The Double-stranded RNA–dependent Protein Kinase Differentially Regulates Insulin Receptor Substrates 1 and 2 in HepG2 Cells
Year: 2010
Type: article
Abstract: Initially identified to be activated upon virus infection, the double-stranded RNA-dependent protein kinase (PKR) is best known for triggering cell defense responses by phosphorylating eIF-2α, thus suppressing RNA translation. We as well as others showed that the phosphorylation of PKR is down-regulated by insulin. In the present study, we further uncovered a novel function of PKR in regulating the IRS proteins. We found that PKR up-regulates the inhibitory phosphorylation of IRS1 at Ser312, which suppresses the tyrosine phosphorylation of IRS1. This effect of PKR on the phosphorylation of IRS1 is mediated by two other protein kinases, JNK and IKK. In contrast, PKR regulates IRS2, another major IRS family protein in the liver, at the transcriptional rather than the posttranslational level, and this effect is mediated by the transcription factor, FoxO1, which has been previously shown to be regulated by insulin and plays a significant role in glucose homeostasis and energy metabolism. In summary, we found for the first time that initially known as a virus infection response gene, PKR regulates the upstream central transmitters of insulin signaling, IRS1 and IRS2, through different mechanisms.
Source: Molecular Biology of the Cell
Institution: Michigan State University
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Awards: Development of a parallel, array-based transcription factor expression assay, CDI-Type II: Discovery of Biophysical Mechanisms Inducing Signaling and Cytotoxicity: An Experimental Approach Enabled by Cyber Tools, Aptamer-based Proteomic Analysis for Cancer Signatures, G316389574, Develop a Dynamic Model that Incoporates Text-mining to Reconstruct Networks, G6490296102
OpenAlex ID: W2169472869