Advanced glycation end product precursors impair epidermal growth factor receptor signalin
Cristina Ruiz, Maria
Nègre Salvayre, Anne
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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 Cγ1 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-Nε(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. The Maillard reaction comprises the nonenzymatic reaction of reducing sugars with molecules containing an amino group, including proteins, phospholipids, and DNA (1,2). After the reversible formation of a Schiff’s base between the reducing sugar and free amino group, this reaction proceeds to form advanced glycation end products (AGEs). Aldehydes such as glyoxal (GO) and methylglyoxal (MGO) are also able to induce AGE formation (3). GO and MGO can be generated during glycation of proteins by glucose (3); during lipid peroxidation (4); from metabolic processes, such as base-catalyzed phosphate elimination of glyceraldehyde 3-phosphate and dihydroxyacetone phosphate; and also during the metabolism of acetone and threonine (5). During chronic complications of diabetes and aging, the levels of AGEs derived from the reaction of GO and MGO with proteins rise in plasma proteins, extracellular matrix, and lens proteins (6–8). Modification of proteins through derivatization by GO and MGO may induce interaction with specific receptors, such as the RAGE and AGE-R family (9), or directly alter protein functions. For instance, MGO inhibits mitochondrial respiration, membrane ATPases and glyceraldehyde-3-phosphate dehydrogenases (10), and DNA and protein synthesis, thereby inducing growth arrest and cell death (11)
Is part ofDiabetes, 2002, vol.51, núm. 5, p.1535-1542
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