title: A functional dissection of PTEN N-terminus: implications in PTEN subcellular targeting and tumor suppressor activity.
abstract: Spatial regulation of the tumor suppressor PTEN is exerted through alternative plasma membrane, cytoplasmic, and nuclear subcellular locations. The N-terminal region of PTEN is important for the control of PTEN subcellular localization and function. It contains both an active nuclear localization signal (NLS) and an overlapping PIP2-binding motif (PBM) involved in plasma membrane targeting. We report a comprehensive mutational and functional analysis of the PTEN N-terminus, including a panel of tumor-related mutations at this region. Nuclear/cytoplasmic partitioning in mammalian cells and PIP3 phosphatase assays in reconstituted S. cerevisiae defined categories of PTEN N-terminal mutations with distinct PIP3 phosphatase and nuclear accumulation properties. Noticeably, most tumor-related mutations that lost PIP3 phosphatase activity also displayed impaired nuclear localization. Cell proliferation and soft-agar colony formation analysis in mammalian cells of mutations with distinctive nuclear accumulation and catalytic activity patterns suggested a contribution of both properties to PTEN tumor suppressor activity. Our functional dissection of the PTEN N-terminus provides the basis for a systematic analysis of tumor-related and experimentally engineered PTEN mutations.
authors: Centro de Investigación Príncipe Felipe, Valencia, Spain.
authors: Anabel
authors: A
authors: Gil
authors: Departamento de Microbiología II, Facultad de Farmacia, Universidad Complutense de Madrid, and Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS), Madrid, Spain.
authors: Isabel
authors: I
authors: Rodríguez-Escudero
authors: Centro de Investigación Príncipe Felipe, Valencia, Spain; Hubrecht Institute, Utrecht, The Netherlands.
authors: Miriam
authors: M
authors: Stumpf
authors: Departamento de Microbiología II, Facultad de Farmacia, Universidad Complutense de Madrid, and Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS), Madrid, Spain.
authors: María
authors: M
authors: Molina
authors: Departamento de Microbiología II, Facultad de Farmacia, Universidad Complutense de Madrid, and Instituto Ramón y Cajal de Investigaciones Sanitarias (IRYCIS), Madrid, Spain.
authors: Víctor J
authors: VJ
authors: Cid
authors: BioCruces Health Research Institute, Barakaldo, Spain; IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
authors: Rafael
authors: R
authors: Pulido
mesh_terms: D000818:Animals; D019556:COS Cells; D002462:Cell Membrane / Q000235:genetics / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics*; D002522:Chlorocebus aethiops; D003593:Cytoplasm / Q000235:genetics / Q000378:metabolism; D006801:Humans; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism; D019913:Nuclear Localization Signals / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000737:chemistry / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics
chemical_list: D019913:Nuclear Localization Signals; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C494929:PTEN protein, human