RHO PROTEINS AND MASS SPECTROMETRY

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目及 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 与Ras一样，小GTP结合蛋白的Rho家族通过激活下游效应蛋白而促进肿瘤发生和转移。响应于不同的上游信号，Rho蛋白将结合的GDP交换为GTP，然后可以结合并激活非常大的和功能多样的效应子集合，包括酶和支架蛋白。这些效应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，但它们如何促成癌症表型在很大程度上是未知的。我们的长期目标是提供通过Rho蛋白运作的信号通路的全面和定量描述，并了解这些通路的生物学重要性，它们是如何被调节的，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物功能的一个主要方法是通过高通量筛选鉴定特定效应物的小分子抑制剂。这些药物样分子然后用于揭示蛋白质功能丧失的后果，因为小分子抑制剂是探索高度动态信号传导途径的生物学的有力工具（Peterson和Mitchison，Chem. Biol.，9：1275，2002）。此外，这些化合物可能代表新疗法的先导。由于许多Rho家族效应子受自身抑制的调节，我们对通过变构稳定其天然的、自身抑制的构象来抑制效应子的化合物特别感兴趣。我们已经提出，该策略可用于开发在其他疾病中的癌症中起核心作用但在很大程度上被制药工业忽视的一大类信号传导蛋白的高度特异性抑制剂（Peterson和Golemis，J. Cell.生化、93：68，2004）--来自彼得森网站。

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.