LncRNAs-directed PTEN enzymatic switch governs epithelial-mesenchymal transition.

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Hu, Q; Li, C; Wang, S; Li, Y; Wen, B; Zhang, Y; Liang, K; Yao, J; Ye, Y; Hsiao, H; Nguyen, TK; Park, PK; Egranov, SD; Hawke, DH; Marks, JR; Han, L; Hung, M-C; Zhang, B; Lin, C; Yang, L

Published Date

  • April 2019

Published In

Volume / Issue

  • 29 / 4

Start / End Page

  • 286 - 304

PubMed ID

  • 30631154

Pubmed Central ID

  • PMC6461864

Electronic International Standard Serial Number (EISSN)

  • 1748-7838

Digital Object Identifier (DOI)

  • 10.1038/s41422-018-0134-3

Language

  • eng

Conference Location

  • England