Volume 272, Number 31, Issue of August 1, 1997 pp. 19269-19276
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

The Linoleic Acid Metabolite, (13S)-Hydroperoxyoctadecadienoic Acid, Augments the Epidermal Growth Factor Receptor Signaling Pathway by Attenuation of Receptor Dephosphorylation
DIFFERENTIAL RESPONSE IN SYRIAN HAMSTER EMBRYO TUMOR SUPPRESSOR PHENOTYPES

(Received for publication, January 23, 1997, and in revised form, April 15, 1997)

Wayne C. Glasgow , Rutai Hui , Angela L. Everhart , Shiranthi P. Jayawickreme , Julie Angerman-Stewart , Bing-Bing Han and Thomas E. Eling

From the Eicosanoid Biochemistry Section, Laboratory of Molecular Carcinogenesis, NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709 and  Division of Basic Medical Sciences, Mercer University School of Medicine, Macon, Georgia 31207

In Syrian hamster embryo (SHE) fibroblasts, epidermal growth factor receptor (EGFR) tyrosine kinase activity regulates the metabolism of endogenous linoleic acid to (13S)-hydroperoxyoctadecadienoic acid (13S)-HPODE). (13S)-HPODE stimulates EGF-dependent mitogenesis in a SHE cell phenotype, which expresses tumor suppressor genes (supB⁺), but was not effective in a variant that does not express these suppressor genes (supB). In the present study, we have investigated the potential effects of this lipid metabolite on the EGFR signaling pathways in these two SHE cell lines. Treatment of quiescent SHE cells with EGF produced a rapid, transient increase in the tyrosine phosphorylation of EGFR. Dependence on EGF concentration for EGFR tyrosine phosphorylation was similar in both SHE cell lines, but a more prolonged phosphorylation was detected in the supB variant. Incubation of supB⁺ cells with (13S)-HPODE and EGF increased EGFR autophosphorylation and tyrosine phosphorylation on several signaling proteins with Src homology-2 domains including GTPase-activating protein. The lipid metabolite did not significantly alter EGF-dependent tyrosine phosphorylation in the supB variant. Tyrosine phosphorylation of mitogen-activated protein (MAP) kinase was also measured. The addition of (13S)-HPODE increased the extent and duration of MAP kinase tyrosine phosphorylation in supB⁺ cells but not in the supB variant. MAP kinase activity in supB⁺ cells, as measured in immunoprecipitates from cells after the addition of EGF, was increased by the presence of (13S)-HPODE. The addition of (13S)-HPODE did not directly alter EGFR kinase activity or the internalization of the EGFR. However, the addition of (13S)-HPODE to supB⁺ cells extended the tyrosine phosphorylation of the EGFR in response to EGF. The dephosphorylation of the EGFR was measured directly, and a slower rate was observed in the supB compared with the supB⁺ cells. Incubation of the supB⁺ cells with (13S)-HPODE attenuated the dephosphorylation of the EGFR. Thus, (13S)-HPODE stimulates EGF-dependent mitogenesis and up-regulation of EGF-dependent tyrosine phosphorylation by inhibiting the dephosphorylation of the EGFR. This study shows that a metabolite of an essential dietary fatty acid, linoleic acid, can modulate tyrosine phosphorylation and activity of key signal transduction proteins in a growth factor mitogenic pathway.

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