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

Ramachandran, A; Vizán, P; Das, D; Chakravarty, P; Vogt, J; Rogers, KW; Müller, P; Hinck, AP; Sapkota, GP; Hill, CS

doi:10.7554/eLife.31756

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

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Rogers, KW
Müller Group, Friedrich Miescher Laboratory, Max Planck Society;

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Müller, P
Müller Group, Friedrich Miescher Laboratory, Max Planck Society;

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Citation

Ramachandran, A., Vizán, P., Das, D., Chakravarty, P., Vogt, J., Rogers, K., et al. (2018). TGF-β uses a novel mode of receptor activation to phosphorylate SMAD1/5 and induce epithelial-to-mesenchymal transition. eLife, 7: e31756. doi:10.7554/eLife.31756.

Cite as: https://hdl.handle.net/21.11116/0000-000A-54BA-6

Abstract

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.