Keratin 8/18 regulation of insulin receptor signaling and trafficking in hepatocytes through a concerted phosphoinositide-dependent Akt and Rab5 modulation.

Abstract

Keratins (Ks) are epithelial cell intermediate filament (IF) proteins that are expressed as pairs in a differentiation-regulated manner. Hepatocyte IFs are made only of K8/K18 pairs, which means that a K8 loss in K8-null mice leads to degradation of K18. Functionally, there is accumulating evidence that IFs contribute to signaling platforms. Here, we investigate the role of K8/K18 IFs in the regulation of insulin receptor (IR) signaling and trafficking in hepatocytes. We find that the IR substrate 1 (IRS1)/PI3K/Akt signaling cascade-downstream of IR-displays prolonged activation in K8-null compared with wild-type hepatocytes. Assessment of the Akt/mammalian target of rapamycin complex 1-mediated feedback loop to IRS1/PI3K, in the absence or presence of drug inhibitors, further supports a preferential K8/K18 IF intervention at the surface membrane. In K8-null hepatocytes, IR trafficking vesicles that are labeled by Rab5/EEA1/phosphatidylinositol 3-phosphate accumulate at a juxtanuclear region via a microtubule-dependent process. Moreover, interference with phosphatidylinositol 4,5-biphosphate signaling aggravates IR/Rab5 accumulation. Overall, results uncover K8/K18 IF regulation of IR signaling via a concerted modulation of phosphatidylinositol 4,5-biphosphate-dependent IRS1/PI3K/Akt signaling and Rab5/phosphatidylinositol 3-phosphate/microtubule trafficking in hepatocytes.-Roux, A., Loranger, A., Lavoie, J. N., Marceau, N. Keratin 8/18 regulation of insulin receptor signaling and trafficking in hepatocytes through a concerted phosphoinositide-dependent Akt and Rab5 modulation.