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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 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.
