GOLPH3 Pathway Regulation of Golgi Structure and Function

高尔基体结构和功能的GOLPH3通路调节 项目总结 通过高尔基体到质膜的分泌运输负责适当的放置 人体的大部分成分。依赖于从高尔基体向血浆运输的蛋白质 膜在构建细胞外基质方面扮演着不同的角色，而细胞外基质构成了我们的大部分质量，但 也参与细胞间信号传递、跨膜物质交换和细胞黏附。 鉴于高尔基体向质膜转运对正常生理的重要性，这很可能是 过程受到高度监管，输入反映细胞的状态。令人惊讶的是，我们目前 对高尔基山脉外贩运的了解对这一过程的监管几乎没有什么帮助，也没有 洞察高尔基体失调是如何导致人类疾病的。这项提议的长期目标是 是了解高尔基体结构和功能在正常生理和疾病中的调节。 我们发现PI4P/GOLPH3/MYO18A/F-肌动蛋白通路在高尔基体向血浆转化过程中起重要作用 膜贩运(Dippold等人，Cell 2009)提供了对高尔基体生物学的新见解。重要的是 这一途径揭示了高尔基体的新调节。例如高尔基体形态和分泌物 最近证实，贩运是通过调节生长因子信号来调节的 PI4P在高尔基体的水平，从而调节GOLPH3通路(Blagoveschenskaya等人，J Cell Biol 2008年)。我们最近证明，DNA损伤会导致高尔基体惊人而戏剧性的调节 通过GOLPH3的磷酸化(Farber-Katz等人，Cell 2014)。这些例子表明，GOLPH3 信号通路可能作为高尔基体在细胞内和细胞内的汇聚性调节的枢纽 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，我们演示了GOLPH3和MYO18A分别是传播 丙型肝炎病毒(Bishéet al.，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)。 综上所述，这些数据表明，GOLPH3通路是高尔基体调控的重要节点 其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 我们发现的PI4P/GOLPH3/MYO18A/F-肌动蛋白通路的研究揭示了新的调控机制 高尔基体的结构和功能，以确定影响这种调节的信号通路，并提供洞察力 它们在人类疾病中的失调。

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.