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Youde Jiang, Qiuhua Zhang, Jena J Steinle; Serine 307 on Insulin Receptor Substrate 1 is Key to Tumor Necrosis Factor alpha and Suppressor of Cytokine Signaling 3 Action in Müller cells. Invest. Ophthalmol. Vis. Sci. 2014;55(13):5828.
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We have previously reported that beta-adrenergic receptors can regulate tumor necrosis factor alpha (TNFα) in retinal Müller cells, which was associated with dysfunctional insulin receptor signaling through altered insulin receptor substrate 1 (IRS-1) phosphorylation. In this study, we sought to determine whether Serine 307 is key to TNFα and SOCS3 actions on insulin signaling in rMC-1 cells.
Rat retinal Müller cells (rMC-1 cell line) were grown in normal (5mM) or high (25mM) glucose medium. Cells in each group were transfected with either the IRS-1 plasmid or a mutated IRS-1 with Serine 307 converted to an alanine. Cells were also treated with recombinant TNFα or SOCS3 to induce overexpression of these proteins. Western blotting and ELISA analyses were done for TNFα, IRS-1, insulin receptorTyr960, SOCS3, Akt and cleaved caspase 3.
Both TNFα and SOCS3 require IRS-1 phosphorylation on Serine 307 to mediate rMC-1 cell apoptosis, since site-directed mutagenesis of this site eliminates the ability of both TNFα and SOCS3 to decrease Akt phosphorylation and increase cleavage of caspase 3.
Both TNFα and SOCS3 regulate rMC-1 cell apoptosis and signaling through phosphorylation on IRS-1Ser307. SOCS3 is able to directly regulate TNFα levels. Development of therapeutics that target IRS-1 actions may allow for normal insulin receptor signaling in rMC-1 cells.
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