MOLECULAR GENETICS OF TYROSINE KINASE AND RAS FUNCTION

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Protein Tyrosine Kinases (PTKs) are important cellular regulators whose activation can control cellular metabolism (e.g., the insulin receptor), differentiation (the CSF-1 receptor), and growth (PDGF and EGF receptors). The goal of the proposed research is to understand how PTKs have these effects on cells. We are addressing this issue by studying the action of a particular receptor PTK, the product of the sevenless gene of Drosophila melanogaster. The activation of the sevenless PTK serves as a switch that causes a single cell within each unit of the Drosophila compound eye to develop as a photoreceptor rather than as a lens-secreting cell. Our approach is to identify essential components of the sevenless signaling pathway by isolating and characterizing mutations that attenuate signaling by the sevenless PTK. These studies have led to the identification of seven genetic loci (called Enhancers of sevenless) that are candidates to encode proteins that act in sevenless signaling pathway. We have molecularly identified two of the Enhancer of sevenless genes. One, Rasl, is the Drosophila homologue of the H-ras gene of vertebrates. The other, Son of Sevenless (Sos), encodes a putative guanine nucleotide exchange factor whose role may be to activate the Rasl protein. Our subsequent studies have demonstrated that the activation of the Rasl protein can bypass the requirement for sevenless activity and have therefore suggested that the activation of the Rasl protein may be the sole essential action of the sevenless PTK. The goal of the proposed research is to further characterize the sevenless signaling pathway by: 1) molecularly characterizing additional Enhancer of sevenless genes, 2) asking whether the Sos protein is an activator of nucleotide exchange by the Rasl protein, and if so, whether Sos protein activity is regulated by the sevenless PTK, and 3) genetically identifying and molecular characterizing loci that encode components of the Rasl effector pathway. The ability of PTKs to regulate crucial cell processes suggests that an understanding of PTK signal transduction pathways will provide insight into the basic control mechanisms that regulate cell division, metabolism and differentiation. Furthermore, the well-documented involvement of PTKs and ras proteins in the etiology of cancer suggests that understanding the pathways that PTKs and ras proteins use to regulate cellular events will shed light on how inappropnate activation of these proteins can contribute to neoplastic transformation.