TGF-β (transforming growth factor-β) signals through serine/threonine kinase receptors and intracellular Smad transcription factors. An important regulatory step involves specific ubiquitination by Smurfs (Smad–ubiquitin regulatory factors), members of the HECT (homologous to E6-associated protein C-terminus) ubiquitin ligase family, which mediate the proteasomal degradation of Smads and/or receptors. Recently, we have defined a novel interaction between Smads and UCH37 (ubiquitin C-terminal hydrolase 37), a DUB (de-ubiquitinating enzyme) that could potentially counteract Smurf-mediated ubiquitination. We have demonstrated specific interactions between UCH37 and inhibitory Smad7, as well as weaker associations with Smad2 and Smad3. Importantly, Smad7 can act as an adaptor able to recruit UCH37 to the type I TGF-β receptor. Consequently, UCH37 dramatically up-regulates TGF-β-dependent gene expression by de-ubiquitinating and stabilizing the type I TGF-β receptor. Our findings suggest that competing effects of ubiquitin ligases and DUBs in complex with Smad7 can serve to fine-tune responses to TGF-βs under various physiological and pathological conditions. Studies are currently under way using activity-based HA (haemagglutinin)-tagged ubiquitin probes to identify the full spectrum of DUBs that impact on Smad/TGF-β signalling activity.
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October 2006
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Conference Article|
October 25 2006
Reversible ubiquitination regulates the Smad/TGF-β signalling pathway
S.J. Wicks;
S.J. Wicks
*School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, U.K.
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T. Grocott;
T. Grocott
*School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, U.K.
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K. Haros;
K. Haros
*School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, U.K.
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M. Maillard;
M. Maillard
*School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, U.K.
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P. ten Dijke;
P. ten Dijke
†Department of Molecular Cell Biology, Leiden University Medical Center, Div. 5, Wassenaarseweg 72, 2333 AL Leiden, The Netherlands
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A. Chantry
A. Chantry
1
*School of Biological Sciences, University of East Anglia, Norwich NR4 7TJ, U.K.
1To whom correspondence should be addressed (email a.chantry@uea.ac.uk).
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Publisher: Portland Press Ltd
Received:
June 29 2006
Online ISSN: 1470-8752
Print ISSN: 0300-5127
© 2006 The Biochemical Society
2006
Biochem Soc Trans (2006) 34 (5): 761–763.
Article history
Received:
June 29 2006
Citation
S.J. Wicks, T. Grocott, K. Haros, M. Maillard, P. ten Dijke, A. Chantry; Reversible ubiquitination regulates the Smad/TGF-β signalling pathway. Biochem Soc Trans 1 October 2006; 34 (5): 761–763. doi: https://doi.org/10.1042/BST0340761
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