Arf GTPases in cell migration, invasion, and directional sensing and persistency

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We aim to elucidate mechanisms controlling cell migration and the polarity formation, via investigating their relationship to intracellular vesicle trafficking. Our other main research interest is to understand the principal mechanisms involved in maintenance of epithelial tissue integrity, as well as cancer cell invasion and metastasis which occurs as a result of the disruption of the epithelial integrity. Although biology is a diverse subject, we are constantly aiming towards understanding whether a common fundamental mechanism actually exists behind the complicated phenomena of living organisms, and if so, to elucidate this mechanism. Elucidating these fundamental mechanisms will be extremely powerful for understanding the essence of the malignant transformation of these diverse cancers, and for developing cancer therapeutics. We have previously shown that Arf6-AMAP1 signaling pathway is specifically upregulated in highly invasive breast cancer cells, and is used for their invasion and metastasis. During last two fiscal years, we have shown that GEP100 is responsible for activation of Arf6 in tumor invasion. We have also elucidated a fine mechanism as to how GEP100 is activated in tumor invasion. With regard to the regulation of Arf6 activity in cell migration and tumor invasion, we have identified a novel mechanism by which Fbx8, a ubiquitin E3 ligase, mediates ubiquitination of Arf6 and makes this small GTPase refractory to function without leading it to the immediate proteosomal degradation. Arf 1 is an isoform of Arf6. Our another analysis on Git2, which is a GTPase-activating protein (GAP) for Arf1, have revealed that this GAP as well s Arf1 play pivotal roles in directional sensing and persistency in chemokine-activated immune cells. We are investigating whether a similar mechanism functions in migration and invasion of epithelial cells and the transformed cells.