Journal
NATURE COMMUNICATIONS
Volume 4, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ncomms3519
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Funding
- Medical Research Council
- DSTT (AstraZeneca, Boehringer-Ingelheim, GlaxoSmithKline, Merck-Serono, Pfizer and Johnson Johnson)
- MRC [MC_UU_12016/3, MC_U127092717] Funding Source: UKRI
- Medical Research Council [MC_UU_12016/3, MC_U127092717] Funding Source: researchfish
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SMAD transcription factors are key intracellular transducers of TGFb cytokines. SMADs are tightly regulated to ensure balanced cellular responses to TGFb 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 TGF beta induction. Further, OTUB1 has a crucial role in TGF beta-mediated gene transcription and cellular migration. OTUB1 inhibits the ubiquitylation of phospho-SMAD2/3 by binding to and inhibiting the E2 ubiquitinconjugating enzymes independent of its catalytic activity. Consequently, depletion of OTUB1 in cells causes a rapid loss in levels of TGF beta-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 TGF beta pathway.
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