Abstract
The epidermal growth factor receptor (EGFR), which regulates cell growth and survival, is integral to colon tumorigenesis. Lipid rafts play a role in regulating EGFR signaling, and docosahexaenoic acid (DHA) is known to perturb membrane domain organization through changes in lipid rafts. Therefore, we investigated the mechanistic link between EGFR function and DHA. Membrane incorporation of DHA into immortalized colonocytes altered the lateral organization of EGFR. DHA additionally increased EGFR phosphorylation but paradoxically suppressed downstream signaling. Assessment of the EGFR-Ras-ERK1/2 signaling cascade identified Ras GTP binding as the locus of the DHA-induced disruption of signal transduction. DHA also antagonized EGFR signaling capacity by increasing receptor internalization and degradation. DHA suppressed cell proliferation in an EGFR-dependent manner, but cell proliferation could be partially rescued by expression of constitutively active Ras. Feeding chronically-inflamed, carcinogen-injected C57BL/6 mice a fish oil containing diet enriched in DHA recapitulated the effects on the EGFR signaling axis observed in cell culture and additionally suppressed tumor formation. We conclude that DHA-induced alteration in both the lateral and subcellular localization of EGFR culminates in the suppression of EGFR downstream signal transduction, which has implications for the molecular basis of colon cancer prevention by DHA.
Highlights
The epidermal growth factor receptor (EGFR;ErbB1) is a transmembrane receptor tyrosine kinase, which contains an extracellular binding domain, a single transmembrane spanning domain, and a cytoplasmic tyrosine kinase domain [1,2]
For the final 16–18 h of fatty acid treatment, cells were incubated in low serum media (0.5% fetal bovine serum (FBS)) prior to harvesting because EGFR has been shown to be localized to lipid rafts prior to activation
The lowest density fraction from each treatment was enriched with caveolin and GM-1, which served as lipid raft markers, and depleted of clathrin, which is excluded from lipid rafts, indicating that this fraction is enriched with lipid rafts
Summary
The epidermal growth factor receptor (EGFR;ErbB1) is a transmembrane receptor tyrosine kinase, which contains an extracellular binding domain, a single transmembrane spanning domain, and a cytoplasmic tyrosine kinase domain [1,2]. The phosphorylated tyrosine residues function as docking sites for adaptor proteins, which serve to activate intracellular signaling cascades. These cascades result in alterations of gene expression, which determines the biological response to receptor activation. Key to the ability of EGFR to activate downstream pathways is its localization in lipid raft domains of the plasma membrane [3,4,5,6,7]. Disruption of lipid rafts results in the relocalization of EGFR to bulk membrane regions, which alters EGFR activation and signaling [5,6,9,11,12,13]. It is likely that these specialized membrane domains provide a mechanism for spatial and temporal control of EGFR signaling
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
