Melvin I. (Mel) Simon

Signal Transduction in Bacteria, Worms, and Mice

We are interested in how cells respond to changes in their external chemical andphysical environments. Bacterial chemotaxis continues to provide us withinsights into the mechanisms that a simple, single cell uses to modify its behavior.These processes are analogous to those that are found in eukaryotic cells. Theyinvolve specific cell surface receptors, the activation of protein kinases, andprotein phosphatases. In the first step in the process, ligands, e.g., amino acidsor sugars, bind to cell surface receptors. The receptor can initiate intracellularprotein phosphorylation or receptor modification. The interaction between thecontrol of protein phosphorylation (the excitation process) and the regulation ofreceptor responsiveness (desensitization) accounts for many of the behavioralfeatures of the organism. We are trying to understand how changes in ligandconcentration relate to these receptor-mediated processes.Signal transduction processes in eukaryotic cells probably involve greater diversity thanthose found in bacteria. Mammalian organisms and their cells can respond tohundreds of different ligands. A family of receptors characterized by theirgeneral structure, i.e., their ability to span the membrane of the cell seven timesmediates large numbers of different responses, including the response to light,odorants, a large group of neuromodulatory substances, hormones, and avariety of regulatory peptides. We are continuing to characterize the proteinsthat transduce signals from these "serpentine" transmembrane receptors. Theygenerally involve a group of guanine nucleotide binding proteins (GTP binding proteins) that are made up of three polypeptides: an a subunit that binds theguanine nucleotide, and a b and a g subunit. We have found that there are 15different a subunits belonging to at least four different classes. Furthermore, there is another family of genes, Regulators of G-protein Signaling (RGS) and a variety of other proteins that regulate receptor function and that control the properties of signaling circuits (arrestins, receptor kinases, etc.). We have been using transgenic mice that are generated to include mutations in specific G proteins in order to study the effects of changes in the G protein circuit on the physiology of the visual system, responses of various other neural systems, and cell culture systems.

We have formed an Alliance for Cell Signaling. In the context of that Alliance we are collaborating with a large number of other investigators to generate a complex data set to describe signaling function in B-cells and in cardiac myocytes. Our laboratory is responsible for the molecular biology aspects of this project. In that context we have developed high throughput systems for transcript analyses, for whole cDNA cloning, modification, and translation.