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

Arf GTPases 在细胞迁移、侵袭、定向传感和持久性中的作用

• 批准号: 18370082
• 负责人: SABE Hisataka
• 金额: $ 11.21万
• 依托单位: Osaka Bioscience Institute
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18370082/
• 关键词: Arf6; GEP100; EGFR; invasion; E-cadherin; neutrophil; Git2; Git1; FEP100; 細胞極性; 細胞運動方向持続性; Arf1; GPCR; ゴルジ体; GEF

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.

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。我们的其他主要研究兴趣是了解上皮组织完整性维持的主要机制，以及上皮完整性破坏导致的癌细胞侵袭和转移。虽然生物学是一门多样化的学科，但我们一直致力于了解在生物体的复杂现象背后是否存在共同的基本机制，如果存在，则阐明这种机制。阐明这些基本机制对于理解这些不同癌症的恶性转化的本质和开发癌症治疗方法将是非常强大的。我们先前已经表明，Arf 6-AMAP 1信号通路在高度侵袭性乳腺癌细胞中特异性上调，并用于其侵袭和转移。在过去的两个财政年度，我们已经表明，GEP 100是负责激活Arf 6在肿瘤侵袭。我们还阐明了GEP 100在肿瘤侵袭中如何被激活的精细机制。关于Arf 6在细胞迁移和肿瘤侵袭中的活性调节，我们已经确定了一种新的机制，通过该机制，Fbx 8，一种泛素E3连接酶，介导Arf 6的泛素化，并使这种小的GTdR难以发挥功能，而不导致其立即蛋白体降解。Arf 1是Arf 6的同种型。我们对Git 2的另一项分析表明，Git 2是Arf 1的GTP酶激活蛋白（GAP），该GAP以及Arf 1在趋化因子激活的免疫细胞中的定向传感和持久性中发挥关键作用。我们正在研究在上皮细胞和转化细胞的迁移和侵袭中是否有类似的机制。

项目成果

CIN85, a Cbl-interacting multiadaptor protein,is a component of AMAP1-mediated breast cancer invasion machinery

CIN85 是一种 Cbl 相互作用多接头蛋白，是 AMAP1 介导的乳腺癌侵袭机制的一个组成部分

• 发表时间: 2007
• 期刊: EMBO J. 26
• 作者: J. Nam;Y. Onodera;Y. Mazaki;H. Miyoshi;S. Hashimoto;H. Sade
• 通讯作者: H. Sade

Arf6 constitutes a central pathway involved in breast cancer cell invasion and metastasis

Arf6构成参与乳腺癌细胞侵袭和转移的中心通路

• 发表时间: 2007
• 作者: Hashimoto;S.;Hashimoto;A.;Yamada;A.;Onodera;Y.;Sabe;H.;Sabe H;Sabe H;Sabe H;Sabe H;Hashimoto S;Miura M;Masaki Y;H. Sabe
• 通讯作者: H. Sabe

「研究成果報告書概要(和文)」より

摘自《研究结果报告摘要（日文）》

• 发表时间: 2005
• 作者: Kawauchi;et. al.;Nishimura et al.;Dezawa et al.;Yoshizawa et al.;星野 幹雄;星野 幹雄
• 通讯作者: 星野 幹雄

ArfGAP family proteins in cell adhesion, migration and tumor invasion

• DOI: 10.1016/j.ceb.2006.08.002
• 发表时间: 2006-10-01
• 期刊: CURRENT OPINION IN CELL BIOLOGY
• 影响因子: 7.5
• 作者: Sabe, Hisataka;Onodera, Yasuhito;Hashimoto, Shigeru
• 通讯作者: Hashimoto, Shigeru