Nature communications 2013,
PMID: 24071738
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
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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