Receptor tyrosine kinase EGFR usually is localized on plasma membrane to induce progression of many cancers including cancers in children (Bodey et al. In Vivo. 2005, 19:931-41), but it contains a nuclear localization signal (NLS) that mediates EGFR nuclear translocation (Lin et al. Nat Cell Biol. 2001, 3:802-8). Here we report that NLS of EGFR has its old evolutionary origin. Protein-protein interaction maps suggests that nEGFR pathways are different from membrane EGFR and EGF is not found in nEGFR network while androgen receptor (AR) is found, which suggests the evolution of prostate cancer, a well-known AR driven cancer, through changes in androgen- or EGF-dependence. Database analysis suggests that nEGFR correlates with the tumor grades especially in prostate cancer patients. Structural predication analysis suggests that NLS can compromise the differential protein binding to EGFR through stretch linkers with evolutionary mutation from N to V. In experiment, elevation of nEGFR but not membrane EGFR was found in castration resistant prostate cancer cells. Finally, systems analysis of NLS and transmembrane domain (TM) suggests that NLS has old origin while NLS neighboring domain of TM has been undergone accelerated evolution. Thus nEGFR has an old origin resembling the cancer evolution but TM may interfere with NLS driven signaling for natural selection of survival to evade NLS induced aggressive cancers. Our data suggest NLS is a dynamic inducer of EGFR oncogenesis during evolution for advanced cancers. Our model provides novel insights into the evolutionary role of NLS of oncogenic kinases in cancers.

中文翻译：

---

对起源和蛋白质-蛋白质相互作用图谱的分析表明核 EGFR 在癌症进化过程中具有独特的致癌作用。


受体酪氨酸激酶 EGFR 通常定位于质膜上，以诱导包括儿童癌症在内的许多癌症的进展（Bodey 等人，In Vivo. 2005, 19:931-41），但它包含介导 EGFR 的核定位信号 (NLS)核易位（Lin 等人，Nat Cell Biol. 2001, 3:802-8）。在这里我们报道EGFR的NLS有其古老的进化起源。蛋白质-蛋白质相互作用图表明，nEGFR 通路与膜 EGFR 不同，并且在 nEGFR 网络中未发现 EGF，而发现了雄激素受体 (AR)，这表明前列腺癌（一种众所周知的 AR 驱动癌症）的进化是通过雄激素或 EGF 依赖性。数据库分析表明 nEGFR 与肿瘤分级相关，尤其是在前列腺癌患者中。结构预测分析表明，NLS 可以通过具有从 N 到 V 的进化突变的拉伸连接子损害差异蛋白与 EGFR 的结合。在实验中，在去势抵抗性前列腺癌细胞中发现 nEGFR 升高，但膜 EGFR 没有升高。最后，对NLS和跨膜结构域（TM）的系统分析表明，NLS具有古老的起源，而TM的NLS邻近结构域经历了加速进化。因此，nEGFR 具有类似于癌症进化的古老起源，但 TM 可能会干扰 NLS 驱动的信号传导，以逃避 NLS 诱导的侵袭性癌症的自然选择。我们的数据表明，NLS 是晚期癌症进化过程中 EGFR 肿瘤发生的动态诱导剂。我们的模型为致癌激酶 NLS 在癌症中的进化作用提供了新的见解。