CAREER: Understanding and Exploiting Sequence Recognition by Cell Signaling Proteins

With the support of the Chemistry of Life Processes program in the Division of Chemistry, Professor Neel Shah from Columbia University is investigating how tyrosine kinases, a class of enzymes found in all animals and many other organisms, accurately relay information within cells. Tyrosine kinases play important roles in regulating cell growth, cell division, cell death, and responsiveness of cells to their environment. They operate by sensing biochemical cues and then chemically modifying other proteins, but in order for this to occur faithfully, tyrosine kinases must recognize specific proteins to modify out of the sea of possible targets in a cell. Professor Shah’s laboratory will explore the molecular rules underpinning protein recognition by tyrosine kinases. This research will illuminate new mechanisms by which tyrosine kinase signaling is controlled and also inspire the design of novel inhibitors of these enzymes. In conjunction with this research, the Shah lab will develop and implement hands-on biochemistry lessons at a local middle school to show students the numerous roles that enzymes and other biomolecules play in everyday life. The 90 tyrosine kinases found in humans have highly similar catalytic domains. Despite their structural homology, subtle differences in the active sites of each tyrosine kinase engender them with the ability to phosphorylate different substrates, in part by recognizing specific linear patterns of amino acid sequences. There now exists a reasonable description of sequence preferences for nearly every human tyrosine kinase. However, a complete picture of the biophysical basis for substrate selection and knowledge of how tyrosine kinases select substrates in different signaling contexts are still lacking. In this work, researchers within the Shah laboratory will first use protein chemistry and high-throughput peptide phosphorylation screens to examine how post-translational modifications to tyrosine kinases alter their substrate specificities. Next, using biochemical measurements coupled with structural analysis, researchers will assess whether the first-order approximations of sequence specificity that currently dominate the field can be improved by taking into account the energetic coupling between individual amino acids within a linear recognition motif. Finally, using the biochemical and biophysical insights into substrate recognition gained, a unique strategy for the design and synthesis of selective kinase inhibitors will be explored. This effort will produce new chemical tools to dissect kinase signaling and provide a template for the development of a new modality of kinase-targeted inhibitors. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.