title: A novel insulin receptor-signaling platform and its link to insulin resistance and type 2 diabetes.
abstract: Insulin-induced insulin receptor (IR) tyrosine kinase activation and insulin cell survival responses have been reported to be under the regulation of a membrane associated mammalian neuraminidase-1 (Neu1). The molecular mechanism(s) behind this process is unknown. Here, we uncover a novel Neu1 and matrix metalloproteinase-9 (MMP-9) cross-talk in alliance with neuromedin B G-protein coupled receptor (GPCR), which is essential for insulin-induced IR activation and cellular signaling. Neu1, MMP-9 and neuromedin B GPCR form a complex with IRβ subunit on the cell surface. Oseltamivir phosphate (Tamiflu®), anti-Neu1 antibodies, broad range MMP inhibitors piperazine and galardin (GM6001), MMP-9 specific inhibitor (MMP-9i), and GPCR neuromedin B specific antagonist BIM-23127 dose-dependently inhibited Neu1 activity associated with insulin stimulated rat hepatoma cells (HTCs) that overly express human IRs (HTC-IR). Tamiflu, anti-Neu1 antibodies and MMP-9i attenuated phosphorylation of IRβ and insulin receptor substrate-1 (IRS1) associated with insulin-stimulated cells. Olanzapine, an antipsychotic agent associated with insulin resistance, induced Neu3 sialidase activity in WG544 or 1140F01 human sialidosis fibroblast cells genetically defective in Neu1. Neu3 antagonist 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA) and anti-Neu3 antibodies inhibited sialidase activity associated with olanzapine treated murine Neu4 knockout macrophage cells. Olanzapine attenuated phosphorylation of IGF-R and IRS1 associated with insulin-stimulated human wild-type fibroblast cells. Our findings identify a novel insulin receptor-signaling platform that is critically essential for insulin-induced IRβ tyrosine kinase activation and cellular signaling. Olanzapine-induced Neu3 sialidase activity attenuated insulin-induced IGF-R and IRS1 phosphorylation contributing to insulin resistance.
authors.affiliation: Department of Biomedical & Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada. Electronic address: farah_gg@hotmail.com.
authors.forename: Farah
authors.initials: F
authors.lastname: Alghamdi
authors.affiliation: Department of Biomedical & Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada. Electronic address: merry.guo11@gmail.com.
authors.forename: Merry
authors.initials: M
authors.lastname: Guo
authors.affiliation: Department of Biomedical & Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada. Electronic address: samarma@hotmail.com.
authors.forename: Samar
authors.initials: S
authors.lastname: Abdulkhalek
authors.affiliation: Department of Biomedical & Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada. Electronic address: nicola.crawford@medportal.ca.
authors.forename: Nicola
authors.initials: N
authors.lastname: Crawford
authors.affiliation: Department of Biomedical & Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada. Electronic address: amith@ualberta.ca.
authors.forename: Schammim Ray
authors.initials: SR
authors.lastname: Amith
authors.affiliation: Department of Biomedical & Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada. Electronic address: szewczuk@queensu.ca.
authors.forename: Myron R
authors.initials: MR
authors.lastname: Szewczuk
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology; D001569:Benzodiazepines / Q000494:pharmacology; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000502:physiology; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007333:Insulin Resistance; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D009439:Neuraminidase / Q000378:metabolism*; D000077152:Olanzapine; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D021381:Protein Transport; D051381:Rats; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D014150:Antipsychotic Agents; C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D001569:Benzodiazepines; D017526:Receptor, IGF Type 1; D011972:Receptor, Insulin; C486385:NEU1 protein, human; C465436:Neu3 protein, human; D009439:Neuraminidase; C579270:MMP9 protein, human; D020780:Matrix Metalloproteinase 9; D000077152:Olanzapine
keywords: Insulin receptor; Matrix metalloproteinase-9; Neuraminidase-1