Abl Tyrosine Kinase Activity Regulates Cellular Adhesion and Actin Dynamics. T.L. Jesse, M. Peifer. Lineberger Cancer Ctr, Univ North Carolina, Chapel Hill, NC.

   Adherens junctions (AJs) are multiprotein complexes that mediate cell-cell adhesion in epithelial tissues and are critical for tissue organization and morphogenesis. AJs link to the actin cytoskeleton, and we are interested in understanding how actin polymerization and cellular adhesion are regulated at AJs. Studies in our lab indicate that the non-receptor tyrosine kinase Abelson (Abl) and its substrate, Enabled (Ena), may play a role in cytoskeletal regulation during cell-cell adhesion. To provide insight into the functions of Abl, we are assessing the effects of increasing Abl tyrosine kinase activity by characterizing the phenotypes of embryos ubiquitously expressing an oncogenic, activated form of Abl, Bcr-Abl. We have found that Drosophila embryos expressing Bcr-Abl die with defects in morphogenetic processes that require cell shape changes and cell migration including dorsal closure. Embryos expressing a mutant form of Bcr-Abl that lacks tyrosine kinase activity are viable, supporting the idea that regulated tyrosine kinase activity of Abl is critical for cell-cell adhesion in epithelial tissues. We hypothesize that Abl substrates may play key roles at AJs and that Abl phosphorylation regulates their function. In support of this, Bcr-Abl localizes primarily to cell junctions, where overall levels of tyrosine phosphorylation are increased. Furthermore, we observed increased tyrosine phosphorylation of Ena and other Ena-binding proteins and a loss of Ena localization to the leading edge and to cell junctions in the presence of Bcr-Abl. This is consistent with parallel studies in our lab on abl mutants that suggest that Abl negatively regulates Ena localized to certain sites, thus influencing actin polymerization. Our preliminary studies suggest that activating Abl disrupts the normal coordinated rearrangements of actin that occur during dorsal closure. Studies are underway to examine the dynamic behavior of actin in live embryos expressing Bcr-Abl.