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OTUB1 enhances TGFβ signalling by inhibiting the ubiquitylation and degradation of active SMAD2/3

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  • Lina Herhaus

    (MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee)

  • Mazin Al-Salihi

    (MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee)

  • Thomas Macartney

    (MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee)

  • Simone Weidlich

    (MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee)

  • Gopal P. Sapkota

    (MRC Protein Phosphorylation Unit, College of Life Sciences, University of Dundee)

Abstract

SMAD transcription factors are key intracellular transducers of TGFβ cytokines. SMADs are tightly regulated to ensure balanced cellular responses to TGFβ signals. Ubiquitylation has a key role in regulating SMAD stability and activity. Several E3 ubiquitin ligases that regulate the turnover of SMADs are known; however, proteins that prevent the ubiquitylation or cause deubiquitylation of active SMADs remain undefined. Here we demonstrate that OTUB1 is recruited to the active phospho-SMAD2/3 complex only on TGFβ induction. Further, OTUB1 has a crucial role in TGFβ-mediated gene transcription and cellular migration. OTUB1 inhibits the ubiquitylation of phospho-SMAD2/3 by binding to and inhibiting the E2 ubiquitin-conjugating enzymes independent of its catalytic activity. Consequently, depletion of OTUB1 in cells causes a rapid loss in levels of TGFβ-induced phospho-SMAD2/3, which is rescued by the proteasomal inhibitor bortezomib. Our findings uncover a signal-induced phosphorylation-dependent recruitment of OTUB1 to its target in the TGFβ pathway.

Suggested Citation

  • Lina Herhaus & Mazin Al-Salihi & Thomas Macartney & Simone Weidlich & Gopal P. Sapkota, 2013. "OTUB1 enhances TGFβ signalling by inhibiting the ubiquitylation and degradation of active SMAD2/3," Nature Communications, Nature, vol. 4(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:4:y:2013:i:1:d:10.1038_ncomms3519
    DOI: 10.1038/ncomms3519
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