RHO PROTEINS AND MASS SPECTROMETRY

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 与RAS一样，Rho家族的小GTP结合蛋白通过激活下游效应蛋白参与肿瘤的发生和转移。作为对不同上游信号的响应，Rho蛋白将结合的GDP交换为GTP，然后可以结合和激活包括酶和支架蛋白在内的一系列非常大的和功能不同的效应器。这些效应分子介导复杂的细胞反应，包括细胞周期进程、细胞骨架重排、细胞极性和基因转录，但它们如何影响癌症表型在很大程度上尚不清楚。我们的长期目标是全面和定量地描述通过Rho蛋白运行的信号通路，并了解这些通路的生物学重要性，它们是如何被调控的，以及它们在人类疾病中是如何被破坏的。我们用来阐明特定效应器功能的一个主要方法是通过高通量筛选识别针对特定效应器的小分子抑制剂。这些类药物分子随后被用来揭示蛋白质功能丧失的后果，因为小分子抑制剂是探索高动态信号通路生物学的强大工具(Peterson和Mitchison，Chem)。生物，2002年9：1275)。此外，这些化合物可能是新疗法的先导。由于许多Rho家族效应器受自身抑制的调节，我们对通过变构稳定其天然的自抑制构象来抑制效应器的化合物特别感兴趣。我们已经提出，这一策略可以用于开发一大类信号蛋白的高度特异性抑制剂，这些蛋白在其他疾病的癌症中发挥核心作用，但在很大程度上被制药业忽视(Peterson和Golemis，J.Cell)。生物化学，93：68,2004)--摘自Peterson网站。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Like Ras, the Rho family of small GTP-binding proteins contributes to tumorigenesis and metastasis through the activation of downstream effector proteins. In response to diverse upstream signals, Rho proteins exchange bound GDP for GTP and can then bind and activate a very large and functionally diverse set of effectors including enzymes and scaffolding proteins. These effectors mediate complex cellular responses including cell cycle progression, cytoskeletal rearrangements, cell polarity, and gene transcription but how they contribute to the cancer phenotype is largely unknown. Our long-term goal is to provide a comprehensive and quantitative description of the signaling pathways operating through the Rho proteins and to understand the biological importance of these pathways, how they are regulated, and how they are corrupted in human diseases. One major approach we are using to elucidate the functions of particular effectors is the identification of small-molecule inhibitors for specific effectors through high-throughput screening. These drug-like molecules are then used to reveal the consequence of protein loss of function, as small-molecule inhibitors are powerful tools to explore the biology of highly dynamic signaling pathways (Peterson and Mitchison, Chem. Biol., 9: 1275, 2002). In addition, these compounds may represent leads for novel therapeutics. Since many Rho family effectors are regulated by autoinhibition, we are particularly interested in compounds that inhibit effectors by allosterically stabilizing their native, autoinhibited conformation. We have proposed that this strategy could be used to develop highly specific inhibitors of a large class of signaling proteins that play central roles in cancer in other diseases but that have been largely ignored by the pharmaceutical industry (Peterson and Golemis, J. Cell. Biochem., 93: 68, 2004)--from Peterson Web Site.