title: A new class of cancer-associated PTEN mutations defined by membrane translocation defects.
abstract: Phosphatase and tensin homolog (PTEN), which negatively regulates tumorigenic phosphatidylinositol (3,4,5)-trisphosphate (PIP3) signaling, is a commonly mutated tumor suppressor. The majority of cancer-associated PTEN mutations block its essential PIP3 phosphatase activity. However, there is a group of clinically identified PTEN mutations that maintain enzymatic activity, and it is unknown how these mutations contribute to tumor pathogenesis. Here, we show that these enzymatically competent PTEN mutants fail to translocate to the plasma membrane where PTEN converts PIP3 to PI(4,5)P2. Artificial membrane tethering of the PTEN mutants effectively restores tumor suppressor activity and represses excess PIP3 signaling in cells. Thus, our findings reveal a novel mechanism of tumorigenic PTEN deficiency.
authors.affiliation: Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: H-N
authors.initials: HN
authors.lastname: Nguyen
authors.affiliation: Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: J-M
authors.initials: JM
authors.lastname: Yang
authors.affiliation: Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Rahdar
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: M
authors.initials: M
authors.lastname: Keniry
authors.affiliation: Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: K F
authors.initials: KF
authors.lastname: Swaney
authors.affiliation: Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: R
authors.initials: R
authors.lastname: Parsons
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: B H
authors.initials: BH
authors.lastname: Park
authors.affiliation: Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: H
authors.initials: H
authors.lastname: Sesaki
authors.affiliation: Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: P N
authors.initials: PN
authors.lastname: Devreotes
authors.affiliation: Department of Cell Biology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Iijima
mesh_terms: D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D004023:Dictyostelium / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics* / Q000378:metabolism*; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010766:Phosphorylation; D021381:Protein Transport; D015398:Signal Transduction
chemical_list: D018129:Phosphatidylinositol Phosphates; C060974:phosphatidylinositol 3,4,5-triphosphate; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human