LncRNAs-directed PTEN enzymatic switch governs epithelial-mesenchymal transition

• 来源期刊: 细胞研究（英文版）
• 年，卷（期）: 2019,（4）
• 页码范围: 286-304
• 页数: 19页
• 语种: 英文

摘要

Despite the structural consenvation 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 TWlST1,SNAI1,and YAP1,leading to accumulation of these master regulators of EMT.Animals with genetic inhibition of PTENK27polyUb,by a single nucieotide 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 IncRNA-dependent switch in PTEN protein serine/threonine phosphatase activity is important for physiological homeostasis and disease development.