生物谷综合：在12月出版的《自然—细胞生物学》期刊上，一篇论文解释了表皮生长因子(EGF)调控乳腺癌细胞侵入的机制。新发现有助于开发出更有针对性的抗癌药物。
侵入性乳腺癌细胞具有高繁殖力，它们不正常地表达出过高水平的表皮生长因子受体(EGFR )，这种受体负责细胞分化和迁移。为了弄清癌细胞入侵过程中受EGFR激活的分子通道，Hisataka Sabe进行了研究，他发现，蛋白质GEP100是被激活的EGFR与Arf6之间的桥梁，Arf6是在乳腺癌细胞中被过度表达的一种蛋白质，它促进了癌细胞的侵入。
研究人员在癌细胞中发现了过高水平的GEP100，在这种情况下，Arf6被激活，导致非侵入性细胞在EGFR 的刺激下变成侵入性细胞。相反地，当GEP100被抑止时，被注入高水平侵入性乳腺癌细胞的小鼠体内癌细胞转移也被抑止了。取自入侵性乳腺癌患者的临床样品中有高水平的GEP100，GEP100和EGFR的同时出现与肿瘤恶性化有关。
原始出处：
Nature Cell Biology
Published online: 16 December 2007; | doi:10.1038/ncb1672
GEP100 links epidermal growth factor receptor signalling to Arf6 activation to induce breast cancer invasion
Masaki Morishige1, 2, 9, Shigeru Hashimoto1, 9, Eiji Ogawa3, 4, Yoshinobu Toda5, Hirokazu Kotani4, 5, Mayumi Hirose6, Shumei Wei1, Ari Hashimoto1, Atsuko Yamada1, Hajime Yano1, Yuichi Mazaki1, Hiroshi Kodama7, Yoshinori Nio7, Toshiaki Manabe4, Hiromi Wada3, Hidenori Kobayashi2 & Hisataka Sabe1, 8
1 Department of Molecular Biology, Osaka Bioscience Institute, Osaka 565-0874, Japan.
2 Department of Neurosurgery, School of Medicine, Oita University, Oita 879-5593, Japan.
3 Department of Thoracic Surgery, Faculty of Medicine, Kyoto University, Kyoto 606-8507, Japan.
4 Laboratory of Diagnostic Pathology, Kyoto University Hospital, Kyoto 606-8501, Japan.
5 Center for Anatomical Studies, Kyoto University Graduate School of Medicine, Kyoto 606-8507, Japan.
6 Laboratory of Supramolecular Crystallography, Institute for Protein Research, Osaka University, Osaka 565-0871, Japan.
7 Kodama Breast Clinic, Kyoto 603-8325, Japan.
8 Graduate School of Biosciences, Kyoto University, Kyoto 606-8607, Japan.
9 These authors contributed equally to this work.
Correspondence should be addressed to Hisataka Sabe sabe@obi.or.jp
Epidermal growth factor (EGF) receptor (EGFR) signalling is implicated in tumour invasion and metastasis1, 2. 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 cells3, 4, 5, 6. 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 cells7 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.
