With-no-lysine 1 (WNK1) kinase is a substrate of the insulin receptor/Akt pathway. Impaired insulin signaling in skeletal muscle disturbs glucose transporter 4 (GLUT4) translocation associated with the onset of type 2 diabetes (T2D). WNK1 is highly expressed in skeletal muscle. However, it is currently unknown how insulin signaling targeting WNK1 regulates GLUT4 trafficking in skeletal muscle, and whether this regulation is perturbed in T2D. Hereby, we show that insulin phosphorylates WNK1 at its activating site via a phosphatidylinositol 3-kinase-dependent mechanism. WNK1 promotes the cell surface abundance of GLUT4 via regulating TBC1D4. Of note, we observed insulin resistance and decreased WNK1 phosphorylation in T2D db/db mice as compared to the control mice. These results provide a new perspective on WNK1 function in the pathogenesis of hyperglycemia in T2D.
Bibliographical noteFunding Information:
We thank professors Chou-Long Huang (University of Iowa Carver College of Medicine) and Hyeon Soo Kim (Korea University, Korea) for providing materials. We also thank to Dr. Sohyun Kim and Eun-Ha Chang for proofreading. This study was supported by the Medical Research Center Program (2017R1A5A2015369) and the Basic Science Research Program (2015R1D1A1A01060454 and 2017R1D1 A3B03031760) through the National Research Foundation of Korea, and the Yonsei University Wonju Campus Future-Leading Research Initiative (2017-52-0082).
All Science Journal Classification (ASJC) codes
- Biochemistry, Genetics and Molecular Biology(all)