A novel insulin receptor-signaling platform and its link to insulin resistance and type 2 diabetes

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• 作者：Farah Alghamdi¹ ; ^{farah_gg@hotmail.com" class="auth_mail} ; Merry Guo² ; ^{merry.guo11@gmail.com" class="auth_mail} ; Samar Abdulkhalek³ ; ^{samarma@hotmail.com" class="auth_mail} ; Nicola Crawford⁴ ; ^{nicola.crawford@medportal.ca" class="auth_mail} ; Schammim Ray Amith⁵ ; ^{amith@ualberta.ca" class="auth_mail} ; Myron R. Szewczuk ; ^{szewczuk@queensu.ca" class="auth_mail}
• 关键词：IR ; insulin receptor ; IRS1 ; insulin receptor substrate-1 ; IGF-R ; insulin growth factor receptor ; EGF ; epidermal growth factor ; MMP ; matrix metalloproteinase ; RTK ; receptor tyrosine kinase ; NGF ; nerve growth factor ; Neu1 ; mammalian neuraminidase-1 ; 4-MUNANA ; [2&prime ; -(4-methylumbelliferyl)-伪-d-N-acetylneuraminic acid] ; DANA ; 2-deoxy-2 ; 3-didehydro-N-acetylneuraminic acid ; IC50 ; the concentration of a drug that is required for 50% inhibition in vitro ; TLR ; Toll-like receptor ; GPCR ; G-protein-coup
• 刊名：Cellular Signalling
• 出版年：June, 2014
• 年：2014
• 卷：26
• 期：6
• 页码：1355-1368
• 全文大小：1864 K

文摘

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 IR尾 subunit on the cell surface. Oseltamivir phosphate (Tamiflu庐), 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 IR尾 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 IR尾 tyrosine kinase activation and cellular signaling. Olanzapine-induced Neu3 sialidase activity attenuated insulin-induced IGF-R and IRS1 phosphorylation contributing to insulin resistance.