Alteration of EGFR spatiotemporal dynamics suppresses signal transduction.
Alteration of EGFR spatiotemporal dynamics suppresses signal transduction.
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DOI：
10.1371/journal.pone.0039682
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Chapkin RS
中科院分区：
文献类型：
--
作者：
Turk HF;Barhoumi R;Chapkin RS
表皮生长因子受体（EGFR）调节细胞生长和存活，是结肠肿瘤发生的组成部分。脂筏在调节EGFR信号传导中起作用，并且已知二十二碳六烯酸（DHA）通过脂筏的变化扰乱膜结构域组织。因此，我们研究了EGFR功能和DHA之间的机制联系。DHA进入永生化的结肠细胞的膜结合改变了EGFR的侧向组织。DHA还增加EGFR磷酸化，但矛盾地抑制下游信号传导。EGFR-Ras-ERK 1/2信号级联的评估确定Ras GTP结合为DHA诱导的信号转导中断的位点。DHA还通过增加受体内化和降解来拮抗EGFR信号传导能力。DHA以EGFR依赖的方式抑制细胞增殖，但细胞增殖可通过表达组成型活性Ras而部分挽救。给慢性炎症、注射致癌物的C57 BL/6小鼠喂食富含DHA的鱼油饮食，重现了在细胞培养中观察到的对EGFR信号传导轴的影响，并抑制了肿瘤形成。我们的结论是DHA诱导的EGFR的侧向和亚细胞定位的改变最终抑制EGFR下游信号转导，这对DHA预防结肠癌的分子基础有影响。
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.
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影响因子：
29.4
作者：
BARTRAM, HP;GOSTNER, A;KASPER, H
通讯作者：
KASPER, H
影响因子：
5.3
作者：
Apolloni, A;Prior, IA;Hancock, JF
通讯作者：
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3.7
作者：
Galizia, Gennaro;Lieto, Eva;Ciardiello, Fortunato
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影响因子：
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作者：
Augsten, M;Pusch, R;Rubio, I
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Rubio, I
影响因子：
4.2
作者：
Chang, WCL;Chapkin, RS;Lupton, JR
通讯作者：
Lupton, JR