Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth
- Nan Li1,
- Yajie Zhang2,
- Xin Han3,4,
- Ke Liang5,
- Jiadong Wang1,
- Lin Feng1,
- Wenqi Wang1,
- Zhou Songyang3,4,6,
- Chunru Lin5,
- Liuqing Yang5,
- Yonghao Yu2 and
- Junjie Chen1
- 1Department of Experimental Radiation Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
- 2Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA;
- 3Key Laboratory of Gene Engineering of the Ministry of Education,
- 4State Key Laboratory for Biocontrol, School of Life Sciences, Sun Yat-sen University, Guangzhou 510275, China;
- 5Department of Molecular and Cellular Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA;
- 6Verna and Marrs Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas 77030, USA
- Corresponding author: jchen8{at}mdanderson.org
Abstract
PTEN [phosphatidylinositol (3,4,5)-trisphosphate phosphatase and tensin homolog deleted from chromosome 10], a phosphatase and critical tumor suppressor, is regulated by numerous post-translational modifications, including phosphorylation, ubiquitination, acetylation, and SUMOylation, which affect PTEN localization and protein stability. Here we report ADP-ribosylation as a new post-translational modification of PTEN. We identified PTEN as a novel substrate of tankyrases, which are members of the poly(ADP-ribose) polymerases (PARPs). We showed that tankyrases interact with and ribosylate PTEN, which promotes the recognition of PTEN by a PAR-binding E3 ubiquitin ligase, RNF146, leading to PTEN ubiquitination and degradation. Double knockdown of tankyrase1/2 stabilized PTEN, resulting in the subsequent down-regulation of AKT phosphorylation and thus suppressed cell proliferation and glycolysis in vitro and tumor growth in vivo. Furthermore, tankyrases were up-regulated and negatively correlated with PTEN expression in human colon carcinomas. Together, our study revealed a new regulation of PTEN and highlighted a role for tankyrases in the PTEN–AKT pathway that can be explored further for cancer treatment.
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Footnotes
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Supplemental material is available for this article.
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Article published online ahead of print. Article and publication date are online at http://www.genesdev.org/cgi/doi/10.1101/gad.251785.114.
- Received August 25, 2014.
- Accepted December 3, 2014.
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