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.
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