The linoleic acid metabolite, 13-HpODE augments the phosphorylation of EGF receptor and SHP-2 leading to their increased association.
In previous studies with Syrian hamster embryo fibroblasts, we found that a specific lipoxygenase metabolite of linoleic acid, 13(S)-hydroperoxyoctadecadienoic acid (HpODE), enhanced epidermal growth factor (EGF) signal transduction in a tumor suppressor gene plus phenotype (supB+); with a diminished response to 13(S)-HpODE in a tumor suppressor gene minus phenotype (supB-). This differential response was attributed to differences in the rate of EGF receptor (EGFR) dephosphorylation. To further define the molecular basis for these observations, in this report we examine the interaction of phosphorylated EGFR with the SH2 domain-containing protein tyrosine phosphatase, SHP-2, a positive modulator of EGF dependent cell growth. SHP-2 associated with phosphorylated EGFR to a greater extent in supB+ cells when compared to supB-. This differential association could not be accounted for by differences between suppressor gene phenotypes in SHP-2 protein level or mutations in the molecular sequence. The addition of 13(S)-HpODE stimulated a concentration-dependent increase in EGF-dependent phosphorylation of SHP-2 and its association with EGFR. A more dramatic response was observed in the supB+ cells. Differences in SHP-2 interaction with EGFR may account, in part, for phenotypic differences in the growth rates and responsiveness to EGF between the supB+ and supB- cells. EGFR-SHP-2 association appears to play an important role in the regulation of EGFR signal transduction.
Hui
R
R
Eicosanoid Biochemistry and Cancer and Aging Sections, Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA.
Kameda
H
H
Risinger
J I
JI
Angerman-Stewart
J
J
Han
B
B
Barrett
J C
JC
Eling
T E
TE
Glasgow
W C
WC
D000818:Animals; D000906:Antibodies; D015153:Blotting, Western; D002460:Cell Line; D066246:ErbB Receptors / Q000378:metabolism*; D016147:Genes, Tumor Suppressor / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008041:Linoleic Acids / Q000494:pharmacology*; D008054:Lipid Peroxides / Q000494:pharmacology*; D010641:Phenotype; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000276:immunology; D011485:Protein Binding; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D018909:src Homology Domains
D000906:Antibodies; D047908:Intracellular Signaling Peptides and Proteins; D008041:Linoleic Acids; D008054:Lipid Peroxides; D019000:Phosphotyrosine; C038649:13-hydroperoxy-9,11-octadecadienoic acid; D066246:ErbB Receptors; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases