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

Cellular Signalling 26 (2014) 1355–1368
Contents lists available at ScienceDirect
Cellular Signalling
journal homepage: ate/cellsig
A novel insulin receptor-signaling platform and its link to insulin
resistance and type 2 diabetes
Farah Alghamdi 1, Merry Guo 2,SamarAbdulkhalek3, Nicola Crawford 4,
Schammim Ray Amith 5, Myron R. Szewczuk ⁎
Department of Biomedical & Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada
article info abstract
Article history: Insulin-induced insulin receptor (IR) tyrosine kinase activation and insulin cell survival responses have been
Received 8 February 2014 reported to be under the regulation of a membrane associated mammalian neuraminidase-1 (Neu1). The molec-
Received in revised form 23 February 2014 ular mechanism(s) behind this process is unknown. Here, we uncover a novel Neu1 and matrix
Accepted 23 February 2014
metalloproteinase-9 (MMP-9) cross-talk in alliance with neuromedin B G-protein coupled receptor (GPCR),
Available online 28 February 2014
which is essential for insulin-induced IR activation and cellular signaling. Neu1, MMP-9 and neuromedin B
GPCR form plex with IRβ subunit on the cell surface. Oseltamivir phosphate (Tamiflu®), anti-Neu1 antibod-
Keywords:
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Neuraminidase-1 ies, broad range MMP inhibitors piperazine and galardin (GM6001), MMP-9 speci c inhibitor (MMP-9i), and
Matrix metalloproteinase-9 GPCR neuromedin B specific antagonist BIM-23127 dose-dependently inhibited Neu1 activity associated with
Insulin receptor insulin stimulated rat hepatoma cells (HTCs) that overly express human IRs (HTC-IR). Tamiflu, anti-Neu1 anti-
bodies 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 ically defective in Neu1. Neu3 an-
tagonist 2-deoxy-2