TGF-β-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI
Copyright policy )TGF-β-mediated phosphorylation of hnRNP E1 induces EMT via transcript-selective translational induction of Dab2 and ILEI
Transforming growth factor-beta (TGF-beta) induces epithelial-mesenchymal transdifferentiation (EMT) accompanied by cellular differentiation and migration. Despite extensive transcriptomic profiling, the identification of TGF-beta-inducible, EMT-specific genes has met with limited success. Here we identify a post-transcriptional pathway by which TGF-beta modulates the expression of EMT-specific proteins and of EMT itself. We show that heterogeneous nuclear ribonucleoprotein E1 (hnRNP E1) binds a structural, 33-nucleotide TGF-beta-activated translation (BAT) element in the 3' untranslated region of disabled-2 (Dab2) and interleukin-like EMT inducer (ILEI) transcripts, and represses their translation. TGF-beta activation leads to phosphorylation at Ser 43 of hnRNP E1 by protein kinase Bbeta/Akt2, inducing its release from the BAT element and translational activation of Dab2 and ILEI messenger RNAs. Modulation of hnRNP E1 expression or its post-translational modification alters the TGF-beta-mediated reversal of translational silencing of the target transcripts and EMT. These results suggest the existence of a TGF-beta-inducible post-transcriptional regulon that controls EMT during the development and metastatic progression of tumours.
- Cleveland Clinic United States
- Case Western Reserve University United States
- Indian Institutes of Science Education and Research India
- Indian Institute of Science Education and Research Kolkata India
- Cleveland Clinic Lerner Research Institute United States
Gene Expression, Epithelial Cells, Cadherins, Neoplasm Proteins, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Mesoderm, Adaptor Proteins, Vesicular Transport, Mice, Mammary Glands, Animal, Cell Transdifferentiation, Animals, Cytokines, Insulin, Female, Apoptosis Regulatory Proteins, Carrier Proteins, 3' Untranslated Regions, Adaptor Proteins, Signal Transducing, Cell Line, Transformed
Gene Expression, Epithelial Cells, Cadherins, Neoplasm Proteins, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Mesoderm, Adaptor Proteins, Vesicular Transport, Mice, Mammary Glands, Animal, Cell Transdifferentiation, Animals, Cytokines, Insulin, Female, Apoptosis Regulatory Proteins, Carrier Proteins, 3' Untranslated Regions, Adaptor Proteins, Signal Transducing, Cell Line, Transformed
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