A mutant of SWAP-70, a phosphatidylinositoltrisphosphate binding protein, transforms mouse embryo fibroblasts, which is inhibited by sanguinarine.
A mutant of SWAP-70, a phosphatidylinositoltrisphosphate binding protein, transforms mouse embryo fibroblasts, which is inhibited by sanguinarine.
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DOI：
10.1371/journal.pone.0014180
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发表时间：
2010-12-02
期刊：
影响因子：
3.7
通讯作者：
Ihara S
中科院分区：
文献类型：
--
作者：
Fukui Y;Ihara S
SWAP-70是一种三磷酸磷脂酰肌醇（PtdIns（3，4，5）P3）结合蛋白，它与小鼠胚胎成纤维细胞（MEFs）的转化以及生长因子刺激后细胞膜的皱褶有关。一个突变体，SWAP-70-374，被发现能够结合到F-肌动蛋白在体外，而野生型SWAP-70未能做到这一点。该突变体存在于质膜上而没有任何刺激，而野生型蛋白质仅存在于胞质溶胶中，除非细胞用EGF刺激。该突变体在MEFs中的表达导致形态转化、快速生长和接触抑制的丧失，表明具有该突变的SWAP-70可以转化细胞。ERK 1/2在SWAP-70-374转化的细胞中被激活。MEK抑制剂的使用表明，ERK 1/2途径不影响MEFs的细胞生长，但负责失去接触抑制。为了进一步研究SWAP-70的功能，筛选了可以抑制SWAP-70依赖性细胞应答的药物。在各种药物中，发现血根碱抑制SWAP-70-374对MEFs的转化。该药物也能够抑制SWAP-70介导的膜皱褶，表明其作用与SWAP-70信号通路密切相关。这些结果表明，SWAP-70-374可以激活一些信号通路，包括ERK 1/2通路，以转化MEFs。
SWAP-70, a phosphatidylinositol trisphosphate (PtdIns(3,4,5)P3) binding protein, has been suggested to be involved in transformation of mouse embryo fibroblasts (MEFs) as well as membrane ruffling after growth factor stimulation of the cells. A mutant, SWAP-70-374, was found to be able to bind to F-actin in vitro, whereas wild-type SWAP-70 failed to do so. This mutant was present at the plasma membrane without any stimulation while the wild-type protein was present only in the cytosol unless cells were stimulated with EGF. Expression of this mutant in MEFs resulted in morphologic transformation, fast growth, and loss of contact inhibition, suggesting that SWAP-70 with this mutation can transform the cells. ERK1/2 was activated in SWAP-70-374-transformed cells. Use of MEK inhibitors revealed that the ERK1/2 pathway does not affect the cell growth of MEFs but is responsible for loss of contact inhibition. To investigate the function of SWAP-70 further, drugs that can inhibit SWAP-70-dependent cell responses were screened. Among various drugs, sanguinarine was found to inhibit transformation of MEFs by SWAP-70-374. This drug was able to inhibit SWAP-70-mediated membrane ruffling as well, suggesting that its effect was closely related to the SWAP-70 signaling pathway. These results suggest that SWAP-70-374 can activate some signaling pathways, including the ERK1/2 pathway, to transform MEFs.
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