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Molecular and Cellular Biology, September 2004, p. 7524-7537, Vol. 24, No. 17
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.17.7524-7537.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Ubiquitination and Proteolysis of Cancer-Derived Smad4 Mutants by SCFSkp2

Min Liang,1,2 Yao-Yun Liang,1,2 Katharine Wrighton,1,2 Dana Ungermannova,3 Xiao-Ping Wang,2 F. Charles Brunicardi,2 Xuedong Liu,3 Xin-Hua Feng,1,2* and Xia Lin2*

Department of Molecular & Cellular Biology,1 Michael E. DeBakey Department of Surgery, Baylor College of Medicine, Houston, Texas,2 Department of Chemistry and Biochemistry, University of Colorado, Boulder, Colorado3

Received 26 February 2004/ Returned for modification 24 March 2004/ Accepted 7 June 2004

Smad4/DPC4, a common signal transducer in transforming growth factor beta (TGF-ß) signaling, is frequently inactivated in human cancer. Although the ubiquitin-proteasome pathway has been established as one mechanism of inactivating Smad4 in cancer, the specific ubiquitin E3 ligase for ubiquitination-mediated proteolysis of Smad4 cancer mutants remains unclear. In this report, we identified the SCFSkp2 complex as candidate Smad4-interacting proteins in an antibody array-based screen and further elucidated the functions of SCFSkp2 in mediating the metabolic instability of cancer-derived Smad4 mutants. We found that Skp2, the F-box component of SCFSkp2, physically interacted with Smad4 at the physiological levels. Several cancer-derived unstable mutants exhibited significantly increased binding to Skp2, which led to their increased ubiquitination and accelerated proteolysis. These results suggest an important role for the SCFSkp2 complex in switching cancer mutants of Smad4 to undergo polyubiquitination-dependent degradation.

* Corresponding author. Mailing address for Xin-Hua Feng: Department of Molecular & Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Room 137D, Houston, TX 77030. Phone: (713) 798-4756. Fax: (713) 798-4093. E-mail: xfeng{at}bcm.tmc.edu. Mailing address for Xia Lin: Department of Surgery, Baylor College of Medicine, One Baylor Plaza, Room 131D, Houston, TX 77030. Phone: (713) 798-4899. Fax: (713) 798-4093. E-mail: xialin{at}bcm.tmc.edu.

Molecular and Cellular Biology, September 2004, p. 7524-7537, Vol. 24, No. 17
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.17.7524-7537.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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