MOLECULAR GENETIC OF TYROSINE KINASE AND RAS FUNCTION

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Receptor Tyrosine Kinases (RTKs) are transmembrane proteins that transduce hormonal signals from the exterior to the interior of cells. The activation of RTKs can control many aspects of cellular metabolism, growth, and differentiation. Inadequate or inappropriate RTK signaling can result in diseases such as diabetes (inadequate insulin receptor signaling), certain forms of cancer (such as familial medullary thyroid carcinoma caused by overly active signaling by the RET RTK), and developmental abnormalities (such as Hirschsprung's disease caused by inadequate signaling by the RET RTK). The aim of the proposed research is to investigate how RTKs biochemically control cellular functions. We are addressing this issue by studying the action of a particular RTK, the product of the sevenless gene of Drosophila. We have chosen to study sevenless because of the ability to perform genetic and biochemical studies that are either difficult or impossible to conduct in vertebrate organisms. The activation of the sevenless RTK serves as a switch that causes a single cell within each subunit of the Drosophila eye to develop as a photoreceptor cell. Our approach is to identify components of the sevenless signaling pathway by characterizing mutations which attenuate sevenless signaling. We have shown that the activity of three proteins (corkscrew, daughter of sevenless and disabled) are essential for sevenless to efficiently induce photoreceptor development. Our results have shown that disabled is a probable substrate for the kinase activity of sevenless. Corkscrew encodes a protein tyrosine phosphatase which we have shown to function by dephosphorylating the daughter of sevenless protein. The goals of the proposed research are to further characterize the sevenless signaling pathway by: 1) biochemical and genetic investigations of the regulation and role of daughter of sevenless during sevenless signaling, 2) molecular characterization of further genes whose products collaborate with corkscrew and daughter of sevenless during sevenless signaling, and 3) biochemical investigation of disabled function. Since the biochemical pathways downstream of RTKs are highly conserved between flies and humans, we hope that a fuller understanding of sevenless signaling will provide the basis for understanding important aspects of human RTK signaling.