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
- Cited 5
- Views 2,513
- Annotations
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.
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.
Reviewing Editor
- Roger J Davis, University of Massachusetts Medical School, United States
Publication history
- Received: September 5, 2017
- Accepted: January 26, 2018
- Accepted Manuscript published: January 29, 2018 (version 1)
- Version of Record published: March 1, 2018 (version 2)
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.
Metrics
-
- 2,513
- Page views
-
- 540
- Downloads
-
- 5
- Citations
Article citation count generated by polling the highest count across the following sources: Crossref, Scopus, PubMed Central.
Download links
Downloads (link to download the article as PDF)
Download citations (links to download the citations from this article in formats compatible with various reference manager tools)
Open citations (links to open the citations from this article in various online reference manager services)
Further reading
-
- Biochemistry and Chemical Biology
- Genetics and Genomics
-
- Biochemistry and Chemical Biology
