Gene interactions and pathways from curated databases and text-mining
Nature communications 2013, PMID: 24071738

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

Herhaus, Lina; Al-Salihi, Mazin; Macartney, Thomas; Weidlich, Simone; Sapkota, Gopal P

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.

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Text Mining Data

Dashed line = No text mining data

Manually curated Databases

  • IRef Biogrid Interaction: UBE2N — NEDD4L (direct interaction, pull down)
  • IRef Biogrid Interaction: UBE2D1 — OTUB1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: SMAD3 — NEDD4L (direct interaction, enzymatic study)
  • IRef Biogrid Interaction: UBE2D1 — NEDD4L (direct interaction, pull down)
  • IRef Biogrid Interaction: OTUB1 — SMAD3 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: OTUB1 — SMAD3 (direct interaction, enzymatic study)
  • IRef Biogrid Interaction: OTUB1 — SMAD2 (direct interaction, pull down)
  • IRef Biogrid Interaction: OTUB1 — SMAD2 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: OTUB1 — SMAD4 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: OTUB1 — SMAD4 (direct interaction, pull down)
  • IRef Biogrid Interaction: UBC — OTUB1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: UBE2N — OTUB1 (physical association, affinity chromatography technology)
  • IRef Biogrid Interaction: UBC — SMAD3 (physical association, affinity chromatography technology)
In total, 10 gene pairs are associated to this article in curated databases