Journal
GENES & DEVELOPMENT
Volume 29, Issue 2, Pages 157-170Publisher
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.251785.114
Keywords
PTEN; PARsylation; tankyrase; RNF146; ubiquitination
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Funding
- M.D. Anderson Start-up fund
- Era of Hope Scholar Research award [W81XWH-09-1-0409]
- M.D. Anderson's Cancer Center Support Grant [CA016672]
- University of Texas Southwestern Medical Center Endowed Scholar Program
- Cancer Prevention and Research Institute of Texas [CPRIT R1103]
- Welch Foundation [I-1800]
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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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