LncRNAs-directed PTEN enzymatic switch governs epithelial–mesenchymal transition

LncRNAs-directed PTEN enzymatic switch governs epithelial–mesenchymal transition

Abstract

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-polyUbactivates 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.

Authors: Qingsong Hu, Chunlai Li, Shouyu Wang, Yajuan Li, Bo Wen, Yanyan Zhang, Ke Liang, Jun Yao, Youqiong Ye, Heidi Hsiao, Tina K. Nguyen, Peter K. Park, Sergey D. Egranov, David H. Hawke, Jeffrey R. Marks, Leng Han, Mien-Chie Hung, Bing Zhang, Chunru Lin & Liuqing Yang

Influence Factor: 15.393

Citation: Cell Research 29, 286-304 (2019).

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