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: 9333407
• 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/9333407
• 关键词: 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; GOLPH3 gene; Goals; Golgi Apparatus; Growth Factor; Hepatitis C; Human; Human body; Impairment; Link; Lipids; Literature; Malignant Neoplasms; Mediating; Membrane; 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; experimental study; human disease; insight; novel; 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.

高尔基体结构和功能的Golph3途径调节 项目摘要 通过高尔基人贩运秘书到质膜，负责适当的位置 人体的大多数成分。依赖于从高尔基人到等离子体的贩运的蛋白质 膜在构成我们大部分质量的细胞外基质中扮演着各种角色，但是 同样在细胞间信号传导中，介导跨膜的材料交换以及细胞粘附。 鉴于高尔基膜到铂膜贩运对正常生理学的重要性，这很可能 过程通过反映细胞状态的输入进行了高度调节。令人惊讶的是，我们的当前 从高尔基人中了解贩运的人几乎没有洞察这一过程的监管，也没有 深入了解高尔基体的失调如何导致人类疾病。该提议的长期目标 是要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PI4P/GOLPH3/MYO18A/F-ACTIN途径，在高尔基体到辉煌中起着重要作用 膜运输（Dippold等人，Cell 2009）为高尔基体生物学提供了新的见解。重要的是， 这一途径揭示了高尔基的新调节。例如，高尔基的形态和分泌 最近证明，通过调节，贩运因生长因子信号传导而受到调节 高尔基体处的PI4P水平，从而调节Golph3途径（Blagoveschhenskaya等，J Cell Biol 2008）。我们最近证明了DNA损伤导致高尔基体的惊喜和戏剧性调节 通过Golph3的磷酸化（Farber-Katz等，Cell 2014）。这些例子表明Golph3 途径可能充当响应细胞内和细胞内的高尔基体收敛调节的枢纽 信号。 最近的证据还表明，Golph3途径将高尔基人的调节与重要人类联系起来 疾病。例如，我们证明了Golph3和Myo18a是每个传播所必需的 丙型肝炎病毒（Bishé等，J Biol Chem 2012）。更令人惊讶的是，Golph3和Myo18A驱动癌 人类（最近在Buschman等人进行了审查，2015年癌症研究）。 数据一起，数据认为Golph3途径是高尔基体调节中的重要节点 具有重要生物学性的形态和秘书职能。在这里，我们建议扩展我们的 我们发现的PI4P/Golph3/MyO18A/F-肌动蛋白途径的研究阐明了新的调节 高尔基体的结构和功能，以识别影响该调节的信号通路，并提供洞察力 进入人类疾病的失调。