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

Anassuya Ramachandran, Pedro Vizan, Debipriya Das, Probir Chakravarty, Janis Vogt, Katherine W. Rogers, Patrick Müller, Andrew P. Hinck, Gopal P. Sapkota, Caroline S. Hill (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

51 Citations (Scopus)
134 Downloads (Pure)

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.

Original languageEnglish
Article numbere31756
Pages (from-to)1-29
Number of pages29
JournaleLife
Volume7
DOIs
Publication statusPublished - 29 Jan 2018

Keywords

  • Journal article
  • ACVR1
  • Epithelial-to-mesenchymal transition
  • ID genes
  • SMAD1/5
  • TGF-β

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