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TGF-β uses a novel mode of receptor activation to phosphorylate SMAD1/5 and induce epithelial-to-mesenchymal transition.

Authors
  • Ramachandran, Anassuya1
  • Vizán, Pedro1
  • Das, Debipriya1
  • Chakravarty, Probir2
  • Vogt, Janis3
  • Rogers, Katherine W4
  • Müller, Patrick4
  • Hinck, Andrew P5
  • Sapkota, Gopal P3
  • Hill, Caroline S1
  • 1 Developmental Signalling Laboratory, The Francis Crick Institute, London, United Kingdom. , (United Kingdom)
  • 2 Bioinformatics and Biostatistics Facility, The Francis Crick Institute, London, United Kingdom. , (United Kingdom)
  • 3 Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, United Kingdom. , (United Kingdom)
  • 4 Friedrich Miescher Laboratory of the Max Planck Society, Tübingen, Germany. , (Germany)
  • 5 Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States. , (United States)
Type
Published Article
Journal
eLife
Publisher
"eLife Sciences Organisation, Ltd."
Publication Date
Jan 29, 2018
Volume
7
Identifiers
DOI: 10.7554/eLife.31756
PMID: 29376829
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

The best characterized signaling pathway downstream of transforming growth factor β (TGF-β) is through SMAD2 and SMAD3. However, TGF-β also induces phosphorylation of SMAD1 and SMAD5, but the mechanism of this phosphorylation and its functional relevance is not known. Here, we show that TGF-β-induced SMAD1/5 phosphorylation requires members of two classes of type I receptor, TGFBR1 and ACVR1, and establish a new paradigm for receptor activation where TGFBR1 phosphorylates and activates ACVR1, which phosphorylates SMAD1/5. We demonstrate the biological significance of this pathway by showing that approximately a quarter of the TGF-β-induced transcriptome depends on SMAD1/5 signaling, with major early transcriptional targets being the ID genes. Finally, we show that TGF-β-induced epithelial-to-mesenchymal transition requires signaling via both the SMAD3 and SMAD1/5 pathways, with SMAD1/5 signaling being essential to induce ID1. Therefore, combinatorial signaling via both SMAD pathways is essential for the full TGF-β-induced transcriptional program and physiological responses. © 2018, Ramachandran et al.

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