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(Circulation Research. 1999;85:892.)
© 1999 American Heart Association, Inc.

Molecular Medicine

Activation of Epithelial Growth Factor Receptor Pathway by Unsaturated Fatty Acids

Nathalie Vacaresse¹, Isabelle Lajoie-Mazenc¹, Nathalie Augé, Isabelle Suc, Marie-Françoise Frisach, Robert Salvayre, Anne Nègre-Salvayre

From INSERM U-466 and Department of Biochemistry, IFR-31, CHU Rangueil, Toulouse, France.

Correspondence Dr A. Negre-Salvayre, Biochimie INSERM U-466, CHU Rangueil, avenue Jean Poulhès, 31403 Toulouse cedex 4, France. E-mail salvayre@rangueil.inserm.fr or anesalv{at}rangueil.inserm.fr

Abstract—Nonesterified fatty acids (NEFAs) are acutely liberated during lipolysis and are chronically elevated in pathological conditions, such as insulin resistance, hypertension, and obesity, which are known risk factors for atherosclerosis. The purpose of this study was to investigate the effect and mechanism of action of NEFAs on the epithelial growth factor (EGF) receptor (EGFR). In the ECV-304 endothelial cell line, unsaturated fatty acids triggered a time- and dose-dependent tyrosine phosphorylation of EGFR (polyunsaturated fatty acids [PUFAs] were the most active), whereas saturated FAs were inactive. Although less potent than PUFAs, oleic acid (OA) was used because it is prominent in the South European diet and is only slightly oxidizable (thus excluding oxidation derivatives). EGFR is activated by OA independent of any autocrine secretion of EGF or other related mediators. OA-induced EGFR autophosphorylation triggered EGFR signaling pathway activation (as assessed through coimmunoprecipitation of SH2 proteins such as SHC, GRB2, and SHP-2) and subsequent p42/p44 mitogen-activated protein kinase (as shown by the use of EGFR- deficient B82L and EGFR- transduced B82LK⁺ cell lines). OA induced in vitro both autophosphorylation and activation of intrinsic tyrosine kinase of immunopurified EGFR, thus suggesting that EGFR is a primary target of OA. EGFR was also activated by mild surfactants, Tween-20 and Triton X-100, both in vitro (on immunopurified EGFR) and in intact living cells, thus indicating that EGFR is sensitive to amphiphilic molecules. These data suggest that EGFR is activated by OA and PUFAs, acts as a sensor for unsaturated fatty acids (and amphiphilic molecules), and is a potential transducer by which diet composition may influence vascular wall biology.

Key Words: fatty acid • growth factor • mitogen-activated protein kinase • EGF receptor

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