Mitogen-activated protein kinase (MAPK) signaling pathways participate in the regulation of many biologically and medically important processes, including normal and pathological aspects of cell growth, division, differentiation, and death. Their ubiquity and versatility raise the issue of how they achieve specific coupling of signal to cellular response. How do the kinases in the cascade distinguish their correct substrates from the vast excess of incorrect substrates? Furthermore, how do different signals elicit distinct responses when they are transmitted by the same components? This competitive renewal proposal presents experiments that address the specificity of recognition between MAP kinases and their substrates and regulators, and that investigate the mechanisms that restrict inappropriate signal crossover (or 'leaking') between distinct pathways sharing components. We continue to investigate both yeast and mammalian MAPK pathways, in order to innovatively exploit the synergistic cross-fertilization of insights gained from these two experimental systems.
Specific Aims are (1) to delineate the selectivity of MAPK-docking sites ('D-sites') in MAPK kinases (MKKs, or MEKs) for their cognate vs. non-cognate MAPKs and to develop a model to explain these relationships; (2) to assess MEK D-site function and specificity in vivo; (3) to identify new substrates and regulators of the JNK MAP kinase by predicting JNK-docking sites; (4) to determine the molecular mechanism of Fus3MAPK-dependent feedback control of specificity in yeast; (5) to investigate how the yeast Ste5 scaffold protein contributes to signaling specificity; (6) to ask if the MAPKs Kss1 and Fus3 have distinct target site preferences. Chronic activation, loss of sensitivity to feedback controls and loss of specificity appear to be important aspects of the MAPK dysregulation seen in many cancers, and this research will increase our understanding of these issues. More generally, this research could lead to a better understanding of how MAP kinases (and other kinases) find their targets and improve our ability to predict substrates and regulators and may ultimately suggest novel approaches to therapy based on the modulation of protein kinase interactions.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Cell Development and Function Integrated Review Group (CDF)
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Anderson, Richard A
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University of California Irvine
Anatomy/Cell Biology
Schools of Arts and Sciences
United States
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Bardwell, A Jane; Bardwell, Lee (2015) Two hydrophobic residues can determine the specificity of mitogen-activated protein kinase docking interactions. J Biol Chem 290:26661-74
Liu, Xinfeng; Bardwell, Lee; Nie, Qing (2010) A combination of multisite phosphorylation and substrate sequestration produces switchlike responses. Biophys J 98:1396-407
Whisenant, Thomas C; Ho, David T; Benz, Ryan W et al. (2010) Computational prediction and experimental verification of new MAP kinase docking sites and substrates including Gli transcription factors. PLoS Comput Biol 6:
Compani, Behnam; Su, Trent; Chang, Ivan et al. (2010) A scalable and integrative system for pathway bioinformatics and systems biology. Adv Exp Med Biol 680:523-34
Haney, Seth; Bardwell, Lee; Nie, Qing (2010) Ultrasensitive responses and specificity in cell signaling. BMC Syst Biol 4:119
Bardwell, A Jane; Frankson, Erlynn; Bardwell, Lee (2009) Selectivity of docking sites in MAPK kinases. J Biol Chem 284:13165-73
Hilioti, Zoe; Sabbagh Jr, Walid; Paliwal, Saurabh et al. (2008) Oscillatory phosphorylation of yeast Fus3 MAP kinase controls periodic gene expression and morphogenesis. Curr Biol 18:1700-6
Bardwell, Lee (2008) Signal transduction: turning a switch into a rheostat. Curr Biol 18:R910-2
Bardwell, Lee; Zou, Xiufen; Nie, Qing et al. (2007) Mathematical models of specificity in cell signaling. Biophys J 92:3425-41
Bardwell, Lee; Shah, Kandarp (2006) Analysis of mitogen-activated protein kinase activation and interactions with regulators and substrates. Methods 40:213-23

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