Incorporation of Oxidized Phenylalanine Derivatives into Insulin Signaling Relevant Proteins May Link Oxidative Stress to Signaling Conditions Underlying Chronic Insulin Resistance
Judit Mohás-Cseh,
Gergő Attila Molnár,
Marianna Pap,
Boglárka Laczy,
Tibor Vas,
Melinda Kertész,
Krisztina Németh,
Csaba Hetényi,
Orsolya Csikós,
Gábor K. Tóth,
Attila Reményi,
István Wittmann
Affiliations
Judit Mohás-Cseh
2nd Department of Medicine and Nephrology-Diabetes Center, University of Pécs Medical School, 7624 Pécs, Hungary
Gergő Attila Molnár
2nd Department of Medicine and Nephrology-Diabetes Center, University of Pécs Medical School, 7624 Pécs, Hungary
Marianna Pap
Department of Medical Biology and Central Electron Microscopic Laboratory, University of Pécs Medical School, 7643 Pécs, Hungary
Boglárka Laczy
2nd Department of Medicine and Nephrology-Diabetes Center, University of Pécs Medical School, 7624 Pécs, Hungary
Tibor Vas
2nd Department of Medicine and Nephrology-Diabetes Center, University of Pécs Medical School, 7624 Pécs, Hungary
Melinda Kertész
2nd Department of Medicine and Nephrology-Diabetes Center, University of Pécs Medical School, 7624 Pécs, Hungary
Krisztina Németh
Institute of Organic Chemistry, Research Centre for Natural Sciences, 1117 Budapest, Hungary
Csaba Hetényi
Department of Pharmacology and Pharmacotherapy, University of Pécs Medical School, 7643 Pécs, Hungary
Orsolya Csikós
Department of Medical Chemistry, Albert Szent-Györgyi Medical School, University of Szeged, 6725 Szeged, Hungary
Gábor K. Tóth
Department of Medical Chemistry, Albert Szent-Györgyi Medical School, University of Szeged, 6725 Szeged, Hungary
Attila Reményi
Institute of Organic Chemistry, Research Centre for Natural Sciences, 1117 Budapest, Hungary
István Wittmann
2nd Department of Medicine and Nephrology-Diabetes Center, University of Pécs Medical School, 7624 Pécs, Hungary
A link between oxidative stress and insulin resistance has been suggested. Hydroxyl free radicals are known to be able to convert phenylalanine (Phe) into the non-physiological tyrosine isoforms ortho- and meta-tyrosine (o-Tyr, m-Tyr). The aim of our study was to examine the role of o-Tyr and m-Tyr in the development of insulin resistance. We found that insulin-induced uptake of glucose was blunted in cultures of 3T3-L1 grown on media containing o- or m-Tyr. We show that these modified amino acids are incorporated into cellular proteins. We focused on insulin receptor substrate 1 (IRS-1), which plays a role in insulin signaling. The activating phosphorylation of IRS-1 was increased by insulin, the effect of which was abolished in cells grown in m-Tyr or o-Tyr media. We found that phosphorylation of m- or o-Tyr containing IRS-1 segments by insulin receptor (IR) kinase was greatly reduced, PTP-1B phosphatase was incapable of dephosphorylating phosphorylated m- or o-Tyr IRS-1 peptides, and the SH2 domains of phosphoinositide 3-kinase (PI3K) bound the o-Tyr IRS-1 peptides with greatly reduced affinity. According to our data, m- or o-Tyr incorporation into IRS-1 modifies its protein–protein interactions with regulating enzymes and effectors, thus IRS-1 eventually loses its capacity to play its role in insulin signaling, leading to insulin resistance.
