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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We thank Mr. D. Aten for assistance with figure presentation and Peter K. Park and Sergey D. Egranov for manuscript preparation. This research work is partially supported by National Cancer Institute (NCI) CPTAC award [U24 CA210954], Cancer Prevention and Research Institutes of Texas [CPRIT RR160027], McNair Medical Institute at The Robert and Janice McNair Foundation to B.Z. This work was supported in part by Cancer Prevention Research Institute of Texas (CPRIT) grant number RP130397 and NIH grant number 1S10OD012304-01 to D.H.H. This work was supported by National Institutes of Health Pathway to Independence Award (R00CA166527), National Cancer Institute R01 award (1 R01 CA218036-01), Cancer Prevention Research Institute of Texas First-time Faculty Recruitment Award (R1218) grants, Department of Defense Breakthrough award (BC151465), Andrew Sabin Family Foundation Fellows award, and AACR-Bayer Innovation and Discovery Grants to L.Q.Y. and National Institutes of Health Pathway to Independence Award (R00DK094981), National Cancer Institute R01 award (1R01CA218025-01, 1R01CA231011-01), Department of Defense Breakthrough award BC180196, and Cancer Prevention Research Institute of Texas Individual Investigator Research Award (150094 and 180259) to C.R.L.

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Author notes

    • Yanyan Zhang

    Present address: Institute of Immunology, Third Military Medical University, 400038, Chongqing, China

  1. These authors contributed equally: Qingsong Hu, Chunlai Li, Shouyu Wang, Yajuan Li.


  1. Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    • Qingsong Hu
    • , Chunlai Li
    • , Shouyu Wang
    • , Yajuan Li
    • , Yanyan Zhang
    • , Ke Liang
    • , Jun Yao
    • , Heidi Hsiao
    • , Tina K. Nguyen
    • , Peter K. Park
    • , Sergey D. Egranov
    • , Mien-Chie Hung
    • , Chunru Lin
    •  & Liuqing Yang
  2. Department of hepatobiliary Surgery, The Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, China

    • Shouyu Wang
  3. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, 77030, USA

    • Bo Wen
    •  & Bing Zhang
  4. Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, 77030, USA

    • Bo Wen
    •  & Bing Zhang
  5. Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGroven Medical School, Houston, TX, 77030, USA

    • Youqiong Ye
    •  & Leng Han
  6. Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    • David H. Hawke
  7. Department of Surgery, Duke University School of Medicine, Durham, NC, 27710, USA

    • Jeffrey R. Marks
  8. Program in Cancer Biology, Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    • Mien-Chie Hung
    • , Chunru Lin
    •  & Liuqing Yang
  9. Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    • Liuqing Yang


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L.Q.Y. and C.R.L. conceived of the project and designed the experiments. Q.S.H. and S.Y.W. executed the primary studies with assistance of Y.Y.Z., Q.S.H., C.L.L. and Y.J.L. performed the experiments with genetic animal models. D.H. executed mass spectrometry analysis. B.W. and B.Z., with assistance of J.Y. performed the phospho-proteomics data analysis. Y.Q.Y. and L.H. ensured the statistical analysis. Clinical specimens were ascertained and processed by J.R.M. and L.Q.Y. The histological staining and corresponding analysis were performed by K.L., C.L.L. and Q.S.H. H.H. and T.K.N. assisted with genetic mouse model breeding. P.K.P. and S.D.E. assisted with manuscript drafting. M.C.H. contributed to experimental design and data interpretation. L.Q.Y. and C.R.L. wrote the manuscript.

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The authors declare no competing interests.

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Correspondence to Chunru Lin or Liuqing Yang.

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