GEP100 links epidermal growth factor receptor signalling to Arf6 activation to induce breast cancer invasion.
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.
Morishige
Masaki
M
Department of Molecular Biology, Osaka Bioscience Institute, Osaka 565-0874, Japan.
Hashimoto
Shigeru
S
Ogawa
Eiji
E
Toda
Yoshinobu
Y
Kotani
Hirokazu
H
Hirose
Mayumi
M
Wei
Shumei
S
Hashimoto
Ari
A
Yamada
Atsuko
A
Yano
Hajime
H
Mazaki
Yuichi
Y
Kodama
Hiroshi
H
Nio
Yoshinori
Y
Manabe
Toshiaki
T
Wada
Hiromi
H
Kobayashi
Hidenori
H
Sabe
Hisataka
H
D000089982:ADP-Ribosylation Factor 6; D020727:ADP-Ribosylation Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D020868:Gene Silencing; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009361:Neoplasm Invasiveness; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction
D000089982:ADP-Ribosylation Factor 6; D020662:Guanine Nucleotide Exchange Factors; C504483:IQSEC1 protein, human; D034741:RNA, Small Interfering; D066246:ErbB Receptors; D020727:ADP-Ribosylation Factors; C000715348:ARF6 protein, human; C000715727:Arf6 protein, mouse