Journal of Biological Chemistry
Volume 275, Issue 47, 24 November 2000, Pages 36818-36822
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MECHANISMS OF SIGNAL TRANSDUCTION
Smurf2 Is a Ubiquitin E3 Ligase Mediating Proteasome-dependent Degradation of Smad2 in Transforming Growth Factor-β Signaling*210

https://doi.org/10.1074/jbc.C000580200Get rights and content
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Smads are important intracellular signaling effectors for transforming growth factor-β (TGF-β) and related factors. Proper TGF-β signaling requires precise control of Smad functions. In this study, we have identified a novel HECT class ubiquitin E3 ligase, designated Smurf2, that negatively regulates Smad2 signaling. In both yeast two-hybrid and in vitro binding assays, we found that Smurf2 could interact with receptor-activated Smads (R-Smads), including Smad1, Smad2, and Smad3 but not Smad4. Ectopic expression of Smurf2 was sufficient to reduce the steady-state levels of Smad1 and Smad2 but not Smad3 or Smad4. Significantly, Smurf2 displayed preference to Smad2 as its target for degradation. Furthermore, Smurf2 exhibited higher binding affinity to activated Smad2 upon TGF-β stimulation. The ability of Smurf2 to promote Smad2 destruction required the HECT catalytic activity of Smurf2 and depended on the proteasome-dependent pathway. Consistent with these results, Smurf2 potently reduced the transcriptional activity of Smad2. These data suggest that a ubiquitin/proteasome-dependent mechanism is important for proper regulation of TGF-β signaling.

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Published, JBC Papers in Press, October 2, 2000, DOI 10.1074/jbc.C000580200

AF301463

*

This research was supported by Baylor College of Medicine start-up funds (to X. L. and X.-H. F.) and American Cancer Society Grant RPG-00-214-01-CCG (to X.-H. F.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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The on-line version of this article (available athttp://www.jbc.org) contains Fig. S1.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank™/EMBL Data Bank with accession number(s) .

To whom correspondence may be addressed: Dept. of Surgery, Baylor College of Medicine, One Baylor Plaza, 404D, Houston, TX 77030. Tel.: 713-798-4994; Fax: 713-798-4093; E-mail: [email protected].

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To whom correspondence may be addressed: Dept. of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Rm. 112A, Houston, TX 77030. Tel.: 713-798-4756; Fax: 713-790-0545; E-mail: [email protected].