Signal Transduction

Growth Factors – In collaboration with Don Bottaro, CCR, we have had a long standing interest in the hepatocyte growth factor (HGF) and its relation to tumor progression. We examined the structure of both the unique N-terminal domain of HGF by NMR methods and the crystal and solution structure of the natural isoform NK1, which contains the first two domains of HGF and retains biological activity. Recent work has led to the engineering of several mutant proteins, based on our studies of NK1 interaction with heparin, that have exciting in vivo anti-tumor activity. These studies represent our multi-disciplinary approach of combining structure, biophysics, and biology to understand and to modulate important biological processes in cancer.

Signal Transduction – We have a long standing interest in the mechanisms of how proteins transmit information or action via protein-protein interactions. An area where we still have interest is in the Stat proteins. These transcription regulators form complexes of differing stoichiometries with recognition sites in DNA. One of the factors that contribute to these recognition stoichiometries is the interaction of the N-terminal domains of the STAT proteins. We continue to examine solution structures of these domains. In part, we use novel NMR methods and are extending our studies to include SAXS and other methods that provide unique long-range distance information to build structural models of the multi-component complexes.