title: Engineering ePTEN, an enhanced PTEN with increased tumor suppressor activities.
abstract: The signaling lipid phosphatidylinositol (3,4,5)-trisphosphate (PIP3) is a key regulator of cell proliferation, survival, and migration and the enzyme that dephosphorylates it, phosphatase and tensin homolog (PTEN), is an important tumor suppressor. As excess PIP3 signaling is a hallmark of many cancers, its suppression through activation of PTEN is a potential cancer intervention. Using a heterologous expression system in which human PTEN-GFP is expressed in Dictyostelium cells, we identified mutations in the membrane-binding regulatory interface that increase the recruitment of PTEN to the plasma membrane due to enhanced association with PI(4,5)P2. We engineered these into an enhanced PTEN (ePTEN) with approximately eightfold increased ability to suppress PIP3 signaling. Upon expression in human cells, ePTEN decreases PIP3 levels in the plasma membrane; phosphorylation of AKT, a major downstream event in PIP3 signaling; and cell proliferation and migration. Thus, the activation of PTEN can readjust PIP3 signaling and may serve as a feasible target for anticancer therapies.
authors: Department of Cell Biology and.
authors: Hoai-Nghia
authors: HN
authors: Nguyen
authors: Department of Cell Biology and.
authors: Jr-Ming
authors: JM
authors: Yang
authors: Department of Cell Biology and.
authors: Yashar
authors: Y
authors: Afkari
authors: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205.
authors: Ben Ho
authors: BH
authors: Park
authors: Department of Cell Biology and.
authors: Hiromi
authors: H
authors: Sesaki
authors: Department of Cell Biology and pnd@jhmi.edu miijima@jhmi.edu.
authors: Peter N
authors: PN
authors: Devreotes
authors: Department of Cell Biology and pnd@jhmi.edu miijima@jhmi.edu.
authors: Miho
authors: M
authors: Iijima
mesh_terms: D002478:Cells, Cultured; D003001:Cloning, Molecular; D004023:Dictyostelium; D015723:Gene Library; D049452:Green Fluorescent Proteins; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D016296:Mutagenesis; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D018129:Phosphatidylinositol Phosphates / Q000037:antagonists & inhibitors*; D015202:Protein Engineering / Q000379:methods*; D011994:Recombinant Proteins / Q000235:genetics* / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D018129:Phosphatidylinositol Phosphates; D011994:Recombinant Proteins; D025521:Tumor Suppressor Proteins; C060974:phosphatidylinositol 3,4,5-triphosphate; D049452:Green Fluorescent Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: PI3 kinase signaling; chemotaxis; membrane localization; protein engineering; protein interaction