Advanced glycation end product precursors impair epidermal growth factor receptor signaling.
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.
Portero-Otín
Manuel
M
Metabolic Pathophysiology Research Group, Department of Basic Medical Sciences, University of Lleida, Lleida, Spain. manuel.portero@cmb.udl.es
Pamplona
Reinald
R
Bellmunt
Maria Josep
MJ
Ruiz
Maria Cristina
MC
Prat
Joan
J
Salvayre
Robert
R
Nègre-Salvayre
Anne
A
D002461:Cell Line, Transformed; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism*; D005347:Fibroblasts / Q000166:cytology; D017127:Glycation End Products, Advanced / Q000378:metabolism*; D006037:Glyoxal / Q000494:pharmacology; D006146:Guanidines / Q000494:pharmacology; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000037:antagonists & inhibitors / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011765:Pyruvaldehyde / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism
D004791:Enzyme Inhibitors; D017127:Glycation End Products, Advanced; D006146:Guanidines; D014443:Tyrosine; D006037:Glyoxal; D011765:Pyruvaldehyde; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D017027:Protein Tyrosine Phosphatases; C004479:pimagedine