Michael A. Simon
Signal Transduction Through Tyrosine KinasesResearch is directed toward understanding how the activation of transmembrane hormone receptors can determine the developmental fate of a cell.
The primary focus of the laboratory is the study of the sevenless protein of Drosophila melanogaster. The sevenless locus encodes a transmembrane receptor molecule that contains an intracellular protein tyrosine kinase domain. The activation of sevenless kinase activity in response to the binding of its ligand, the product of the bride of sevenless locus, is crucial for the proper development of a single cell within each unit of the compound eye. In the absence of sevenless activity, a precursor cell that would normally differentiate as the R7 photoreceptor instead becomes a non-neuronal lens-secreting cell.
In previous work, mutations that can attenuate signaling by the sevenless protein were found. These mutations defined seven genetic loci, called Enhancers of sevenless, as candidates to encode components of the signal transduction pathway used by the sevenless protein. Two of the Enhancer of sevenless loci have been molecularly characterized. One, Ras1, encodes the Drosophila homologue of the H-ras gene of vertebrates. The other, Son of sevenless (Sos), encodes a putative guanine nucleotide exchange factor that may function to stimulate the activity of the Ras1 protein. The third, downsteam of receptor kinases (drk) encodes a protein that binds to the sevenless and Sos proteins. These results have suggested that an important action of the sevenless protein may be to stimulate the activity of the Ras1 protein. Furthermore, this stimulation of Ras1 protein activity may be accomplished through the formation of a complex between the sevenless, drk, Sos, and Ras1 proteins.
Current work in the laboratory is aimed at understanding the detailed mechanism Ras1 activity. In addition, we are characterizing the products of additional Enhancer of sevenless loci in hopes of defining more components of the sevenless signaling pathway. The ultimate goal of all of these experiments is eventually to understand the biochemical steps of signal transduction by sevenless and other protein tyrosine kinases. Hopefully, these experiments will also lead to an understanding of pathways by which an undetermined cell can acquire a neuronal fate.