The Naegle Lab at Washington University in St. Louis
Post-translational modifications in cell signaling
Cell signaling describes the process by which cells translate extracellular cues into phenotypic changes such as differentiation, growth, or apoptosis. For example, healthy skeletal muscle cells exposed to insulin increase their uptake of glucose. Cell signaling occurs through cascades of molecular changes within the cell. These networks function by transiently controlling the propagation of signal and protein post-translational modification is a critical element in cellular networks because it is fast, reversible, and regulatable. Post-translational modifications (PTMs) represent a fascinating molecular mechanism, not only because of their central role in controlling protein function, life-time, and localization, but because they represent the drastic expansion of amino acid properties that are not directly encoded by the genome (currently 366 different modified residues have been discovered). Relatively recent advances in technology have allowed for the high-throughput discovery and quantitative measurements of PTMs in a variety of organism, cell, and tissue contexts. The Naegle Lab developed ProteomeScout to house these systems-level experiments and maintain an up-to-date compendia of all know protein post-translational modifications.
The Naegle Lab is particularly interested in phosphorylation of tyrosine residues, which entails the addition of a phosphate group to a tyrosine residue by a tyrosine kinase and removal by a tyrosine phosphatase. Out of all 366 possible modified residues to study, we focus on tyrosine phosphorylation because it is the primary mechanism used early in signaling cascades in those networks that appear to have evolved with multicellularity. These networks are driven by receptor tyrosine kinases (such as the insulin and epidermal growth factor receptros) and tyrosine kinase linked receptors (such as the interleukin receptors). Currently there are more than 30,000 sites of tyrosine phosphorylation that have been identified in human cells and tissues and a very small percentage of these have a known function. In order to understand how networks that are fundamentally important for human development and homeostasis become dysregulated and lead to disease, our lab is trying to understand the function and regulation of tyrosine phosphorylation within cell signaling networks. To achieve our goals we develop computational and mathematical methods and use these in conjunction with existing systems- and proteome-level data to infer the function of tyrosine phosphorylation within cell signaling networks. We pursue relevant hypotheses using molecular and cellular experimental techniques.