LncRNAs-directed PTEN enzymatic switch governs epithelial–mesenchymal transition

查看全文 作　　者：Qingsong [1]Hu;Chunlai [1]Li;Shouyu [1,2]Wang;Yajuan [1]Li;Bo [3,4]Wen;Yanyan [1,10]Zhang;Ke [1]Liang;Jun [1]Yao;Youqiong [5]Ye;Heidi [1]Hsiao;Tina [1]K.Nguyen;Peter [1]K.Park;Sergey [1]D.Egranov;David [6]H.Hawke;Jeffrey [7]R.Marks;Leng [5]Han;Mien-Chie [1,8]Hung;Bing [3,4]Zhang;Chunru [1,8]Lin;Liuqing [1,8,9]Yang

机构地区：[1]Department of Molecular and Cellular Oncology,The University of Texas MD Anderson Cancer Center,Houston,TX 77030,USA;[10]Institute of Immunology,Third Military Medical University,400038 Chongqing,China;[2]Department of hepatobiliary Surgery,The Affiliated Drum Tower Hospital of Nanjing University Medical School,Nanjing,Jiangsu Province,China;[3]Department of Molecular and Human Genetics,Baylor College of Medicine,Houston,TX 77030,USA;[4]Lester and Sue Smith Breast Center,Baylor College of Medicine,Houston,TX 77030,USA;[5]Department of Biochemistry and Molecular Biology,The University of Texas Health Science Center at Houston McGroven Medical School,Houston,TX 77030,USA;[6]Department of Systems Biology,The University of Texas MD Anderson Cancer Center,Houston,TX 77030,USA;[7]Department of Surgery,Duke University School of Medicine,Durham,NC 27710,USA;[8]Program in Cancer Biology,Graduate School of Biomedical Sciences,The University of Texas MD Anderson Cancer Center,Houston,TX 77030,USA;[9]Center for RNA Interference and Non-Coding RNAs,The University of Texas MD Anderson Cancer Center,Houston,TX 77030,USA

出　　处：《Cell Research》索引2019年第29卷第4期,共19页

摘　　要：Despite the structural conservation of PTEN with dual-specificity phosphatases,there have been no reports regarding the regulatory mechanisms that underlie this potential dual-phosphatase activity.Here,we report that K27-linked polyubiquitination of PTEN at lysines 66 and 80 switches its phosphoinositide/protein tyrosine phosphatase activity to protein serine/threonine phosphatase activity.Mechanistically,high glucose,TGF-β,CTGF,SHH,and IL-6 induce the expression of a long non-coding RNA,GAEA(Glucose Aroused for EMT Activation),which associates with an RNA-binding E3 ligase,MEX3C,and enhances its enzymatic activity,leading to the K27-linked polyubiquitination of PTEN.The MEX3C-catalyzed PTEN^K27-polyUb activates its protein serine/threonine phosphatase activity and inhibits its phosphatidylinositol/protein tyrosine phosphatase activity.With this altered enzymatic activity,PTEN^K27-polyUb dephosphorylates the phosphoserine/threonine residues of TWIST1,SNAI1,and YAP1,leading to accumulation of these master regulators of EMT.Animals with genetic inhibition of PTEN^K27-polyUb,by a single nucleotide mutation generated using CRISPR/Cas9(Pten^K80R/K80R),exhibit inhibition of EMT markers during mammary gland morphogenesis in pregnancy/lactation and during cutaneous wound healing processes.Our findings illustrate an unexpected paradigm in which the lncRNA-dependent switch in PTEN protein serine/threonine phosphatase activity is important for physiological homeostasis and disease development. 关键词：SWITCH PTEN expression MUTATION TGF-β its CTGF IL-6

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LncRNAs-directed PTEN enzymatic switch governs epithelial–mesenchymal transition

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