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

• Published in: The FASEB journal Vol. 31; no. 8; pp. 3555 - 3573
• Main Authors: Roux, Alexandra, Loranger, Anne, Lavoie, Josée N., Marceau, Normand
• Format: Journal Article
• Language: English
• Published: United States Federation of American Societies for Experimental Biology 01-08-2017; Federation of American Societies for Experimental Biology (FASEB)
• Subjects: 1-Phosphatidylinositol 3-kinase; Accumulation; AKT protein; Animals; endosomes; Epithelial cells; Feedback loops; Hepatocytes; Hepatocytes - physiology; Insulin; intermediate filament; Keratin; Keratin-18 - genetics; Keratin-18 - metabolism; Keratin-8 - genetics; Keratin-8 - metabolism; Mice; Mice, Knockout; microtubules; Modulation; Phosphates; Phosphatidylinositol 3-Kinases - genetics; Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositol 3-phosphate; Phosphatidylinositols - metabolism; PI3K; PIP signaling; Protein Transport; Proteins; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - metabolism; rab5 GTP-Binding Proteins - genetics; rab5 GTP-Binding Proteins - metabolism; Rapamycin; Receptor, Insulin - physiology; Rodents; Signal Transduction - physiology; Signaling; Substrates; TOR protein; Vesicular Transport Proteins - genetics; Vesicular Transport Proteins - metabolism; PIP signaling; endosomes; intermediate filament; microtubules; PI3K
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.201700036R

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 K8null 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. FASEB J. 31, 3555–3573 (2017). www.fasebj.org