(670f) Pkr Is Involved In Mediating Insulin Signaling and Inducing Insulin Resistance

The major functions of insulin, e.g., regulation of the blood glucose level, amino acid uptake, lipid metabolism, are modulated by a signaling process called insulin signaling, which is initiated by the binding of insulin with its cellular membrane receptor protein, insulin receptor (IR) [1]. Upon binding with insulin, IR induces phosphorylation of its intracellular substrate, i.e., insulin receptor substrate (IRS), which plays a central role in triggering downstream pathways and thus signaling the effects of insulin on the cellular activities. The double-stranded RNA-dependent protein kinase (PKR) is best known for triggering cell defense responses by phosphorylating eIF-2α and thus activating cellular apoptosis during virus infection [2]. As a Ser/Thr protein kinase, PKR is also known for its role in mediating signaling pathways [3, 4] by interacting with downstream proteins such as NF-κB, MAPKs, and PP2A [5-8]. In the present study, we identified that in liver cells PKR suppressed the insulin signaling activity by inducing the inhibitory phosphorylation of IRS at its serine residues, which in its turn suppresses the tyrosine phosphorylation of IRS and blocks insulin signaling. It is the first time that PKR is shown to induce insulin resistance at the level of IRS. In addition, we also showed that insulin transiently inhibits the phosphorylation of PKR, which is potentially mediated by IRS and PP1. In summary, our results suggest, for the first time, that PKR is involved in mediating insulin signaling pathways and inducing insulin resistance, and we propose a feedback mechanism on the involvement of PKR in regulating the insulin signaling network.

1. Saltiel, A.R. and C.R. Kahn, Insulin signalling and the regulation of glucose and lipid metabolism. Nature, 2001. 414(6865): p. 799-806.

2. Barber, G.N., The dsRNA-dependent protein kinase, PKR and cell death. Cell Death Differ, 2005. 12(6): p. 563-70.

3. Williams, B.R., PKR; a sentinel kinase for cellular stress. Oncogene, 1999. 18(45): p. 6112-20.

4. Williams, B.R., Signal integration via PKR. Sci STKE, 2001. 2001(89): p. RE2.

5. Kumar, A., et al., Double-stranded RNA-dependent protein kinase activates transcription factor NF-kappa B by phosphorylating I kappa B. Proc Natl Acad Sci U S A, 1994. 91(14): p. 6288-92.

6. Gil, J., J. Alcami, and M. Esteban, Activation of NF-kappa B by the dsRNA-dependent protein kinase, PKR involves the I kappa B kinase complex. Oncogene, 2000. 19(11): p. 1369-78.

7. Zhou, H.R., A.S. Lau, and J.J. Pestka, Role of double-stranded RNA-activated protein kinase R (PKR) in deoxynivalenol-induced ribotoxic stress response. Toxicol Sci, 2003. 74(2): p. 335-44.

8. Xu, Z. and B.R. Williams, The B56alpha regulatory subunit of protein phosphatase 2A is a target for regulation by double-stranded RNA-dependent protein kinase PKR. Mol Cell Biol, 2000. 20(14): p. 5285-99.