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Advanced glycation end product precursors impair epidermal growth factor receptor signaling
Manuel Portero-Otín1, Reinald Pamplona, Maria Josep Bellmunt
1Metabolic Pathophysiology Research Group, Department of Basic Medical Sciences, University of Lleida, Lleida, Spain. manuel.portero@cmb.udl.es
Abstract:
Formation of advanced glycation end products (AGEs) is considered a potential link between hyperglycemia and chronic diabetic complications, including disturbances in cell signaling. It was hypothesized that AGEs alter cell signaling by interfering with growth factor receptors. Therefore, we studied the effects of two AGE precursors, glyoxal (GO) and methylglyoxal (MGO), on the epidermal growth factor receptor (EGFR) signaling pathway in cultured cells. Both compounds prevented tyrosine autophosphorylation induced by epidermal growth factor (EGF) in a time- and dose-dependent manner as well as phospholipase Cgamma1 recruitment and subsequent activation of extracellular signal-regulated kinases. AGE precursors inhibit EGF-induced EGFR autophosphorylation and tyrosine kinase activity in cell membranes and in EGFR immunoprecipitates. In addition, AGE precursors strongly inhibited cellular phosphotyrosine phosphatase activities and residual EGFR dephosphorylation. AGE precursors induced the formation of EGFR cross-links, as shown by the cross-reactivity of modified EGFR with an anti-N(epsilon)(carboxymethyl)lysine antibody, suggesting that altered EGFR signaling was related to carbonyl-amine reactions on EGFR. Aminoguanidine, an inhibitor of AGE formation, partially prevented the EGFR dysfunction induced by GO and MGO. These data introduce a novel mechanism for impaired cellular homeostasis in situations that lead to increased production of these reactive aldehydes, such as diabetes.
Insights
Advanced glycation end products (AGEs) disrupt cell signaling by damaging the epidermal growth factor receptor (EGFR). This damage, caused by AGE precursors like glyoxal and methylglyoxal, impairs crucial cell functions, contributing to diabetic complications.
Area of Science:
- Biochemistry
- Cell Biology
- Endocrinology
Background:
- Advanced glycation end products (AGEs) are implicated in diabetic complications and may disrupt cell signaling pathways.
- Growth factor receptors, such as the epidermal growth factor receptor (EGFR), are critical for cellular communication and homeostasis.
Purpose of the Study:
- To investigate the effects of AGE precursors, glyoxal (GO) and methylglyglyoxal (MGO), on the EGFR signaling pathway.
- To elucidate the mechanism by which AGEs interfere with EGFR function and cellular signaling.
Main Methods:
- Cultured cells were treated with GO and MGO, key AGE precursors.
- EGFR signaling was assessed by measuring tyrosine autophosphorylation, phospholipase Cgamma1 recruitment, and extracellular signal-regulated kinase activation.
- EGFR tyrosine kinase activity, phosphotyrosine phosphatase activity, and EGFR cross-linking were analyzed.
- Aminoguanidine was used to inhibit AGE formation and assess its protective effects.
Main Results:
- GO and MGO inhibited EGF-induced EGFR autophosphorylation and tyrosine kinase activity in a time- and dose-dependent manner.
- AGE precursors reduced phospholipase Cgamma1 recruitment and extracellular signal-regulated kinase activation.
- AGEs inhibited cellular phosphotyrosine phosphatase activity and EGFR dephosphorylation, and induced EGFR cross-linking.
- Aminoguanidine partially prevented the EGFR dysfunction caused by GO and MGO.
Conclusions:
- AGE precursors directly impair EGFR signaling by inducing cross-linking and inhibiting kinase activity.
- This EGFR dysfunction contributes to impaired cellular homeostasis in conditions of hyperglycemia, such as diabetes.
- The findings reveal a novel mechanism linking AGE formation to diabetic complications via disrupted growth factor receptor signaling.