Volume 29, No 4, Apr 2019

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 29 Issue 4, April 2019: 286-304

ORIGINAL ARTICLES

LncRNAs-directed PTEN enzymatic switch governs epithelial–mesenchymal transition

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

¹Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; ²Department of hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China; ³Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; ⁴Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; ⁵Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGroven Medical School, Houston, TX 77030, USA; ⁶Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA; ⁷Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA; ⁸Program in Cancer Biology,Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA and ⁹Center for RNA Interference and Non-Coding RNAs,
The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA ¹⁰ Present address: Institute of Immunology, Third Military Medical University, 400038 Chongqing, China
Correspondence: Chunru Lin (clin2@mdanderson.org) or Liuqing Yang (lyang7@mdanderson.org)These authors contributed equally: Qingsong Hu, Chunlai Li, Shouyu Wang, Yajuan Li.

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 PTENK27-polyUb activates its protein serine/threonine phosphatase activity and inhibits its phosphatidylinositol/protein tyrosine phosphatase activity. With this altered enzymatic activity, PTENK27-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 PTENK27-polyUb, by a single nucleotide mutation generated using CRISPR/Cas9 (PtenK80R/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.

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