This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Google Scholar
Right arrow Articles by Li, X.
Right arrow Articles by Gao, T.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Li, X.
Right arrow Articles by Gao, T.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, December 2009, p. 6192-6205, Vol. 29, No. 23
0270-7306/09/$08.00+0     doi:10.1128/MCB.00681-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

β-TrCP-Mediated Ubiquitination and Degradation of PHLPP1 Are Negatively Regulated by Akt{triangledown}

Xin Li,1 Jianyu Liu,1 and Tianyan Gao1,2*

Markey Cancer Center,1 Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky 40536-05092

Received 26 May 2009/ Returned for modification 27 June 2009/ Accepted 14 September 2009

PHLPP1 belongs to a novel family of Ser/Thr protein phosphatases that serve as tumor suppressors by negatively regulating Akt signaling. Our recent studies have demonstrated that loss of PHLPP expression occurs at high frequency in colorectal cancer. In this study, we identified PHLPP1 as a proteolytic target of a β-TrCP-containing Skp-Cullin 1-F-box protein (SCF) complex (SCFβ-TrCP) E3 ubiquitin ligase in a phosphorylation-dependent manner. Overexpression of wild-type but not {Delta}F-box mutant β-TrCP leads to decreased expression and increased ubiquitination of PHLPP1, whereas knockdown of endogenous β-TrCP has the opposite effect. In addition, we show that the β-TrCP-mediated degradation requires phosphorylation of PHLPP1 by casein kinase I and glycogen synthase kinase 3β (GSK-3β), and activation of the phosphatidylinositol 3-kinase/Akt pathway suppresses the degradation of PHLPP1 by inhibiting the GSK-3β activity. Furthermore, expression of a degradation-deficient PHLPP1 mutant in colon cancer cells results in a more effective dephosphorylation of Akt and inhibition of cell growth. Taken together, our findings demonstrate a key role for β-TrCP in controlling the level of PHLPP1, and activation of Akt negatively regulates this degradation process.

* Corresponding author. Mailing address: Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40536-0509. Phone: (859) 323-3454. Fax: (859) 323-2074. E-mail: tianyan.gao{at}uky.edu

{triangledown} Published ahead of print on 21 September 2009.

Molecular and Cellular Biology, December 2009, p. 6192-6205, Vol. 29, No. 23
0270-7306/09/$08.00+0     doi:10.1128/MCB.00681-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»