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

doi:10.1016/j.cellsig.2014.02.015

Cellular Signalling

Volume 26, Issue 6, June 2014, Pages 1355-1368

https://doi.org/10.1016/j.cellsig.2014.02.015 Get rights and content

Under a Creative Commons license

open access

Highlights

•
The mechanism(s) behind insulin-induced receptors is unknown.
•
Insulin binding receptor activates Neu1-MMP9-GPCR crosstalk tethered to IRβ subunits.
•
Olanzapine-induced Neu3 inhibits insulin-induced IRβ leading to insulin resistance.
•
Neu1-MMP9-GPCR crosstalk coupled to IRβ is the critical link to insulin resistance.

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.

Graphical abstract

A novel molecular organizational G-protein-coupled receptor (GPCR)-signaling platform potentiates neuraminidase-1 (Neu1) and matrix metalloproteinase-9 (MMP-9) cross talk on the cell surface that is essential for the activation of the insulin receptor β subunit (IRβ) tyrosine kinases. Notes: Insulin-binding receptor α subunits (IRα) potentiates the GPCR-signaling and MMP-9 activation to induce Neu1 sialidase. Activated MMP-9 is proposed to remove the elastin-binding protein (EBP) as part of the molecular multienzymatic complex that contains β-galactosidase/Neu1 and protective protein cathepsin A (PPCA). Activated Neu1 hydrolyzes α-2,3 sialyl residues of IRβ at the ectodomain to remove steric hindrance to facilitate IRβ subunits association and tyrosine kinase activation. Abbreviations: Pi3K, phosphatidylinositol 3-kinase; GTP, guanine triphosphate. Citation: Taken in part from Research and Reports in Biochemistry 2013:3 17–30. © 2013 Abdulkhalek et al, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted non-commercial use, provided the original work is properly cited.

Abbreviations

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′-(4-methylumbelliferyl)-α-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-coupled receptor

MAPK

mitogen-activated protein kinase

IGF-1

insulin like growth factor-1

GRK

G-protein-coupled receptor kinase

PDGF

platelet-derived growth factor

PDGFβR

PDGF β receptor

PI3K

phosphoinositide 3-kinase

EGF

epidermal growth factor

S1P

sphingosine 1-phosphate

inhibitory G-protein

Gαi

α subunit of Gi

Grb

growth factor receptor binding protein

Keywords

Neuraminidase-1

Matrix metalloproteinase-9

Insulin receptor

Cited by (0)

¹: Present address: The King Fahd Armed Forces Hospital, Serology, Jeddah, Saudi Arabia.

²: Present address: Faculty of Medicine, University of Ottawa, Ottawa, ON K1N 6N5, Canada.

³: Present address: Department of Molecular Genetics, Cleveland Clinic Foundation Molecular Genetics, Lerner Research Institute, Cleveland, Ohio, U.S.A.

⁴: Present address: Department of Family Medicine, McMaster University, Hamilton, Ontario, Canada.

⁵: Present address: Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada.