DHA alters EGFR spatiotemporal dynamics to suppress signal transduction
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abstract
The epidermal growth factor receptor (EGFR), which regulates cell growth and survival, is integral in colon tumorigenesis. Lipid rafts play a role in controlling EGFR signaling, and docosahexaenoic acid (DHA) is known to perturb lipid rafts. Here, we investigated the mechanistic link between EGFR function and DHA. DHA treatment of immortalized colonocytes and C57BL6 mouse colonic mucosa increased EGFR phosphorylation but paradoxically suppressed downstream activation of STAT3 and ERK1/2. DHA also suppressed cell proliferation in an EGFRdependent manner. The EGFRRasERK1/2 signaling cascade was assessed to identify the locus of the DHAinduced disruption of signal transduction. Recruitment of Grb2 to EGFR, assessed using total internal reflective fluorescence (TIRF) microscopy, was increased by DHA treatment, whereas Ras GTP binding, a lipid raftdependent process, was suppressed by DHA treatment. Colocalization and membrane subfractionation experiments demonstrated that DHA reduced the localization of EGFR to lipid rafts. DHA further antagonized EGFR signaling capacity by increasing the rates of EGFR internalization and degradation. From these results, we conclude that DHAinduced dissociation of EGFR from lipid rafts culminates in the suppression of EGFR downstream signal transduction, which has implications for the molecular basis of colon cancer prevention by DHA.Grant Funding Source: NIH CA59034
