期刊
CELL RESEARCH
卷 29, 期 4, 页码 286-304出版社
SPRINGERNATURE
DOI: 10.1038/s41422-018-0134-3
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资金
- 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
- Cancer Prevention Research Institute of Texas (CPRIT) [RP130397]
- NIH [1S10OD012304-01]
- National Institutes of Health Pathway to Independence Award [R00CA166527, R00DK094981]
- National Cancer Institute R01 award [1 R01 CA218036-01, 1R01CA218025-01, 1R01CA231011-01]
- Cancer Prevention Research Institute of Texas First-time Faculty Recruitment Award [R1218]
- Department of Defense Breakthrough award [BC151465, BC180196]
- Andrew Sabin Family Foundation Fellows award
- AACR-Bayer Innovation and Discovery Grants
- Cancer Prevention Research Institute of Texas Individual Investigator Research Award [150094, 180259]
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-beta, 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 (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 IncRNA-dependent switch in PTEN protein serine/threonine phosphatase activity is important for physiological homeostasis and disease development.
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