Neuraminidase-1 Sialidase and Matrix Metalloproteinase-9 Crosstalk in Alliance With Insulin Receptors is an Essential Molecular Signaling Platform for Insulin-Induced Receptor Activation

dc.contributor.authorAlghamdi, Farahen
dc.contributor.departmentMicrobiology and Immunologyen
dc.contributor.supervisorSzewczuk, Myron R.en
dc.date2013-02-20 11:27:44.861's University at Kingstonen
dc.descriptionThesis (Master, Microbiology & Immunology) -- Queen's University, 2013-02-20 11:27:44.861en
dc.description.abstractMolecular-targeting therapeutics directed towards growth factor receptors have become promising interventions in cancer. They include the family of mammalian receptor tyrosine kinases such as epidermal growth factor, TrkA and insulin. In particular, the insulin receptor (IR) is one of the most well-known members of the RTK family of receptors playing a role in cancer. IRs are covalently-linked heterodimers of αβ subunits on the cell membrane in the absence of insulin. The IR signaling pathways are initially triggered by insulin binding to the α subunits followed by the interaction of β subunits and ATP. The parameter(s) controlling IR activation remains unknown. Here, we report a membrane receptor signaling platform initiated by insulin binding to its receptor to induce Neu1 in live HTC-IR and MiaPaCa-2 cell lines. Microscopy colocalization and co-immunoprecipitation analyses reveal that Neu1 and MMP9 form a complex with naïve and insulin-treated receptors. Tamiflu (neuraminidase inhibitor), galardin and piperazine (broad range MMP inhibitors), MMP9 specific inhibitor and anti-Neu1 antibody blocked Neu1 activity associated with insulin stimulated live cells. Moreover, Tamiflu, anti-Neu1 antibody, and MMP9 specific inhibitor blocked insulin induced insulin receptor substrate-1 phosphorylation (p-IRS1). The previous findings reveal a molecular organizational signaling platform of Neu1 and MMP-9 crosstalk in alliance with insulin receptors. It proposes that insulin binding to the receptor induces MMP9 to activate Neu1, which hydrolyzes α-2,3 sialic acid in removing steric hindrance to generate a functional receptor. The results predict a prerequisite desialylation process by activated Neu1. A complete understanding of IR activation and the role of sialic acids in the iii signaling pathways may provide a therapeutic strategy in the prevention of different diseases such as diabetes mellitus and cancer.en
dc.description.restricted-thesisI am going to puplish my worken
dc.relation.ispartofseriesCanadian thesesen
dc.rightsThis publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner.en
dc.subjectInsulin Receptorsen
dc.titleNeuraminidase-1 Sialidase and Matrix Metalloproteinase-9 Crosstalk in Alliance With Insulin Receptors is an Essential Molecular Signaling Platform for Insulin-Induced Receptor Activationen
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