title: Engineering PTEN function: membrane association and activity.
abstract: Many tumors are associated with deficiency of the tumor suppressor, PTEN, a PIP3 phosphatase that turns off PIP3 signaling. The major site of PTEN action is the plasma membrane, where PIP3 is produced by PI3 kinases. However, the mechanism and functional importance of PTEN membrane recruitment are poorly defined. Using the heterologous expression system in which human PTEN is expressed in Dictyostelium discoideum, we defined the molecular mechanisms that regulate the membrane-binding site through inhibitory interactions with the phosphorylated C-terminal tail. In addition, we potentiated mechanisms that mediate PTEN membrane association and engineered an enhanced PTEN with increased tumor suppressor functions. Moreover, we identified a new class of cancer-associated PTEN mutations that are specifically defective in membrane association. In this review, we summarize recent advances in PTEN-membrane interactions and methods useful in addressing PTEN function.
authors.affiliation: Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.
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, United States.
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, United States.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sesaki
authors.affiliation: Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD, United States.
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, United States. Electronic address: miijima@jhmi.edu.
authors.forename: Miho
authors.initials: M
authors.lastname: Iijima
mesh_terms: D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism*; D004023:Dictyostelium / Q000235:genetics / Q000378:metabolism*; D005818:Genetic Engineering / Q000379:methods*; D057809:HEK293 Cells; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary; D025521:Tumor Suppressor Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: D025521:Tumor Suppressor Proteins; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
keywords: Dictyostelium; Membrane; Mutation; PIP3