Neddylation of PTEN regulates its nuclear import and promotes tumor development  

作　　者：Ping Xie Zhiqiang Peng Yujiao Chen Hongchang Li Mengge Du Yawen Tan Xin Zhang Zhe Lu Chun-Ping Cui Cui Hua Liu Fuchu He Lingqiang Zhang 

机构地区：[1]Department of Cell Biology,The Municipal Key Laboratory for Liver Protection and Regulation of Regeneration,Capital Medical University,Beijing 100069,China [2]State Key Laboratory of Proteomics,National Center for Protein Sciences(Beijing),Beijing Institute of Lifeomics,Beijing 100850,China [3]Department of Breast and Thyroid Surgery,The Second People’s Hospital of Shenzhen,Shenzhen,Guangdong 518035,China [4]CAS Key Laboratory of Pathogenic Microbiology and Immunology,Institute of Microbiology(Chinese Academy of Sciences),Savaid Medical School,University of Chinese Academy of Sciences,Beijing 100101,China

出　　处：《Cell Research》2021年第3期291-311,共21页细胞研究（英文版）

基　　金：This work was jointly supported by the National Key R&D Program of China(2017YFA0505602);Chinese National Basic Research Programs(2015CB910401);Chinese National Natural Science Foundation Project(31670774,31971229);Beijing Natural Science Foundation Project(Z151100003915083);Open Project Program of the State Key Laboratory of Proteomics(SKLP-0201901);Support Project of High-level Teachers in Beijing Municipal Universities in the Period of 13th Five-year Plan(CIT&TCD201704097);Beijing excellent talents training project.

摘　　要：PTEN tumor suppressor opposes the PI3K/Akt signaling pathway in the cytoplasm and maintains chromosomal integrity in the nucleus.Nucleus–cytoplasm shuttling of PTEN is regulated by ubiquitylation,SUMOylation and phosphorylation,and nuclear PTEN has been proposed to exhibit tumor-suppressive functions.Here we show that PTEN is conjugated by Nedd8 under high glucose conditions,which induces PTEN nuclear import without effects on PTEN stability.PTEN neddylation is promoted by the XIAP ligase and removed by the NEDP1 deneddylase.We identify Lys197 and Lys402 as major neddylation sites on PTEN.Neddylated PTEN accumulates predominantly in the nucleus and promotes rather than suppresses cell proliferation and metabolism.The nuclear neddylated PTEN dephosphorylates the fatty acid synthase(FASN)protein,inhibits the TRIM21-mediated ubiquitylation and degradation of FASN,and then promotes de novo fatty acid synthesis.In human breast cancer tissues,neddylated PTEN correlates with tumor progression and poor prognosis.Therefore,we demonstrate a previously unidentified pool of nuclear PTEN in the Nedd8-conjugated form and an unexpected tumor-promoting role of neddylated PTEN.

关 键 词：PI3K/AKT PTEN removed 

分 类 号：R730.1[医药卫生—肿瘤]