Recruitment of Tiam1 to Semaphorin 4D Activates Rac and Enhances Proliferation, Invasion, and Metastasis in Oral Squamous Cell Carcinoma.
Recruitment of Tiam1 to Semaphorin 4D Activates Rac and Enhances Proliferation, Invasion, and Metastasis in Oral Squamous Cell Carcinoma.
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DOI：
10.1016/j.neo.2016.12.004
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发表时间：
2017-02
期刊：
影响因子：
4.8
通讯作者：
Basile, John R.
中科院分区：
文献类型：
--
作者：
Zhou, Hua;Kann, Maricel G.;Mallory, Emily K.;Yang, Ying-Hua;Bugshan, Amr;Binmadi, Nada O.;Basile, John R.
脑信号蛋白和丛蛋白是一个大的富含半胱氨酸的蛋白质家族，最初被鉴定为轴突生长和淋巴细胞活化的调节剂，现在已知其为许多细胞和组织类型提供运动性和位置信息。例如，我们的小组和其他人已经表明，一些恶性肿瘤过度表达Semaphorin 4D（S4 D），它通过其受体丛蛋白-B1（PB 1）作用于内皮细胞，吸引周围基质中的血管，以支持肿瘤生长。虽然丛蛋白是已知的脑信号蛋白的功能受体，但有证据表明跨膜脑信号蛋白可以通过其短的胞质尾传递信号，这种现象称为“反向信号传导”。我们使用基于相互作用蛋白质序列的相关进化、突变分析以及肿瘤侵袭性的体外和体内测量的计算方法来显示，当与PB 1结合时，跨膜S4 D与Rac GT3交换因子T淋巴瘤侵袭和转移（Tiam）1相关联，其激活Rac并促进口腔鳞状细胞癌（OSCC）细胞的增殖、侵袭和转移。这些结果表明，肿瘤细胞产生的S4 D不仅可以影响微环境，而且这种信号蛋白在细胞表面的参与激活了影响OSCC中肿瘤侵袭性的反向信号传导机制。
The semaphorins and the plexins are a family of large, cysteine-rich proteins originally identified as regulators of axon growth and lymphocyte activation that are now known to provide motility and positional information for a number of cell and tissue types. For example, our group and others have shown that some malignancies over express Semaphorin 4D (S4D), which acts through its receptor Plexin-B1 (PB1) on endothelial cells to attract blood vessels from the surrounding stroma for the purpose of supporting tumor growth. While plexins are the known functional receptors for the semaphorins, there is evidence that transmembrane semaphorins may transmit a signal themselves through their short cytoplasmic tail, a phenomenon known as ‘reverse signaling.’ We used computational methods based upon correlated evolution of sequences of interacting proteins, mutational analysis and in vitro and in vivo measurements of tumor aggressiveness to show that when bound to PB1, transmembrane S4D associates with the Rac GTPase exchange factor T lymphoma invasion and metastasis (Tiam) 1, which activates Rac and promotes proliferation, invasion and metastasis in oral squamous cell carcinoma (OSCC) cells. These results suggest that not only can S4D production by tumor cells affect the microenvironment, but engagement of this semaphorin at the cell surface activates a reverse signaling mechanism that influences tumor aggressiveness in OSCC.
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