ligase for the transcriptional regulator SnoN1.
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.
authors: From the Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, the Departments of Neurobiology and.
authors: Yoshiho
authors: Y
authors: Ikeuchi
authors: the Southern Alberta Cancer Research Institute and Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors: Shorafidinkhuja
authors: S
authors: Dadakhujaev
authors: the Southern Alberta Cancer Research Institute and Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors: Amrita S
authors: AS
authors: Chandhoke
authors: the Departments of Neurobiology and.
authors: Mai Anh
authors: MA
authors: Huynh
authors: From the Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110.
authors: Anna
authors: A
authors: Oldenborg
authors: the Departments of Neurobiology and.
authors: Mikako
authors: M
authors: Ikeuchi
authors: the Southern Alberta Cancer Research Institute and Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada.
authors: Lili
authors: L
authors: Deng
authors: Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, and.
authors: Eric J
authors: EJ
authors: Bennett
authors: Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, and.
authors: J Wade
authors: JW
authors: Harper
authors: From the Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, Missouri 63110, the Departments of Neurobiology and sbonni@ucalgary.ca.
authors: Azad
authors: A
authors: Bonni
authors: the Southern Alberta Cancer Research Institute and Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, Alberta T2N 4N1, Canada sbonni@ucalgary.ca.
authors: Shirin
authors: S
authors: Bonni
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D015870:Gene Expression / Q000187:drug effects; D057809:HEK293 Cells; D056945:Hep G2 Cells; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics* / Q000378:metabolism; D008321:Mammary Glands, Animal / Q000166:cytology / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D011485:Protein Binding; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017386:Sequence Homology, Amino Acid; D058207:Sumoylation / Q000187:drug effects; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics* / Q000378:metabolism
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011518:Proto-Oncogene Proteins; C060615:SKIL protein, human; C511956:TRIM33 protein, human; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D044767:Ubiquitin-Protein Ligases
keywords: Cell Signaling; Epithelial-Mesenchymal Transition (EMT); Protein-Protein Interaction; SnoN; Sumoylation; TIF1γ; Transforming Growth Factor β (TGFβ)