Submicromolar doses of alkyl-lysophospholipids induce rapid internalization, but not activation, of epidermal growth factor receptor and concomitant MAPK/ERK activation in A431 cells

被引:20
作者
Ruiter, GA
Verheij, M
Zerp, SF
Moolenaar, WH
Van Blitterswijk, WJ
机构
[1] Antoni Van Leeuwenhoek Ziekenhuis, Netherlands Canc Inst, Div Cellular Biochem, Amsterdam, Netherlands
[2] Antoni Van Leeuwenhoek Ziekenhuis, Netherlands Canc Inst, Dept Radiotherapy, Amsterdam, Netherlands
关键词
alkyl-lysophospholipid; epidermal growth factor receptor; internalization; MAPK/ERK;
D O I
10.1002/ijc.10741
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Synthetic ALPs, e.g., Et-18-OCH3 and HePC, are anticancer agents that accumulate in cell membranes, where they interfere with lipid-mediated signal transduction. We previously reported that ALPs, when added at micromolar concentrations (5-25 muM), inhibit growth factor-induced MAPK/ERK activation and enhance radiation-induced apoptosis. We now show that, at nanomolar doses (10-500 nM) ALPs activate the MAPK/ERK pathway in A431 cells without stimulating cell proliferation. Strikingly, ALPs (500 nM) also trigger rapid clustering and internalization of the EGFR in A431 cells. Tyrphostin AG1478, an EGFR tyrosine kinase inhibitor, blocks ALP-induced MAPK/ERK activation but not EGFR internalization. We found no evidence for ALPs acting via G protein-coupled receptors and/or transactivation of EGFRs, as determined by calcium mobilization, EGFR phosphorylation and Grb2 binding assays. Since ALPs readily intercalate into the plasma membrane, our data suggest that they induce subtle changes in the lipid microenvironment of the EGFR, resulting in clustering and internalization of the EGFR and concomitant MAPK/ERK activation. (C) 2002 Wiley-Liss, Inc.
引用
收藏
页码:343 / 350
页数:8
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