Morishige Masaki, Hashimoto Shigeru, Ogawa Eiji, Toda Yoshinobu, Kotani Hirokazu, Hirose Mayumi, Wei Shumei, Hashimoto Ari, Yamada Atsuko, Yano Hajime, Mazaki Yuichi, Kodama Hiroshi, Nio Yoshinori, Manabe Toshiaki, Wada Hiromi, Kobayashi Hidenori, Sabe Hisataka
Department of Molecular Biology, Osaka Bioscience Institute, Osaka 565-0874, Japan.
Nat Cell Biol. 2008 Jan;10(1):85-92. doi: 10.1038/ncb1672. Epub 2007 Dec 16.
Epidermal growth factor (EGF) receptor (EGFR) signalling is implicated in tumour invasion and metastasis. However, whether there are EGFR signalling pathways specifically used for tumour invasion still remains elusive. Overexpression of Arf6 and its effector, AMAP1, correlates with and is crucial for the invasive phenotypes of different breast cancer cells. Here we identify the mechanism by which Arf6 is activated to induce tumour invasion. We found that GEP100/BRAG2, a guanine nucleotide exchanging factor (GEF) for Arf6, is responsible for the invasive activity of MDA-MB-231 breast cancer cells, whereas the other ArfGEFs are not. GEP100, through its pleckstrin homology domain, bound directly to Tyr1068/1086-phosphorylated EGFR to activate Arf6. Overexpression of GEP100, together with Arf6, caused non-invasive MCF7 cells to become invasive, which was dependent on EGF stimulation. Moreover, GEP100 knockdown blocked tumour metastasis. GEP100 was expressed in 70% of primary breast ductal carcinomas, and was preferentially co-expressed with EGFR in the malignant cases. Our results indicate that GEP100 links EGFR signalling to Arf6 activation to induce invasive activities of some breast cancer cells, and hence may contribute to their metastasis and malignancy.
表皮生长因子（EGF）受体（EGFR）信号传导与肿瘤侵袭和转移有关。然而，是否存在专门用于肿瘤侵袭的EGFR信号通路仍不清楚。Arf6及其效应器AMAP1的过表达与不同乳腺癌细胞的侵袭表型相关且至关重要。在此，我们确定了Arf6被激活以诱导肿瘤侵袭的机制。我们发现，Arf6的鸟嘌呤核苷酸交换因子（GEF）GEP100/BRAG2负责MDA-MB-231乳腺癌细胞的侵袭活性，而其他ArfGEF则不然。GEP100通过其普列克底物蛋白同源结构域直接结合酪氨酸1068/1086磷酸化的EGFR以激活Arf6。GEP100与Arf6一起过表达会使非侵袭性MCF7细胞变得具有侵袭性，这依赖于EGF刺激。此外，GEP100基因敲低可阻断肿瘤转移。GEP100在70%的原发性乳腺导管癌中表达，并且在恶性病例中优先与EGFR共表达。我们的结果表明，GEP100将EGFR信号传导与Arf6激活联系起来，以诱导某些乳腺癌细胞的侵袭活性，因此可能促成它们的转移和恶性程度。
