TY - JOUR
T1 - Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth
AU - Li, Nan
AU - Zhang, Yajie
AU - Han, Xin
AU - Liang, Ke
AU - Wang, Jiadong
AU - Feng, Lin
AU - Wang, Wenqi
AU - Songyang, Zhou
AU - Lin, Chunru
AU - Yang, Liuqing
AU - Yu, Yonghao
AU - Chen, Junjie
N1 - Publisher Copyright:
© 2015 Li et al.
PY - 2015/1/15
Y1 - 2015/1/15
N2 - 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.
AB - 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.
KW - PARsylation
KW - PTEN
KW - RNF146
KW - Tankyrase
KW - Ubiquitination
UR - http://www.scopus.com/inward/record.url?scp=84921526092&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84921526092&partnerID=8YFLogxK
U2 - 10.1101/gad.251785.114
DO - 10.1101/gad.251785.114
M3 - Article
C2 - 25547115
AN - SCOPUS:84921526092
SN - 0890-9369
VL - 29
SP - 157
EP - 170
JO - Genes and Development
JF - Genes and Development
IS - 2
ER -