title: Conjugation of SUMO to p85 leads to a novel mechanism of PI3K regulation.
abstract: Class IA phosphatidylinositol 3-kinases (PI3Ks) are composed of p110 catalytic and p85 regulatory subunits. How regulatory subunits modulate PI3K activity remains only partially understood. Here we identified SUMO (small ubiquitin-related modifier) as a new player modulating this regulation. We demonstrate that both p85β and p85α are conjugated to SUMO1 and SUMO2. We identified two lysine residues located at the inter-SH2 domain on p85β, a critical region required for inhibition of p110, as being required for SUMO conjugation. A SUMOylation-defective mutant p85β shows higher activation of the PI3K pathway, and increased cell migration and transformation. Moreover, the cancer-related KS459del mutant in p85α was less efficiently SUMOylated compared with the wild-type protein. Finally, our results show that SUMO modulates p85 tyrosine phosphorylation, a modification correlating with PI3K pathway activation. Thus, SUMO reduces the levels of tyrosine-phosphorylated-p85 while loss of SUMOylation results in increased tyrosine phosphorylation of p85. In summary, we identify SUMO as a new important player in the regulation of the PI3K pathway through modulation of p85.
authors.affiliation: Departmento de Biología Molecular y Celular, Centro Nacional de Biotecnología-CSIC, Darwin 3, Madrid, Spain.
authors.forename: C F
authors.initials: CF
authors.lastname: de la Cruz-Herrera
authors.affiliation: Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela, Instituto de Investigaciones Sanitarias (IDIS), Santiago de Compostela, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Baz-Martínez
authors.affiliation: Ubiquitylation and Cancer Molecular Biology Laboratory, Inbiomed, San Sebastian-Donostia, Gipuzkoa, Spain.
authors.forename: V
authors.initials: V
authors.lastname: Lang
authors.affiliation: Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela, Instituto de Investigaciones Sanitarias (IDIS), Santiago de Compostela, Spain.
authors.forename: A
authors.initials: A
authors.lastname: El Motiam
authors.affiliation: Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Santiago de Compostela, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Barbazán
authors.affiliation: Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Santiago de Compostela, Spain.
authors.forename: R
authors.initials: R
authors.lastname: Couceiro
authors.affiliation: Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Santiago de Compostela, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Abal
authors.affiliation: Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela, Instituto de Investigaciones Sanitarias (IDIS), Santiago de Compostela, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Vidal
authors.affiliation: Departmento de Biología Molecular y Celular, Centro Nacional de Biotecnología-CSIC, Darwin 3, Madrid, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Esteban
authors.affiliation: Heinrich Pette Institute, Leibniz Institute for Experimental Virology, Hamburg, Germany.
authors.forename: C
authors.initials: C
authors.lastname: Muñoz-Fontela
authors.affiliation: Departmento de Biología Molecular y Celular, Centro Nacional de Biotecnología-CSIC, Darwin 3, Madrid, Spain.|CIBER de Enfermedades Respiratorias (CIBERES), Mallorca, Illes Balears, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Nieto
authors.affiliation: Ubiquitylation and Cancer Molecular Biology Laboratory, Inbiomed, San Sebastian-Donostia, Gipuzkoa, Spain.
authors.forename: M S
authors.initials: MS
authors.lastname: Rodríguez
authors.affiliation: Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela (CHUS), SERGAS, Santiago de Compostela, Spain.
authors.forename: M
authors.initials: M
authors.lastname: Collado
authors.affiliation: Departmento de Biología Molecular y Celular, Centro Nacional de Biotecnología-CSIC, Darwin 3, Madrid, Spain.|Centro de Investigación en Medicina Molecular y Enfermedades Crónicas (CIMUS), Universidade de Santiago de Compostela, Instituto de Investigaciones Sanitarias (IDIS), Santiago de Compostela, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Rivas
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009154:Mutation; D010766:Phosphorylation; D011485:Protein Binding; D025841:Small Ubiquitin-Related Modifier Proteins / Q000378:metabolism*
chemical_list: D025841:Small Ubiquitin-Related Modifier Proteins; D058543:Class Ia Phosphatidylinositol 3-Kinase