title: Opening the conformation is a master switch for the dual localization and phosphatase activity of PTEN.
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.
authors.affiliation: Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Hoai-Nghia
authors.initials: HN
authors.lastname: Nguyen
authors.affiliation: Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Jr-Ming
authors.initials: JM
authors.lastname: Yang
authors.affiliation: Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Takafumi
authors.initials: T
authors.lastname: Miyamoto
authors.affiliation: Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Kie
authors.initials: K
authors.lastname: Itoh
authors.affiliation: Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Elmer
authors.initials: E
authors.lastname: Rho
authors.affiliation: Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Takanari
authors.initials: T
authors.lastname: Inoue
authors.affiliation: Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Devreotes
authors.affiliation: Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sesaki
authors.affiliation: Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Miho
authors.initials: M
authors.lastname: Iijima
mesh_terms: D004023:Dictyostelium / Q000166:cytology / Q000201:enzymology; D004795:Enzyme Stability; D051059:PTEN Phosphohydrolase / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D015398:Signal Transduction
chemical_list: D051059:PTEN Phosphohydrolase