Oncogenic Synergism between ErbB1, Nucleolin, and Mutant Ras
Oncogenic Synergism between ErbB1, Nucleolin, and Mutant Ras
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DOI：
10.1158/0008-5472.can-10-2887
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发表时间：
2011-03-15
期刊：
影响因子：
11.2
通讯作者：
Pinkas-Kramarski, Ronit
中科院分区：
文献类型：
--
作者：
Farin, Keren;Schokoroy, Sari;Pinkas-Kramarski, Ronit
生长因子受体ErbB家族的改变及其信号成分和Ras蛋白的突变激活是恶性转化的主要原因。最近，突变体Ras被证明能够以不依赖配体的方式激活ErbB受体。此外，研究还发现转录调节因子和核糖体生物发生因子核蛋白可以结合K-Ras和ErbB受体的胞质尾部，从而增强ErbB受体的激活。然而，这些相互作用对癌症发病机制的功能意义尚未探讨。在这里，我们发现内源性核蛋白在体内与癌细胞中的内源性Ras和ErbB1 （EGFR）同时相互作用。核仁蛋白c端212个氨基酸被确定足以与ErbB1和所有Ras蛋白亚型（H-， N-和K-Ras）相互作用。核蛋白部分与Ras在质膜上共定位。此外，激活而非野生型Ras促进核蛋白与ErbB1的相互作用，并稳定ErbB1受体水平。最重要的是，这三种癌基因协同促进体外非锚定细胞生长和体内肿瘤生长。我们的研究结果建议将核蛋白作为抑制ErbB和ras驱动的癌症的一般方法。癌症Res;71 (6);2140 - 51。(c) 2011年aacr。
Alterations in the ErbB family of growth factor receptors, their signaling components, and mutational activation of Ras proteins are major contributors to malignant transformation. Recently, mutant Ras was shown to be capable of activating ErbB receptors in a ligand-independent manner. Furthermore, it was observed that nucleolin, a transcriptional regulator and ribosome biogenesis factor, can bind both K-Ras and the cytoplasmic tail of ErbB receptors to enhance ErbB receptor activation. However, the functional significance of these interactions to cancer pathogenesis has not been probed. Here, we show that endogenous nucleolin interacts simultaneously in vivo with endogenous Ras and ErbB1 (EGFR) in cancer cells. The C-terminal 212 amino acids of nucleolin were determined to be sufficient to interact with ErbB1 and all Ras protein isoforms (H-, N-, and K-Ras). Nucleolin partially colocalizes with Ras at the plasma membrane. Moreover, activated but not wild-type Ras facilitates nucleolin interaction with ErbB1 and stabilizes ErbB1 receptor levels. Most importantly, these three oncogenes synergistically facilitate anchorage-independent cell growth in vitro and tumor growth in vivo. Our findings suggest strategies to target nucleolin as a general approach to inhibiting ErbB- and Ras-driven cancers. Cancer Res; 71(6); 2140-51. (C) 2011 AACR.