Our laboratory is interested in a fundamental understanding of signal transduction. Cells use signal transduction pathways to convert external stimuli into an internal form that can generate an appropriate response, and many cancers are the direct result of aberrant signal transduction processes. Biological information processing systems, whether in bacteria or man, have to solve similar problems and thus share many common properties (e.g. modular design, multiprotein complexes, unstable signaling molecules) and often employ common mechanisms (e.g. transient protein phosphorylation). Therefore, investigation of one type of signal transduction pathway often provides insights into many others. The superior experimental accessibility of bacteria make it possible to achieve a comprehensive understanding of signal transduction at the molecular level currently unparalleled in other organisms. Our research builds on one of the best understood phosphorylation-mediated signal transduction systems, that governing chemotaxis by Escherichia coli.

One project employs a traditional reductionist approach of breaking a problem down into its smallest pieces. We typically deduce critical features of the signal transduction process by isolating and thoroughly characterizing informative mutant signaling proteins using a wide variety of techniques drawn from genetics, molecular biology, biochemistry, and biophysics. Our goal is a fundamental understanding of the mechanisms and regulation of phosphoryl group transfer among proteins, including the ways proteins interact to achieve these ends, and of the impact of phosphorylation on protein activity.

Another project employs an integrative approach to see what happens when we try to put all the pieces back together. If we really know all there is to know about the chemotaxis signal transduction pathway, we should be able to reproduce it in a computer simulation. Such a molecularly-based simulation, incorporating the uniquely complete data set of biochemical reactions, rate constants, intracellular protein concentrations, etc. available for bacterial chemotaxis has been developed by our collaborator, Dennis Bray's group at Cambridge University. Discrepancies between computer simulation and laboratory experiment highlight areas of incomplete understanding and have proven immensely valuable in focusing our research. The computer simulation is now sufficiently sophisticated to motivate new experiments and even reveal problems with previous experiments. Many of the intellectual concepts and software approaches arising from this project should be directly relevant to modeling eukaryotic signal transduction pathways.

Finally, we are initiating new projects on the role of signal transduction in pathogenic bacteria and to characterize proteins of unknown function revealed by genome sequencing that appear to utilize phosphoaspartate.