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

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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

The following data sets were generated

1. Ramachandran A
2. Chakravarty P
3. Vizan P
4. Das D
5. Voyt J
6. Hinck AP
7. Sapkota GP
8. Hill CS
(2016) TGF-beta signalling through SMAD1/5 is required for epithelial-to-mesenchymal transition
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE92443).

http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE92443
1. Ramachandran A
2. Chakravarty P
3. Vizan P
4. Das D
5. Voyt J
6. Rogers KW
7. Müller P
8. Hinck AP
9. Sapkota GP
10. Hill CS
(2017) TGF-b utilizes a novel receptor activation mechanism to phosphorylate SMAD1/5 and regulate epithelial-to-mesenchymal transition
Publicly available at the NCBI Gene Expression Omnibus (accession no: GSE103372).

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE103372

Article and author information

Author details

Anassuya Ramachandran

Developmental Signalling Laboratory, The Francis Crick Institute, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Pedro Vizan

Developmental Signalling Laboratory, The Francis Crick Institute, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Debipriya Das

Developmental Signalling Laboratory, The Francis Crick Institute, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Probir Chakravarty

Bioinformatics and Biostatistics Facility, The Francis Crick Institute, London, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Janis Vogt

MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, United Kingdom

Competing interests
The authors declare that no competing interests exist.
Katherine W Rogers

Systems Biology of Development Group, Friedrich Miescher Laboratory of the Max Planck Society, Tübingen, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-5700-2662
Patrick Müller

Systems Biology of Development Group, Friedrich Miescher Laboratory of the Max Planck Society, Tübingen, Germany

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-0702-6209
Andrew P Hinck

Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, United States

Competing interests
The authors declare that no competing interests exist.
Gopal P Sapkota

MRC Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, United Kingdom

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-9931-3338
Caroline S Hill

Developmental Signalling Laboratory, The Francis Crick Institute, London, United Kingdom

For correspondence
caroline.hill@crick.ac.uk

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-8632-0480

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

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.