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

我们的目的是阐明控制细胞迁移和极性形成的机制，通过研究它们与细胞内囊泡运输的关系。我们的另一个主要研究兴趣是了解上皮组织完整性维持的主要机制，以及由于上皮完整性破坏而发生的癌细胞侵袭和转移。尽管生物学是一门多样化的学科，但我们一直致力于了解生物体复杂现象背后是否存在共同的基本机制，如果存在，则阐明这一机制。阐明这些基本机制将对理解这些不同癌症恶性转化的本质以及开发癌症治疗方法具有极其强大的作用。我们之前的研究表明，Arf6-AMAP1信号通路在高侵袭性乳腺癌细胞中特异性上调，并参与其侵袭和转移。在过去的两个财政年度，我们已经证明GEP100在肿瘤侵袭中负责激活Arf6。我们还阐明了GEP100在肿瘤侵袭中如何被激活的良好机制。关于Arf6活性在细胞迁移和肿瘤侵袭中的调控，我们发现了一种新的机制，通过Fbx8，一个泛素E3连接酶，介导Arf6的泛素化，使这个小的GTPase难以发挥作用，而不会导致其立即蛋白体降解。arf1是Arf6的同分异构体。我们对Git2的另一项分析表明，Git2是Arf1的gtpase激活蛋白（GAP），该GAP和Arf1在趋化因子激活的免疫细胞的定向传感和持久性中起关键作用。我们正在研究是否有类似的机制在上皮细胞和转化细胞的迁移和侵袭中起作用。

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.