Src kinase activation is mandatory for MDA-9/syntenin-mediated activation of nuclear factor-kappaB.
Src kinase activation is mandatory for MDA-9/syntenin-mediated activation of nuclear factor-kappaB.
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DOI：
10.1038/onc.2010.65
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发表时间：
2010-05-27
期刊：
影响因子：
8
通讯作者：
Fisher, P. B.
中科院分区：
文献类型：
--
作者：
Boukerche, H.;Aissaoui, H.;Prevost, C.;Hirbec, H.;Das, S. K.;Su, Z-Z;Sarkar, D.;Fisher, P. B.
含有MDA-9/syntenin蛋白的脚手架PDZ结构域是在人黑色素瘤、乳腺癌和胃癌细胞中过表达的串联PDZ蛋白。MDA-9/syntenin通过不同的生化和信号通路影响癌细胞的运动和侵袭，包括局灶黏着激酶（FAK）和p38丝裂原活化蛋白激酶（MAPK），从而激活NFκ B通路。MDA9/syntenin也通过激活c-Src促进黑色素瘤转移，但c-Src如何调节NFκ B激活尚不清楚。使用人类黑色素瘤模型，我们证明MDA-9/syntenin/c-Src相互作用是NFκ B激活的积极调节因子。PP2处理，通过siRNA阻断c-Src或mda-9/syntenin的表达，或在c-Src（- / -）敲除细胞系中抑制c-Src，可降低mda-9/syntenin或c-Src过表达后的NFκ B激活。PDZ结合基序的缺失或点突变阻止了MDA-9/syntenin与c-Src的关联，这表明两个PDZ结构域（以PDZ2为主导模块）都是激活下游信号通路（包括p38 MAPK和NFκ B）所必需的。我们还发现，MDA-9/syntenin/c-Src复合物与NFκ B协同作用，促进锚定非依赖性生长、运动和侵袭黑色素瘤细胞。这些发现强调了MDA-9/syntenin的PDZ结构域作为干预癌症进展决定性成分（即转移性肿瘤扩散）的有希望的潜在治疗靶点。
The scaffolding PDZ-domain containing protein MDA-9/syntenin is a tandem PDZ protein overexpressed in human melanoma, and breast and gastric cancer cells. MDA-9/syntenin affects cancer cell motility and invasion through distinct biochemical and signaling pathways, including focal adhesion kinase (FAK) and p38 mitogen-activated protein kinase (MAPK), resulting in activation of the NFκ B pathway. MDA9/syntenin also promotes melanoma metastasis by activating c-Src, but how c-Src regulates NFκ B activation is unclear. Using a human melanoma model, we document that MDA-9/syntenin/c-Src interactions are positive regulators of NFκ B activation. Inhibition of c-Src by PP2 treatment, by blocking c-Src or mda-9/syntenin expression with siRNA, or in c-Src (−/−) knockout cell lines, reduces NFκ B activation following overexpression of mda-9/syntenin or c-Src. Deletion or point mutations of the PDZ binding motif preventing MDA-9/syntenin association with c-Src reveals that both PDZ domains, with PDZ2 being the dominant module, are required for activating downstream signaling pathways, including p38 MAPK and NFκ B. We also document that MDA-9/syntenin/c-Src complexes functionally cooperate with NFκ B to promote anchorage-independent growth, motility and invasion of melanoma cells. These findings underscore PDZ domains of MDA-9/syntenin as promising potential therapeutic targets for intervening in a decisive component of cancer progression, namely metastatic tumor spread.
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影响因子：
4.8
作者：
Liu, AMF;Wong, YH
通讯作者：
Wong, YH
DOI：
10.1073/pnas.0808171105
发表时间：
2008-10-14
影响因子：
11.1
作者：
Boukerche, Habib;Su, Zao-zhong;Fisher, Paul B.
通讯作者：
Fisher, Paul B.
影响因子：
3.5
作者：
Boukerche, H;Su, ZZ;Fisher, PB
通讯作者：
Fisher, PB
影响因子：
4.8
作者：
Koroll, M;Rathjen, FG;Volkmer, H
通讯作者：
Volkmer, H
影响因子：
15.9
作者：
Aikawa, R;Komuro, I;Yazaki, Y
通讯作者：
Yazaki, Y