Kinase mediated phosphorylation of proteins broadly regulates cellular responses in normal and diseasestates. Kinases in cellular signaling networks play the role of `micro-processors' that couple different stimuli todistinct signaling outputs. The versatility and specificity of their cellular function arise from the coordination ofseveral intra-molecular and inter-molecular protein interactions. However, current approaches to probe kinasestreat them as simple `on-off' switches and do not address their complex spatial and temporal regulation in cells.We have developed a technology, termed the kinase toolbox, which monitors and/or controls these proteininteractions to provide a detailed mechanistic understanding of the cellular function of any kinase. In addition,the kinase toolbox overcomes the limitations of existing techniques to identify small molecules/therapeuticsthat differentiate between closely related kinases. We have developed and tested kinase toolboxes for focaladhesion kinase (FAK) and protein kinase C (PKC). We propose to pursue three complementary and parallelgoals in order to realize the transformative potential of this new technology, while distributing risk. Our first goalis to use the PKC toolbox to map the spatial and temporal regulation of two closely related PKC isoforms incellular models of cardiac hypertrophy and diabetic retinopathy. In addition to proof-of-concept, the PKCtoolbox has already provided us with new conceptual insights that broadly apply to the AGC kinase superfamily(60 members). Our second goal is to use these insights to understand the similarities and differences in theregulation of five closely related AGC kinases (PKA, Akt/PKB, PKC, PDK1 and S6K1). Our third goal is toconduct pilot studies of three new approaches, based on the kinase toolbox, to design isoform-specificinhibitors of AGC kinases. Taken together, the proposed research is an essential first step towards our long-term goal of designing and characterizing high-specificity inhibitors of AGC kinases, which are important drugtargets in disease states such as diabetes, heart failure and cancer. Successful completion of the outlinedstudies will transform our understanding of kinases in general, while providing researchers with new tools anda roadmap to study their cellular function.
Kinases are a family of proteins that are an integral part of cellular signaling networks. Kinases are a prominentdrug target for diseases such as diabetes; heart failure and cancer. The proposed research will use aninnovative technology to provide detailed mechanistic insights into the cellular function of kinases; along withpilot studies using transformative approaches to identify/design new therapeutics that target them.
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