Department of Thoracic Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
PLoS One. 2011;6(9):e25301. doi: 10.1371/journal.pone.0025301. Epub 2011 Sep 22.
Overexpression of Her2/ErbB2/Neu in cancer is often correlated with recurrent distant metastasis, although the mechanism still remains largely elusive. We have previously shown that EGFR, when tyrosine-phosphorylated, binds to GEP100/BRAG2 to activate Arf6, which induces cancer invasion and metastasis. We now show that overexpressed Her2 in lung adenocarcinoma cells also employs GEP100. Like EGFR-GEP100 binding, this association is primarily mediated by the pleckstrin homology (PH) domain of GEP100 and Tyr1139/Tyr1196 of Her2. Tyr1139/Tyr1196 are autonomously phosphorylated, when Her2 is overexpressed. Accordingly, invasive activities mediated by the Her2-GEP100 pathway are not dependent on external factors. Blocking Her2-GEP100 binding, as well as its signaling pathway all inhibit cancer invasive activities. Moreover, our clinical study indicates that co-overexpression of Her2 with GEP100 in primary lung adenocarcinomas of patients is correlated with the presence of their node-metastasis with a statistical significance. Since the GEP100 PH domain interacts with both Her2 and EGFR, targeting this domain may provide novel cancer therapeutics.
在癌症中，Her2/ErbB2/Neu 的过度表达通常与复发性远处转移相关，尽管其机制在很大程度上仍难以捉摸。我们之前已经表明，当 EGFR 酪氨酸磷酸化时，它与 GEP100/BRAG2 结合以激活 Arf6，从而诱导癌症侵袭和转移。我们现在表明，肺腺癌细胞中过表达的 Her2 也利用 GEP100。与 EGFR-GEP100 结合一样，这种关联主要是由 GEP100 的 pleckstrin 同源（PH）结构域和 Her2 的 Tyr1139/Tyr1196 介导的。当 Her2 过表达时，Tyr1139/Tyr1196 会自动磷酸化。因此，Her2-GEP100 途径介导的侵袭活性不依赖于外部因素。阻断 Her2-GEP100 结合及其信号通路均可抑制癌症侵袭活性。此外，我们的临床研究表明，患者原发性肺腺癌中 Her2 与 GEP100 的共过表达与淋巴结转移的存在相关，具有统计学意义。由于 GEP100 PH 结构域与 Her2 和 EGFR 相互作用，针对该结构域可能为癌症治疗提供新的方法。
