TY - JOUR
T1 - LncRNAs-directed PTEN enzymatic switch governs epithelial–mesenchymal transition
AU - Hu, Qingsong
AU - Li, Chunlai
AU - Wang, Shouyu
AU - Li, Yajuan
AU - Wen, Bo
AU - Zhang, Yanyan
AU - Liang, Ke
AU - Yao, Jun
AU - Ye, Youqiong
AU - Hsiao, Heidi
AU - Nguyen, Tina K.
AU - Park, Peter K.
AU - Egranov, Sergey D.
AU - Hawke, David H.
AU - Marks, Jeffrey R.
AU - Han, Leng
AU - Hung, Mien Chie
AU - Zhang, Bing
AU - Lin, Chunru
AU - Yang, Liuqing
N1 - Funding Information:
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.
Funding Information:
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
Publisher Copyright:
© 2019, IBCB, SIBS, CAS.
PY - 2019/4/1
Y1 - 2019/4/1
N2 - 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 PTEN K27-polyUb activates its protein serine/threonine phosphatase activity and inhibits its phosphatidylinositol/protein tyrosine phosphatase activity. With this altered enzymatic activity, PTEN K27-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 PTEN K27-polyUb , by a single nucleotide mutation generated using CRISPR/Cas9 (Pten K80R/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.
AB - 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 PTEN K27-polyUb activates its protein serine/threonine phosphatase activity and inhibits its phosphatidylinositol/protein tyrosine phosphatase activity. With this altered enzymatic activity, PTEN K27-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 PTEN K27-polyUb , by a single nucleotide mutation generated using CRISPR/Cas9 (Pten K80R/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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U2 - 10.1038/s41422-018-0134-3
DO - 10.1038/s41422-018-0134-3
M3 - Article
C2 - 30631154
AN - SCOPUS:85059854912
SN - 1001-0602
VL - 29
SP - 286
EP - 304
JO - Cell research
JF - Cell research
IS - 4
ER -