Arf GTP-binding proteins and membrane traffic

Arf GTP 结合蛋白和膜运输

• 批准号: 8149467
• 负责人: Julie G Donaldson
• 金额: $ 30.66万
• 依托单位: NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8149467
• 关键词: GTP-Binding Proteins; Membrane; trafficking

The Arf6 GTP-binding protein has been shown to regulate both membrane traffic and the cytoskeleton at the plasma membrane. In a number of cancer model systems including breast cancer, Arf6 and its regulators have been observed to be upregulated. We have reported that one of the functions of active Arf6 at the plasma membrane is to recruit guanine nucleotide exchange factors of the ARNO/Cytohesin family that in turn lead to activation of Arf1 at the cell surface (Cohen et al 2007). This finding suggests that Arf proteins act sequentially and in a cascade at the plasma membrane. Furthermore, the finding that Arf proteins, such as Arf1, previously thought to only function at the Golgi complex, might function at the cell surface led us to investigate what functions Arf1 might serve there. We have found that Arf1 plays a specific role in rearranging the actin cytoskeleton to form ventral ruffles or podosome-like structures. Cells in which Arf1 levels were diminished by siRNA did not form these ventral ruffles. This finding leads us to suggest that many of the activites ascribed to Arf6 for both membrane traffic and the actin cytoskeleton might in fact involve roles for "Golgi-associated" Arfs such as Arf1.

Arf6 GTP 结合蛋白已被证明可以调节膜运输和质膜上的细胞骨架。 在包括乳腺癌在内的许多癌症模型系统中，Arf6 及其调节因子被发现上调。我们已经报道，质膜上活性 Arf6 的功能之一是募集 ARNO/Cytohesin 家族的鸟嘌呤核苷酸交换因子，进而导致细胞表面 Arf1 的激活 (Cohen et al 2007)。 这一发现表明 Arf 蛋白在质膜上按顺序并以级联方式发挥作用。 此外，Arf 蛋白（例如 Arf1）以前被认为仅在高尔基复合体中发挥作用，但现在可能在细胞表面发挥作用，这一发现促使我们研究 Arf1 可能在细胞表面发挥什么作用。 我们发现 Arf1 在重新排列肌动蛋白细胞骨架以形成腹侧褶边或足小体样结构中发挥着特定作用。 Arf1 水平被 siRNA 降低的细胞不会形成这些腹侧褶边。 这一发现使我们认为，许多归因于 Arf6 的膜运输和肌动蛋白细胞骨架活性实际上可能涉及“高尔基体相关”Arfs（例如 Arf1）的作用。