TGF-β uses a novel mode of receptor activation to phosphorylate SMAD1/5 and induce epithelial-to-mesenchymal transition
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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.
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TGF-β signaling through ACVR1/ALK2 activating Smad1/5 is also required for TGF-β-induced EMT.
“Additionally, TGF-β signaling through another type I receptor, ACVR1/ALK2, which activates Smad1 and Smad5, is also required for TGF-β-induced EMT129.”
From TGFβ biology in cancer progression and immunotherapy (2021) · cites this paper as [129]
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- Authors
- Ramachandran, A., Vizán, P., Das, D., Chakravarty, P., Vogt, J., Rogers, K. W., Müller, P., Hinck, A. P., Sapkota, G. P., & Hill, C. S.
- Affiliations
- The Francis Crick Institute (GB)
- University of Dundee (GB)
- Max Planck Society (DE)
- University of Pittsburgh (US)
- Corresponding author
- Hill, Caroline S
- ORCID
- Venue
- eLife
- Publisher
- eLife Sciences Publications, Ltd
- Published
- 2018-01-29
- Volume
- 7
- ISSN
- 2050-084X (ISSN-L)
- PMC
- PMC5832415
- OpenAlex
- W2787586915
- Cited by
- 204
- References
- 78
- Citations by year
- 2026: 13 · 2025: 24 · 2024: 20 · 2023: 17 · 2022: 22 · 2021: 36 · 2020: 40 · 2019: 24 · 2018: 8
- FWCI
- 9.60
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- eLife (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Discovery Research Portal (University of Dundee) (acceptedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- KOPS (University of Konstanz) (submittedVersion, cc-by)
- Funders
- Francis Crick Institute (FC001095)
- NIH Office of the Director (GM58670, CA172886)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Kruppel-like factors research
- Keywords
- TGF-beta signaling, Smad1/5 phosphorylation, Smad2/3 signaling, TGFBR1, ACVR1, receptor activation, epithelial-mesenchymal transition, Id genes, Id1, combinatorial signaling, transcriptional regulation
- MeSH terms
- Receptor, Transforming Growth Factor-beta Type I, Animals, Cell Line, Humans, Phosphorylation, Protein Processing, Post-Translational, Transforming Growth Factor beta, Gene Expression Profiling, Activin Receptors, Type I, Inhibitor of Differentiation Protein 1, Smad1 Protein, Smad5 Protein, Gene Regulatory Networks, Epithelial-Mesenchymal Transition
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