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Updated: Apr 6, 2026
Assessing Cellular Target Engagement by SHP2 PTPN11 Phosphatase Inhibitors
Published on: July 17, 2020
Opening the conformation is a master switch for the dual localization and phosphatase activity of PTEN
Hoai-Nghia Nguyen1, Jr-Ming Yang1, Takafumi Miyamoto1
1Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD.
Abstract:
Tumor suppressor PTEN mainly functions at two subcellular locations, the plasma membrane and the nucleus. At the plasma membrane, PTEN dephosphorylates the tumorigenic second messenger PIP3, which drives cell proliferation and migration. In the nucleus, PTEN controls DNA repair and genome stability independently of PIP3. Whereas the concept that a conformational change regulates protein function through post-translational modifications has been well established in biology, it is unknown whether a conformational change simultaneously controls dual subcellular localizations of proteins. Here, we discovered that opening the conformation of PTEN is the crucial upstream event that determines its key dual localizations of this crucial tumor suppressor. We identify a critical conformational switch that regulates PTEN's localization. Most PTEN molecules are held in the cytosol in a closed conformation by intramolecular interactions between the C-terminal tail and core region. Dephosphorylation of the tail opens the conformation and exposes the membrane-binding regulatory interface in the core region, recruiting PTEN to the membrane. Moreover, a lysine at residue 13 is also exposed and when ubiquitinated, transports PTEN to the nucleus. Thus, opening the conformation of PTEN is a key mechanism that enhances its dual localization and enzymatic activity, providing a potential therapeutic strategy in cancer treatments.
Insights
The tumor suppressor PTEN
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- The tumor suppressor PTEN (Phosphatase and tensin homolog) plays critical roles in cell growth and survival.
- PTEN functions at both the plasma membrane, regulating PIP3 levels, and in the nucleus, controlling DNA repair.
- The mechanism by which PTEN achieves dual subcellular localization and function remains largely unknown.
Purpose of the Study:
- To investigate the role of protein conformation in regulating PTEN's dual subcellular localization.
- To identify the molecular switch controlling PTEN's localization and activity.
Main Methods:
- Conformational analysis of PTEN.
- Site-directed mutagenesis to probe PTEN's intramolecular interactions.
- Biochemical assays to assess PTEN's enzymatic activity and localization.
- Ubiquitination studies.
Main Results:
- PTEN exists in a closed conformation in the cytosol, stabilized by intramolecular interactions.
- Dephosphorylation of PTEN's C-terminal tail triggers a conformational opening.
- This opening exposes the membrane-binding interface, recruiting PTEN to the plasma membrane.
- Ubiquitination of a newly exposed lysine residue (K13) mediates nuclear import.
- Conformational opening enhances both PTEN's localization and enzymatic activity.
Conclusions:
- PTEN's conformational state is a critical determinant of its dual localization and tumor-suppressive functions.
- A conformational switch, regulated by dephosphorylation and ubiquitination, controls PTEN's recruitment to the plasma membrane and nucleus.
- Targeting PTEN's conformational dynamics offers a potential therapeutic strategy for cancer treatment.
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