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GOLPH3 Pathway Regulation of Golgi Structure and Function

高尔基体结构和功能的 GOLPH3 通路调节

基本信息

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
项目类别：
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

项目摘要

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 通路调节项目概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，但是还参与细胞间信号传导、介导跨膜物质交换和细胞粘附。鉴于高尔基体到质膜的运输对正常生理的重要性，这很可能是该过程受到反映细胞状态的输入的高度调节。令人惊讶的是，我们现在的对高尔基体贩运的理解几乎没有提供对这一过程调节的深入了解，也没有提供对高尔基体贩运的了解。深入了解高尔基体的失调如何导致人类疾病。本提案的长期目标是为了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 通路在高尔基体到血浆中发挥重要作用膜运输（Dippold 等人，Cell 2009）提供了对高尔基体生物学的新见解。重要的是，这条通路揭示了高尔基体的新调节。例如，高尔基体形态和分泌最近证明，贩运是通过调节生长因子信号而受到调节的高尔基体中的 PI4P 水平，从而调节 GOLPH3 通路（Blagoveschchenskaya 等人，J Cell Biol 2008）。我们最近证明 DNA 损伤会对高尔基体产生令人惊讶和戏剧性的调节通过 GOLPH3 的磷酸化（Farber-Katz 等人，Cell 2014）。这些例子表明 GOLPH3 通路可能作为高尔基体响应细胞间和细胞内的聚合调节的枢纽。信号。最近的证据还表明，GOLPH3 通路将高尔基体的调节与重要的人类疾病。例如，我们证明了 GOLPH3 和 MYO18A 都是传播丙型肝炎病毒（Bishé 等人，J Biol Chem 2012）。更令人惊讶的是，GOLPH3 和 MYO18A 会导致癌症人类（最近在 Buschman 等人的癌症研究 2015 中进行了综述）。总之，数据表明 GOLPH3 通路是高尔基体调节的重要节点形态和分泌功能具有重要的生物学意义。在此，我们建议延长我们的我们发现 PI4P/GOLPH3/MYO18A/F-actin 通路的研究阐明了新的调控高尔基体结构和功能，以确定影响这种调节的信号通路，并提供见解其在人类疾病中的失调。