Bicarbonate is essential for protein-tyrosine phosphatase 1B (PTP1B) oxidation and cellular signaling through EGF-triggered phosphorylation cascades
| Autor: | Elias S.J. Arnér, Benoit Boivin, Syed Husain Mustafa Rizvi, Paul E. Pace, Qing Cheng, Markus Dagnell, Christine C. Winterbourn |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Thioredoxin Reductase 1 medicine.medical_treatment Peroxiredoxin 2 Biochemistry Phosphorylation cascade 03 medical and health sciences chemistry.chemical_compound Thioredoxins Epidermal growth factor Cell Line Tumor medicine Humans Editors' Picks Protein phosphorylation Phosphorylation Molecular Biology Acid-Base Equilibrium Homeodomain Proteins Protein Tyrosine Phosphatase Non-Receptor Type 1 Epidermal Growth Factor 030102 biochemistry & molecular biology Kinase Growth factor Tyrosine phosphorylation Hydrogen Peroxide Cell Biology Cell biology Bicarbonates 030104 developmental biology chemistry Oxidation-Reduction NADP Signal Transduction |
| Zdroj: | Journal of Biological Chemistry. 294:12330-12338 |
| ISSN: | 0021-9258 |
| Popis: | Protein-tyrosine phosphatases (PTPs) counteract protein tyrosine phosphorylation and cooperate with receptor-tyrosine kinases in the regulation of cell signaling. PTPs need to undergo oxidative inhibition for activation of cellular cascades of protein-tyrosine kinase phosphorylation following growth factor stimulation. It has remained enigmatic how such oxidation can occur in the presence of potent cellular reducing systems. Here, using in vitro biochemical assays with purified, recombinant protein, along with experiments in the adenocarcinoma cell line A431, we discovered that bicarbonate, which reacts with H(2)O(2) to form the more reactive peroxymonocarbonate, potently facilitates H(2)O(2)-mediated PTP1B inactivation in the presence of thioredoxin reductase 1 (TrxR1), thioredoxin 1 (Trx1), and peroxiredoxin 2 (Prx2) together with NADPH. The cellular experiments revealed that intracellular bicarbonate proportionally dictates total protein phosphotyrosine levels obtained after stimulation with epidermal growth factor (EGF) and that bicarbonate levels directly correlate with the extent of PTP1B oxidation. In fact, EGF-induced cellular oxidation of PTP1B was completely dependent on the presence of bicarbonate. These results provide a plausible mechanism for PTP inactivation during cell signaling and explain long-standing observations that growth factor responses and protein phosphorylation cascades are intimately linked to the cellular acid–base balance. |
| Databáze: | OpenAIRE |
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