Mechanisms of Signal Transduction by Ras Proteins

描述（由申请人提供）：已确定Ras蛋白是促生长信号网络的基本控制元件。此外，Ras信号转导的失调与许多人类恶性肿瘤有因果关系。然而，我们对Ras蛋白的生理和致病活性的分子原理的理解仍然有限。这项正在进行的研究计划的广泛目标是阐明这些原则，并确定它们如何在功能上与细胞内稳态的控制有关。在目前的资助期间，我们已经描述了一个以前未被认识到的机制，优先分配Ras蛋白的内吞途径，其中涉及泛素结合。此外，我们已经表明这种靶向机制调节Ras依赖性信号传导。本申请中提出的研究的目标是获得Ras泛素化的调节和功能后果的详细知识。我们将利用亚细胞，细胞和有机体模型追求以下目标：1。确定控制Ras泛素化的分子机制。在这个目标内提出的研究是针对介导泛素缀合和从Ras去除的酶的鉴定和表征，以及Ras泛素化的空间调控的描绘。 2.探讨Ras泛素化的功能意义。在这个目标内提出的研究是针对测试的假设，即Ras信号转导的结果的影响Ras泛素化状态在生理和病理设置。 总之，这些研究将提供新的见解规范机制，管理Ras信号，并可能发现新的治疗干预方式。

DESCRIPTION (provided by applicant): It is firmly established that Ras proteins are essential control elements of growth promoting signaling networks. Moreover, the deregulation of Ras signaling has been causally linked to a number of human malignancies. However, our understanding of molecular principles that govern the physiological and pathogenic activities of Ras proteins is still limited. The broad objective of this ongoing research program is to elucidate these principles and to determine how they are functionally linked to the control of cellular homeostasis. During the current funding period, we have described a previously unrecognized mechanism for the preferential partitioning of Ras proteins to the endocytic pathway which involves ubiquitin conjugation. Furthermore, we have shown that this targeting mechanism modulates Ras- dependent signaling. The goal of the studies proposed in the current application is to gain detailed knowledge of the regulation and functional consequences of Ras ubiquitination. We will exploit subcellular, cellular and organismal models to pursue the following aims: 1. To define the molecular machinery that controls Ras ubiquitination. Studies proposed within this aim are directed at the identification and characterization of the enzymes that mediate ubiquitin conjugation to and removal from Ras, as well as the delineation of the spatial regulation of Ras ubiquitination. 2. To establish the functional significance of Ras ubiquitination. Studies proposed within this aim are directed at testing the hypothesis that Ras signaling outcomes are influenced by Ras ubiquitination status both in physiological and pathological settings. Together, these studies will provide new insights into specification mechanisms that govern Ras signaling and may uncover new modalities for therapeutic intervention.