TGF-β uses a novel mode of receptor activation to phosphorylate SMAD1/5 and induce epithelial-to-mesenchymal transition
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
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.
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Further reading
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Activin ligands are formed from two disulfide-linked inhibin β (Inhβ) subunit chains. They exist as homodimeric proteins, as in the case of activin A (ActA; InhβA/InhβA) or activin C (ActC; InhβC/InhβC), or as heterodimers, as with activin AC (ActAC; InhβA:InhβC). While the biological functions of ActA and activin B (ActB) have been well characterized, little is known about the biological functions of ActC or ActAC. One thought is that the InhβC chain functions to interfere with ActA production by forming less active ActAC heterodimers. Here, we assessed and characterized the signaling capacity of ligands containing the InhβC chain. ActC and ActAC activated SMAD2/3-dependent signaling via the type I receptor, activin receptor-like kinase 7 (ALK7). Relative to ActA and ActB, ActC exhibited lower affinity for the cognate activin type II receptors and was resistant to neutralization by the extracellular antagonist, follistatin. In mature murine adipocytes, which exhibit high ALK7 expression, ActC elicited a SMAD2/3 response similar to ActB, which can also signal via ALK7. Collectively, these results establish that ActC and ActAC are active ligands that exhibit a distinct signaling receptor and antagonist profile compared to other activins.