Involvement of VHL, Awd, and Akt in the regulation of tracheal development. K.R. Lavenburg , V.R. Dammai , R.C Muise-Helmericks , T. Hsu. Laboratory of Cancer Genomics, Medical University of SC, Charleston, SC.

   Initial studies in our laboratory focused on cloning and examining the developmental role of the tumor suppressor gene, von Hippel Lindau (VHL), in Drosophilaembryogenesis. We concluded from these experiments that D-VHLis involved in terminating cell migration in the developing tracheal system, ultimately resulting in cessation of tubular outgrowth. In order to determine how D-VHLmay regulate cell migration, we utilized the yeast 2-hybrid system. We found that D-VHL interacts with the product of abnormal wing disc (awd), the Drosophila nm23homologue. Theawdlocus encodes a nucleoside diphosphate kinase, which supplies GTP to the Rho GTPases. One such GTPase, Rac, has been shown to signal to the cytoskeleton and regulate cell motility. Immunostaining studies revealed AWD protein expression in the developing tracheal system. Furthermore, mutations in awdresulted in an abnormal tracheal phenotype. Genetic interactions between D-VHLand awdwill also be presented.
    Recent findings suggest that Rac signals through PI3-kinase and Akt/PKB to induce cytoskeleton reorganization. When tested in our tracheal system, the Drosophila Akthomologue (D-Akt)demonstrated an essential function in tubular outgrowth. Embryos deficient in D-Aktdisplayed tracheal defects, such as breakage in the dorsal trunk as well as a decrease or complete absence of the smaller primary branches. We are thus beginning to elucidate the signaling pathway that modulates cell motility during tracheal development.