New frontiers in extracellular signaling

摘要-我们NIGMS支持的研究的总体目标一直是确定EGF受体如何 (EGFR)家族成员和Rho GTP酶触发正常生物所必需的信号通路 过程，当解除管制时，会导致疾病状态。我们的工作依赖于 生化、细胞生物学和结构方法，以及最近的小鼠模型。这些 经过努力，我们发现了一种新的信号通路，它可以激活一种关键的代谢 谷氨酰胺酶C(GAC)，催化谷氨酰胺代谢的第一步，是 包括癌细胞在内的高增殖细胞。然后我们发现，这些项目的一个重要结果 代谢变化是产生微泡(MVS)，这是非经典分泌的一个特殊子集 属于较大的细胞外小泡(EVS)家族的小泡。MVS和其他专业 电动汽车的一类，Exosome，由于其在广泛的领域中的作用而引起了人们的极大关注 以及在不同疾病中的正常生理过程。它们被认为与生物学有关 从细菌到病毒感染性，再到各种不同进化阶段的活动 高等生物体的生理过程，包括免疫反应和神经功能，如 以及与癌症和神经退行性疾病等疾病有关。此外，电动汽车 也与干细胞生物学有关，我们的实验室最近发现MVS脱落 胚胎干细胞在激活滋养层细胞方面起着关键作用，滋养层细胞是胚胎中必不可少的一步。 植入。尽管如此，我们仍处于理解这些新模式的作用的早期阶段 细胞间的信息传递。特别是，迫切需要定义生化和 作为MV功能基础的信号机制。围绕这一点的重要问题包括 令人兴奋的领域包括癌症导致MVS生物发生的信号机制是什么 它们的行为被研究得最多的细胞，以及决定 MVS是否携带蛋白质和RNA货物，以及它们是否在不同类型的细胞中保守。 此外，我们需要更多地了解触发MVS脱落的信号的性质 从它们的亲代(供体)细胞中分离出来，从而使它们能够参与并将蛋白质和RNA货物转移到 目标单元格。解决这些问题将需要一些新的研究和开发路线， 因为它们代表了信号转导中一个重要且迅速兴起的前沿。鉴于我们实验室的 经验和专业知识，我们能够很好地定义负责 这种新的细胞间通讯形式的生物起源和功能，最终应该会产生 对根本上重要的生物过程的新见解，以及各种 疾病和病理性疾病。

Abstract- The overall goals of our NIGMS-supported research have been to determine how EGF receptor (EGFR) family members and Rho GTPases trigger signaling pathways essential for normal biological processes and, when de-regulated, give rise to disease states. Our work has relied upon a combination of biochemical, cell biological, and structural approaches, as well as more recently, mouse models. These efforts led to our discovery of a novel signaling-pathway that results in the activation of a key metabolic enzyme, glutaminase C (GAC), which catalyzes the first step in glutamine metabolism and is essential for highly proliferative cells including cancer cells. We then discovered that an important outcome of these metabolic changes is the generation of microvesicles (MVs), a specific subset of non-classical secretory vesicles that fall within the larger family of extracellular vesicles (EVs). MVs, together with the other major class of EVs, exosomes, are now garnering a great deal of attention because of their roles in a wide range of normal physiological processes as well as in different diseases. They have been linked to biological activities that span the evolutionary spectrum from bacteria to viral infectivity, and to a diversity of physiological processes in higher organisms including the immune response and neuronal function, as well as being connected to diseases such as cancer and neurodegenerative disorders. Moreover, EVs have also been implicated in stem cell biology, with our laboratory recently discovering that MVs shed from embryonic stem cells play a critical role in activating trophoblasts, an essential step in embryo implantation. Still, we are at an early stage in understanding the actions of these novel modes of information transfer between cells. In particular, there is a critical need to define the biochemical and signaling mechanisms that underlie MV functions. Among the important questions surrounding this exciting field include what are the signaling mechanisms responsible for the biogenesis of MVs by cancer cells where their actions have been most heavily studied, as well as the specific cues that dictate the loading of MVs with protein and RNA cargo, and whether they are conserved across different cell types. Moreover, we need to learn much more about the nature of the signals that trigger the shedding of MVs from their parental (donor) cells, thus enabling them to engage and transfer protein and RNA cargo to their target cells. Addressing these questions will require a number of new lines of research and development, as they represent an important and rapidly emerging frontier in signal transduction. Given our laboratory's experience and expertise, we are well positioned to define the signaling mechanisms responsible for the biogenesis and function of this novel form of intercellular communication, which ultimately should yield new insights into fundamentally important biological processes, as well as the molecular basis of various diseases and pathological disorders.