GOLPH3 Pathway Regulation of Golgi Structure and Function

高尔基体结构和功能的 GOLPH3 通路调节

• 批准号: 9152791
• 负责人: SETH J FIELD
• 金额: $ 32.55万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9152791
• 关键词: Accounting; Affect; Binding; Binding Proteins; Biological; Biology; Cancer Biology; Cell Adhesion; Cell Density; Cell Proliferation; Cell Proliferation Regulation; Cell membrane; Cells; Complex; Conflict (Psychology); Crowding; DNA Damage; DNA-dependent protein kinase; Data; Disease; Extracellular Matrix; F-Actin; Functional disorder; Goals; Golgi Apparatus; Growth; Hepatitis C virus; Human; Human body; Link; Lipids; Literature; Malignant Neoplasms; Maps; Mediating; Membrane; Membrane Protein Traffic; Morphology; Myosin ATPase; Oncogenes; Pathway interactions; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiology; Play; Process; Proteins; Regulation; Reporting; Role; Signal Pathway; Signal Transduction; Structure; Therapeutic; Travel; Vesicle; Yeasts; anticancer research; human disease; insight; novel; research study; response; trafficking; tumorigenesis

GOLPH3 Pathway Regulation of Golgi Structure and Function PROJECT SUMMARY Secretory trafficking through the Golgi to the plasma membrane is responsible for the proper placement of most of the constituents of the human body. Proteins that depend on trafficking from the Golgi to the plasma membrane play diverse roles in construction of the extracellular matrix that makes up most of our mass, but also in intercellular signaling, mediating exchange of materials across membranes, and cellular adhesion. Given the importance of Golgi-to-plasma membrane trafficking to normal physiology, it is likely that this process is highly regulated with inputs that reflect the status of the cell. Surprisingly, our current understanding of trafficking out of the Golgi provides little insight into the regulation of this process, nor insight into how dysregulation of the Golgi contributes to human disease. The long-term goal of this proposal is to understand the regulation of Golgi structure and function in normal physiology and in disease. Our discovery of the PI4P/GOLPH3/MYO18A/F-actin pathway that plays an important role in Golgi-to-plasma membrane trafficking (Dippold et al., Cell 2009) provides new insight into the biology of the Golgi. Importantly, this pathway has revealed novel regulation of the Golgi. For example, Golgi morphology and secretory trafficking were recently demonstrated to be regulated in response to growth factor signaling via regulation of PI4P levels at the Golgi, thereby regulating the GOLPH3 pathway (Blagoveschchenskaya et al., J Cell Biol 2008). We recently demonstrated that DNA damage results in surprising and dramatic regulation of the Golgi via phosphorylation of GOLPH3 (Farber-Katz et al., Cell 2014). These examples suggest that the GOLPH3 pathway may function as a hub for convergent regulation of the Golgi in response to inter- and intracellular signals. Recent evidence also indicates that the GOLPH3 pathway links regulation of the Golgi to important human disease. For example, we demonstrated that GOLPH3 and MYO18A are each required for propagation of the hepatitis C virus (Bishé et al., J Biol Chem 2012). More surprisingly, GOLPH3 and MYO18A drive cancers in humans (recently reviewed in Buschman et al., Cancer Research 2015). Together, the data argue that the GOLPH3 pathway is an important node in the regulation of Golgi morphology and secretory function with important biological significance. Here we propose to extend our studies of the PI4P/GOLPH3/MYO18A/F-actin pathway that we discovered to illuminate novel regulation of Golgi structure and function, to identify signaling pathways that effect this regulation, and to provide insight into their dysregulation in human disease.

GOLPH 3通路对高尔基体结构和功能的调控 项目摘要 通过高尔基体到质膜的分泌运输负责正确放置 人体的大部分成分。依赖于从高尔基体运输到血浆的蛋白质 膜在构成我们大部分质量的细胞外基质的构建中发挥着不同的作用，但是 还在细胞间信号传导、介导跨膜物质交换和细胞粘附中起作用。 考虑到高尔基体到质膜的运输对正常生理的重要性，这可能是因为 这一过程受到反映细胞状态的输入的高度调节。令人惊讶的是，目前 对高尔基体外运输的理解对这一过程的调控几乎没有提供任何见解， 深入了解高尔基体的失调如何导致人类疾病。这项提案的长期目标是 目的是了解正常生理和疾病中高尔基体结构和功能的调节。 我们发现PI 4P/GOLPH 3/MYO 18 A/F-actin通路在高尔基体到血浆中起重要作用， 膜运输（Dippold等，Cell 2009）提供了对高尔基体生物学的新见解。重要的是， 该途径揭示了高尔基体的新的调节。例如，高尔基体形态和分泌 最近证明，通过调节生长因子信号传导， 高尔基体的PI 4P水平，从而调节GOLPH 3途径（Blagoveschchenskaya等人，J Cell Biol 2008年）。我们最近证明，DNA损伤导致高尔基体的惊人和戏剧性的调节， 通过GOLPH 3的磷酸化（Farber-Katz等人，Cell 2014）。这些例子表明，GOLPH 3 信号通路可能作为一个枢纽，对高尔基体的会聚调节作出反应， 信号. 最近的证据还表明GOLPH 3通路将高尔基体的调节与重要的人类免疫功能联系起来。 疾病例如，我们证明了GOLPH 3和MYO 18 A都是细胞增殖所必需的。 丙型肝炎病毒（Bishé等人，J Biol Chem 2012）。更令人惊讶的是，GOLPH 3和MYO 18 A驱动癌症， 人类（最近在Buschman等人，Cancer Research 2015）。 总之，这些数据表明GOLPH 3通路是调节高尔基体的重要节点 具有重要的生物学意义。在这里，我们建议扩大我们的 PI 4P/GOLPH 3/MYO 18 A/F-actin通路的研究，我们发现该通路阐明了 高尔基体的结构和功能，以确定影响这种调节的信号通路，并提供见解 在人类疾病中的失调。