ACTIVATION OF EGF RECEPTOR BY OXIDIZED LDL

Oxidized low density lipoproteins (oxLDL) are thought to play a major role: in atherosclerosis, OxLDL exhibit a wide variety of biological e ffects resulting from their ability to interfere with intracellular si gnaling, The cellular targets and primary signaling events of oxLDL ar e unknown. We report that oxLDL elicit, in intact cells, tyrosine phos phorylation of the epithelial growth factor receptor (EGFR) and activa tion of its signaling pathway. This activation triggered by oxLDL was associated with derivatization of reactive amino groups of EGFR and wa s mimicked by 4-hydroxynonenal (4-HNE, a major lipid peroxidation prod uct of oxLDL), Immunopurified EGFR was derivatized and activated in vi tro by oxLDL lipid extracts and 4-HNE, thus indicating that 1) EGFR ma y be a primary target of oxidized lipids and 2) EGFR derivatization ma y be associated with activation. The reported data suggest that EGFR a cts as a sensor for oxidized lipids. We therefore propose a novel conc ept of the mechanism by which oxidized lipids (contained in oxLDL or m ore generally produced during oxidative stress) are able to activate r eceptor tyrosine kinase and subsequent signaling pathways, resulting f inally in a gain of function.