title: The p85 regulatory subunit of PI3K mediates cAMP-PKA and insulin biological effects on MCF-7 cell growth and motility.
abstract: Recent studies have shown that hyperinsulinemia may increase the cancer risk. Moreover, many tumors demonstrate an increased activation of IR signaling pathways. Phosphatidylinositol 3-kinase (PI3K) is necessary for insulin action. In epithelial cells, which do not express GLUT4 and gluconeogenic enzymes, insulin-mediated PI3K activation regulates cell survival, growth, and motility. Although the involvement of the regulatory subunit of PI3K (p85α (PI3K)) in insulin signal transduction has been extensively studied, the function of its N-terminus remains elusive. It has been identified as a serine (S83) in the p85α (PI3K) that is phosphorylated by protein kinase A (PKA). To determine the molecular mechanism linking PKA to insulin-mediated PI3K activation, we used p85α (PI3K) mutated forms to prevent phosphorylation (p85A) or to mimic the phosphorylated residue (p85D). We demonstrated that phosphorylation of p85α (PI3K)S83 modulates the formation of the p85α (PI3K)/IRS-1 complex and its subcellular localization influencing the kinetics of the insulin signaling both on MAPK-ERK and AKT pathways. Furthermore, the p85α (PI3K)S83 phosphorylation plays a central role in the control of insulin-mediated cell proliferation, cell migration, and adhesion. This study highlights the p85α (PI3K)S83 role as a key regulator of cell proliferation and motility induced by insulin in MCF-7 cells breast cancer model.
authors.affiliation: Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy.
authors.forename: E
authors.initials: E
authors.lastname: Di Zazzo
authors.affiliation: Department of Biology, University Federico II of Naples, Naples, Italy ; Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Feola
authors.affiliation: Department of Biology, University Federico II of Naples, Naples, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Zuchegna
authors.affiliation: Department of Biology, University Federico II of Naples, Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Romano
authors.affiliation: Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: C F
authors.initials: CF
authors.lastname: Donini
authors.affiliation: Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Bartollino
authors.affiliation: Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy.
authors.forename: C
authors.initials: C
authors.lastname: Costagliola
authors.affiliation: Department of Biology, University Federico II of Naples, Naples, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Frunzio
authors.affiliation: Department of Biology, University Federico II of Naples, Naples, Italy.
authors.forename: P
authors.initials: P
authors.lastname: Laccetti
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Italy ; Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, Temple University, Philadelphia, PA, USA.
authors.forename: M
authors.initials: M
authors.lastname: Di Domenico
authors.affiliation: Department of Biology, University Federico II of Naples, Naples, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Porcellini
mesh_terms: D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation; D002470:Cell Survival; D058543:Class Ia Phosphatidylinositol 3-Kinase / Q000378:metabolism*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D061986:MCF-7 Cells; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction / Q000187:drug effects
chemical_list: C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D058543:Class Ia Phosphatidylinositol 3-Kinase; D017868:Cyclic AMP-Dependent Protein Kinases