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

Publication ,  Journal Article
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 ...
Published in: Cell Res
April 2019

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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Published In

Cell Res

DOI

EISSN

1748-7838

Publication Date

April 2019

Volume

29

Issue

4

Start / End Page

286 / 304

Location

England

Related Subject Headings

  • Ubiquitination
  • RNA, Long Noncoding
  • PTEN Phosphohydrolase
  • Mice
  • Male
  • Humans
  • Female
  • Epithelial-Mesenchymal Transition
  • Developmental Biology
  • Cell Line
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Hu, Q., Li, C., Wang, S., Li, Y., Wen, B., Zhang, Y., … Yang, L. (2019). LncRNAs-directed PTEN enzymatic switch governs epithelial-mesenchymal transition. Cell Res, 29(4), 286–304. https://doi.org/10.1038/s41422-018-0134-3
Hu, Qingsong, Chunlai Li, Shouyu Wang, Yajuan Li, Bo Wen, Yanyan Zhang, Ke Liang, et al. “LncRNAs-directed PTEN enzymatic switch governs epithelial-mesenchymal transition.Cell Res 29, no. 4 (April 2019): 286–304. https://doi.org/10.1038/s41422-018-0134-3.
Hu Q, Li C, Wang S, Li Y, Wen B, Zhang Y, et al. LncRNAs-directed PTEN enzymatic switch governs epithelial-mesenchymal transition. Cell Res. 2019 Apr;29(4):286–304.
Hu, Qingsong, et al. “LncRNAs-directed PTEN enzymatic switch governs epithelial-mesenchymal transition.Cell Res, vol. 29, no. 4, Apr. 2019, pp. 286–304. Pubmed, doi:10.1038/s41422-018-0134-3.
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. LncRNAs-directed PTEN enzymatic switch governs epithelial-mesenchymal transition. Cell Res. 2019 Apr;29(4):286–304.

Published In

Cell Res

DOI

EISSN

1748-7838

Publication Date

April 2019

Volume

29

Issue

4

Start / End Page

286 / 304

Location

England

Related Subject Headings

  • Ubiquitination
  • RNA, Long Noncoding
  • PTEN Phosphohydrolase
  • Mice
  • Male
  • Humans
  • Female
  • Epithelial-Mesenchymal Transition
  • Developmental Biology
  • Cell Line