TGF-β uses a novel mode of receptor activation to phosphorylate SMAD1/5 and induce epithelial-to-mesenchymal transition
- The Francis Crick Institute, United Kingdom
- University of Dundee, United Kingdom
- Friedrich Miescher Laboratory of the Max Planck Society, Germany
- University of Pittsburgh School of Medicine, United States
Abstract
The best characterized signaling pathway downstream of the transforming growth factor β (TGF-β) pathway 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.
Data availability
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TGF-beta signalling through SMAD1/5 is required for epithelial-to-mesenchymal transitionPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE92443).
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TGF-b utilizes a novel receptor activation mechanism to phosphorylate SMAD1/5 and regulate epithelial-to-mesenchymal transitionPublicly available at the NCBI Gene Expression Omnibus (accession no: GSE103372).
Article and author information
Author details
Katherine W Rogers
Funding
Francis Crick Institute (FC001095)
- Anassuya Ramachandran
- Pedro Vizan
- Debipriya Das
- Probir Chakravarty
- Caroline S Hill
NIH Office of the Director (GM58670)
- Andrew P Hinck
NIH Office of the Director (CA172886)
- Andrew P Hinck
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2018, Ramachandran et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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TGF-β uses a novel mode of receptor activation to phosphorylate SMAD1/5 and induce epithelial-to-mesenchymal transition
eLife 7:e31756.
https://doi.org/10.7554/eLife.31756
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