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DHA alters EGFR spatiotemporal dynamics to suppress signal transduction
Author(s) -
Turk Harmony Faith,
Chapkin Robert S.
Publication year - 2012
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.26.1_supplement.366.4
Subject(s) - lipid raft , signal transduction , microbiology and biotechnology , epidermal growth factor receptor , internalization , phosphorylation , colocalization , chemistry , epidermal growth factor , docosahexaenoic acid , cell signaling , erbb , biology , cancer research , biochemistry , receptor , fatty acid , polyunsaturated fatty acid
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 EGFR‐dependent manner. The EGFR‐Ras‐ERK1/2 signaling cascade was assessed to identify the locus of the DHA‐induced 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 raft‐dependent 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 DHA‐induced 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