Journal
CELLULAR SIGNALLING
Volume 26, Issue 6, Pages 1355-1368Publisher
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2014.02.015
Keywords
Neuraminidase-1; Matrix metalloproteinase-9; Insulin receptor
Categories
Funding
- Natural Sciences and Engineering Research Council of Canada (NSERC)
- King Abdullah Scholarship from the Ministry of Higher Education, Saudi Arabia
- R.S. McLaughlin Scholarship
- Ontario Graduate Scholarship
- Canadian Institutes of Health Research (CIHR) Doctoral Award: Frederick Banting
- Charles Best Canada Graduate Scholarship
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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 Neul 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 1R beta subunit on the cell surface. Oseltamivir phosphate (Tamiflu (R)), 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 Neul activity associated with insulin stimulated rat hepatoma cells (HTCs) that overly express human IRs (HTC-IR). Tamiflu, anti-Neul antibodies and MMP-9i attenuated phosphotylation of IR beta and insulin receptor substrate-1 (IRS1) associated with insuliri-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 beta tyrosine kinase activation and cellular signaling. Olanzapine-induced Neu3 sialidase activity attenuated insulin-induced IGF-R and IRSI phosphorylation contributing to insulin resistance. (C) 2014 The Authors. Published by Elsevier Inc.
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