Invasion Signal

Abstract

Epidermal growth factor receptor (EGFR), a receptor tyrosine kinase, is implicated in many cancers; however, it is unclear specifically which EGFR pathways are involved in triggering tumor cell invasiveness. The abundance of the small guanosine triphosphatase Arf6, which regulates processes such as membrane trafficking and endocytosis, correlates with the invasiveness of malignant breast cancer cells. In this context, Morishige et al . used small interfering RNA (siRNA) to individually decrease the expression of the 10 genes that encode guanine nucleotide exchange factors (GEFs) that activate Arf family proteins in the invasive human breast cancer cell line MDA-MB-231. GEP100 was the only ArfGEF whose depletion resulted in the inhibition of MDA-MB-231 invasion activity, as measured by an in-gel invasiveness assay. Coimmunoprecipitation studies showed that EGF treatment of MDA-MB-231 cells triggered the association of GEP100 with EGFR. In transfected Cos-7 cells, the authors showed the EGF-dependent association of EGFR, GEP100, and Arf6. Further studies showed the usual involvement of the pleckstrin homology (PH) domain in the binding of GEP100 to phosphorylated Tyr 1068 and Tyr 1086 residues on EGF-activated EGFR. Immunohistochemical analyses of ductal carcinoma specimens revealed a correlation between the coexpression of EGFR and GEP100 and tumor severity. Transfection of noninvasive MCF7 cells with both GEP100 and Arf6 was sufficient to induce their invasiveness in response to EGF. Finally, lung metastasis in mice injected with mammary tumor cells that contained GEP100-specific siRNA was reduced compared with that in mice injected with control siRNA-transfected cells. As Valderrama and Ridley discuss in commentary, the specificity of the GEP100-Arf6 interaction in mediating tumor cell invasion may make it an attractive therapeutic target, especially in patients resistant to EGFR inhibitors. M. Morishige, S. Hashimoto, E. Ogawa, Y. Toda, H. Kotani, M. Hirose, S. Wei, A. Hashimoto, A. Yamada, H. Yano, Y. Mazaki, H. Kodama, Y. Nio, T. Manabe, H. Wada, H. Kobayashi, H. Sabe, GEP100 links epidermal growth factor receptor signalling to Arf6 activation to induce breast cancer invasion. Nat. Cell Biol. 10 , 85-92 (2008). [PubMed] F. Valderrama, A. J. Ridley, Getting invasive with GEP100 and Arf6. Nat. Cell Biol . 10 , 16-18 (2008). [PubMed]