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.

National Institute of Health (NIH)
National Center for Research Resources (NCRR)
Biotechnology Resource Grants (P41)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-BCMB-K (40))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Washington University
Internal Medicine/Medicine
Schools of Medicine
Saint Louis
United States
Zip Code
Yue, Xuyi; Dhavale, Dhruva D; Li, Junfeng et al. (2018) Design, synthesis, and in vitro evaluation of quinolinyl analogues for ?-synuclein aggregation. Bioorg Med Chem Lett 28:1011-1019
Ohlemacher, Shannon I; Giblin, Daryl E; d'Avignon, D André et al. (2017) Enterobacteria secrete an inhibitor of Pseudomonas virulence during clinical bacteriuria. J Clin Invest 127:4018-4030
Lin, Xiaobo; Racette, Susan B; Ma, Lina et al. (2017) Endogenous Cholesterol Excretion Is Negatively Associated With Carotid Intima-Media Thickness in Humans. Arterioscler Thromb Vasc Biol 37:2364-2369
Ovod, Vitaliy; Ramsey, Kara N; Mawuenyega, Kwasi G et al. (2017) Amyloid ? concentrations and stable isotope labeling kinetics of human plasma specific to central nervous system amyloidosis. Alzheimers Dement 13:841-849
Cade, W Todd; Levy, Philip T; Tinius, Rachel A et al. (2017) Markers of maternal and infant metabolism are associated with ventricular dysfunction in infants of obese women with type 2 diabetes. Pediatr Res 82:768-775
Lucey, Brendan P; Mawuenyega, Kwasi G; Patterson, Bruce W et al. (2017) Associations Between ?-Amyloid Kinetics and the ?-Amyloid Diurnal Pattern in the Central Nervous System. JAMA Neurol 74:207-215
Wei, Xiaochao; Song, Haowei; Yin, Li et al. (2016) Fatty acid synthesis configures the plasma membrane for inflammation in diabetes. Nature 539:294-298
Shields-Cutler, Robin R; Crowley, Jan R; Miller, Connelly D et al. (2016) Human Metabolome-derived Cofactors Are Required for the Antibacterial Activity of Siderocalin in Urine. J Biol Chem 291:25901-25910
Mertins, Philipp; Mani, D R; Ruggles, Kelly V et al. (2016) Proteogenomics connects somatic mutations to signalling in breast cancer. Nature 534:55-62
Murata, Takahiro; Dietrich, Hans H; Horiuchi, Tetsuyoshi et al. (2016) Mechanisms of magnesium-induced vasodilation in cerebral penetrating arterioles. Neurosci Res 107:57-62

Showing the most recent 10 out of 696 publications