Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth.
Poly-ADP ribosylation of PTEN by tankyrases promotes PTEN degradation and tumor growth.
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DOI：
10.1101/gad.251785.114
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发表时间：
2015-01-15
影响因子：
10.5
通讯作者：
Chen J
中科院分区：
文献类型：
--
作者：
Li N;Zhang Y;Han X;Liang K;Wang J;Feng L;Wang W;Songyang Z;Lin C;Yang L;Yu Y;Chen J
Li等报道了ADP-核糖基化作为肿瘤抑制因子PTEN的一种新的翻译后修饰。端锚聚合酶与PTEN相互作用并使其核糖基化，这促进PAR结合E3泛素连接酶RNF 146对PTEN的识别，导致PTEN泛素化和降解。端锚聚合酶在结肠癌组织中表达上调，与PTEN表达呈负相关。PTEN [从10号染色体上删除的磷脂酰肌醇（3，4，5）-三磷酸酶和张力蛋白同源物]是一种磷酸酶和关键的肿瘤抑制因子，受多种翻译后修饰的调节，包括磷酸化、遍在蛋白化、乙酰化和SUMO化，这些修饰影响PTEN定位和蛋白稳定性。在这里，我们报告ADP-核糖基化作为一种新的翻译后修饰的PTEN。我们鉴定了PTEN作为端锚聚合酶的新底物，端锚聚合酶是聚（ADP-核糖）聚合酶（PARP）的成员。我们发现端锚聚合酶与PTEN相互作用并使其核糖基化，这促进了PAR结合E3泛素连接酶RNF 146对PTEN的识别，导致PTEN泛素化和降解。端锚聚合酶1/2的双敲低稳定了PTEN，导致随后AKT磷酸化的下调，从而抑制体外细胞增殖和糖酵解以及体内肿瘤生长。此外，端锚聚合酶在人结肠癌中表达上调，并与PTEN表达呈负相关。总之，我们的研究揭示了PTEN的新调控，并强调了端锚聚合酶在PTEN-AKT通路中的作用，可以进一步探索用于癌症治疗。
Li et al. report ADP-ribosylation as a new post-translational modification of the tumor suppressor PTEN. 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. Tankyrases were up-regulated and negatively correlated with PTEN expression in human colon carcinomas. 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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通讯作者：
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5.3
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