Analysis of Drosophila Kekkon1: an Inhibitor of the Epidermal Growth Factor Receptor

Indiana University, Bloomington IN

Investigators

Abstract

0131707 Duffy The Epidermal Growth Factor Receptor (EGFR or ErbB) family of receptor tyrosine kinases has been implicated in a myriad of developmental decisions including mitogenesis, apoptosis, cellular migration, determination, differentiation, and dedifferentiation. Despite our knowledge of the role of this family in cellular decisions, our understanding of receptor activation and signal propagation is still in its infancy. The studies proposed by Dr. Duffy will use the model system, Drosophila melanogaster, to shed further light on the activation of EGFR signaling. This will be accomplished by dissecting the role of the inhibitory molecule, Kek1, in EGFR signaling. Kek1 encodes a transmembrane protein of the Leucine Rich Repeat (LRR) and Immunoglobulin (Ig) family that acts in a negative feedback loop to inhibit EGFR signaling. The availability of an abundance of genetic and molecular tools in Drosophila provide the means to decipher the mechanism of EGFR inhibition by Kek1 in vivo. This analysis will determine if Kek1 represents a new mode of inhibition and contribute to an improved understanding of EGFR signaling. The specific objectives proposed by Dr. Duffy are: (1) to define the mechanism through which Kek1 inhibits D-EGFR signaling by generating modified forms of Kek1. These constructs will by assayed biochemically, genetically, and molecularly for their effects on D-EGFR activity, both in vivo and in cell culture; (2) to define the residues of Kek1 and D-EGFR that mediate their interaction; and (3) to determine if Kek1's inhibitory function is conserved to the vertebrate receptors. To elucidate the role of the EGFR/ErbB family in development, a continuing effort must be made to characterize inhibitory molecules, such as Kek1.