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- Title
The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGF-β signalling.
- Authors
Wicks, Stephen J.; Haros, Katherine; Maillard, Marjorie; Ling Song; Cohen, Robert E.; ten Dijke, Peter; Chantry, Andrew
- Abstract
Disruption of components in the transforming growth factor-β (TGF-β) signalling cascade is a common occurrence in human cancers. TGF-β pathway activation is accomplished via serine/threonine kinase receptors and intracellular Smad transcription factors. A key regulatory step involves specific ubiquitination by Smurfs that mediate the proteasomal degradation of Smads and/or receptors. Here, we report a novel interaction between Smads and ubiquitin C-terminal hydrolase UCH37, a deubiquitinating enzyme that could potentially reverse Smurf-mediated ubiquitination. In GST pull down experiments, UCH37 bound weakly to Smad2 and Smad3, and bound very strongly to Smad7 in a region that is distinct from the –PY– motif in Smad7 that interacts with Smurf ubiquitin ligases. Endogenous Smad7 and UCH37 formed a stable complex in U4A/JAK1 cells, and FLAG-Smad7 co-immunoprecipitated with HA-UCH37 in transfected HEK-293 cells. In addition, we show that UCH37 can deubiquitinate and stabilize the type I TGF-β receptor. Furthermore, overexpression of UCH37 upregulates TGF-β-dependent transcription, and this effect is reversed in cells subject to RNAi-mediated knockdown of endogenous UCH37. These findings support a new role for deubiquitinating enzymes in the control of the TGF-β signalling pathway, and provide a novel molecular target for the design of inhibitors with therapeutic potential in cancer.Oncogene (2005) 24, 8080–8084. doi:10.1038/sj.onc.1208944; published online 18 July 2005
- Subjects
CANCER; CANCER treatment; UBIQUITIN; CHEMICAL reactions; ONCOGENES; PROTEIN-tyrosine kinases; ENZYMES
- Publication
Oncogene, 2005, Vol 24, Issue 54, p8080
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/sj.onc.1208944