title: G protein-coupled receptor-mediated activation of p110β by Gβγ is required for cellular transformation and invasiveness.
abstract: Synergistic activation by heterotrimeric guanine nucleotide-binding protein (G protein)-coupled receptors (GPCRs) and receptor tyrosine kinases distinguishes p110β from other class IA phosphoinositide 3-kinases (PI3Ks). Activation of p110β is specifically implicated in various physiological and pathophysiological processes, such as the growth of tumors deficient in phosphatase and tensin homolog deleted from chromosome 10 (PTEN). To determine the specific contribution of GPCR signaling to p110β-dependent functions, we identified the site in p110β that binds to the Gβγ subunit of G proteins. Mutation of this site eliminated Gβγ-dependent activation of PI3Kβ (a dimer of p110β and the p85 regulatory subunit) in vitro and in cells, without affecting basal activity or phosphotyrosine peptide-mediated activation. Disrupting the p110β-Gβγ interaction by mutation or with a cell-permeable peptide inhibitor blocked the transforming capacity of PI3Kβ in fibroblasts and reduced the proliferation, chemotaxis, and invasiveness of PTEN-null tumor cells in culture. Our data suggest that specifically targeting GPCR signaling to PI3Kβ could provide a therapeutic approach for tumors that depend on p110β for growth and metastasis.
authors.affiliation: Department of Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Hashem A
authors.initials: HA
authors.lastname: Dbouk
authors.forename: Oscar
authors.initials: O
authors.lastname: Vadas
authors.forename: Aliaksei
authors.initials: A
authors.lastname: Shymanets
authors.forename: John E
authors.initials: JE
authors.lastname: Burke
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Salamon
authors.forename: Bassem D
authors.initials: BD
authors.lastname: Khalil
authors.forename: Mathew O
authors.initials: MO
authors.lastname: Barrett
authors.forename: Gary L
authors.initials: GL
authors.lastname: Waldo
authors.forename: Chinmay
authors.initials: C
authors.lastname: Surve
authors.forename: Christine
authors.initials: C
authors.lastname: Hsueh
authors.forename: Olga
authors.initials: O
authors.lastname: Perisic
authors.forename: Christian
authors.initials: C
authors.lastname: Harteneck
authors.forename: Peter R
authors.initials: PR
authors.lastname: Shepherd
authors.forename: T Kendall
authors.initials: TK
authors.lastname: Harden
authors.forename: Alan V
authors.initials: AV
authors.lastname: Smrcka
authors.forename: Ronald
authors.initials: R
authors.lastname: Taussig
authors.forename: Anne R
authors.initials: AR
authors.lastname: Bresnick
authors.forename: Bernd
authors.initials: B
authors.lastname: Nürnberg
authors.forename: Roger L
authors.initials: RL
authors.lastname: Williams
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Backer
mesh_terms: D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D058534:Class I Phosphatidylinositol 3-Kinases; D005347:Fibroblasts / Q000378:metabolism* / Q000473:pathology; D044387:GTP-Binding Protein beta Subunits / Q000235:genetics / Q000378:metabolism*; D044388:GTP-Binding Protein gamma Subunits / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D044387:GTP-Binding Protein beta Subunits; D044388:GTP-Binding Protein gamma Subunits; D009363:Neoplasm Proteins; D043562:Receptors, G-Protein-Coupled; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C497132:PIK3CB protein, human