Skip to main content

Thank you for visiting You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGF-β signalling


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.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Figure 1
Figure 2
Figure 3


  • Chantry A . (1995). J. Biol. Chem., 270, 3068–3073.

  • Ebisawa T, Fukuchi M, Murakami G, Chiba T, Tanaka K, Imamura T and Miyazono K . (2001). J. Biol. Chem., 276, 12477–12480.

  • Glickman MH and Ciechanover A . (2002). Physiol. Rev., 82, 373–428.

  • Jensen DE, Proctor M, Marquis ST, Gardner HP, Ha SI, Chodosh LA, Ishov AM, Tommerup N, Vissing H, Sekido Y, Minna J, Borodovsky A, Schultz DC, Wilkinson KD, Maul GG, Barlev N, Berger SL, Prendergast GC and Rauscher III FJ . (1998). Oncogene, 16, 1097–1112.

  • Kavsak P, Rasmussen RK, Causing CG, Bonni S, Zhu H, Thomsen GH and Wrana JL . (2000). Mol. Cell., 6, 1365–1375.

  • Lam YA, DeMartino GN, Pickart CM and Cohen RE . (1997a). J. Biol. Chem., 272, 28438–28446.

  • Lam YA, Xu W, DeMartino GN and Cohen RE . (1997b). Nature, 385, 737–740.

  • Li M, Chen D, Shiloh A, Luo J, Nikolaev AY, Qin J and Gu W . (2002). Nature, 416, 648–653.

  • Lo RS and Massague J . (1999). Nat. Cell Biol., 1, 472–478.

  • Shi Y and Massague J . (2003). Cell, 113, 685–700.

  • Suzuki C, Murakami G, Fukuchi M, Shimanuki T, Shikauchi Y, Imamura T and Miyazono K . (2002). J. Biol. Chem., 277, 39919–39925.

  • Ulloa L, Doody J and Massague J . (1999). Nature, 397, 710–713.

  • Wicks SJ, Lui S, Abdel-Wahab N, Mason RM and Chantry A . (2000). Mol. Cell. Biol., 20, 8103–8111.

  • Wing SS . (2003). Int. J. Biochem. Cell Biol., 35, 590–605.

  • Zhu H, Kavsak P, Abdollah S, Wrana JL and Thomsen GH . (1999). Nature, 400, 687–693.

Download references


This study was supported by research grants from the BBSRC (AC), Wellcome Trust, UK (AC), NIH Grant R01 GM37666 (REC) and the Dutch Cancer Society (PTD). We thank Caroline Hill, Takeshi Imamura, Ian Kerr and Ana Costa-Pereira for vectors and cell lines. We also thank the Nederlands Kanker Instituut (NKI) and Cancer Research UK for allowing us to use the RNAi-UCH37 construct.

Author information

Authors and Affiliations


Rights and permissions

Reprints and Permissions

About this article

Cite this article

Wicks, S., Haros, K., Maillard, M. et al. The deubiquitinating enzyme UCH37 interacts with Smads and regulates TGF-β signalling. Oncogene 24, 8080–8084 (2005).

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI:


  • transforming growth factor-β
  • Smads
  • ubiquitin

This article is cited by


Quick links