Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth.

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.
Mesh Terms:
Cell Line, Tumor, Cell Proliferation, Colonic Neoplasms, Colorectal Neoplasms, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Glycolysis, HCT116 Cells, HEK293 Cells, HT29 Cells, Humans, Oncogene Protein v-akt, PTEN Phosphohydrolase, Phosphorylation, Poly Adenosine Diphosphate Ribose, Protein Processing, Post-Translational, Tankyrases, Ubiquitination
Genes Dev.
Date: Jan. 15, 2015
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