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Cell Signal. 2014 Jun;26(6):1355-68. doi: 10.1016/j.cellsig.2014.02.015. Epub 2014 Feb 28.

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

Author information

1
Department of Biomedical & Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada. Electronic address: farah_gg@hotmail.com.
2
Department of Biomedical & Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada. Electronic address: merry.guo11@gmail.com.
3
Department of Biomedical & Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada. Electronic address: samarma@hotmail.com.
4
Department of Biomedical & Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada. Electronic address: nicola.crawford@medportal.ca.
5
Department of Biomedical & Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada. Electronic address: amith@ualberta.ca.
6
Department of Biomedical & Molecular Sciences, Queen's University, Kingston, Ontario K7L 3N6, Canada. Electronic address: szewczuk@queensu.ca.

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.

KEYWORDS:

Insulin receptor; Matrix metalloproteinase-9; Neuraminidase-1

PMID:
24583283
DOI:
10.1016/j.cellsig.2014.02.015
[Indexed for MEDLINE]
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