Regulated Abl Tyrosine Kinase Activity is Critical for Cellular Adhesion. 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 and are critical for tissue organization and morphogenesis. The adhesive function of AJs is dependent on cadherins. In epithelial cells, Drosophila Armadillo (Arm), the homologue of vertebrate b-catenin, is a key component of AJs that mediates linkage of cadherins to the actin cytoskeleton. Arm is critical for cell-cell adhesion during development, and our lab has found that Arm interacts genetically with the non-receptor tyrosine kinase Abelson (Abl) and its substrate, Enabled (Ena), during cell-cell adhesion in epithelial cells. To understand the functions of Abl kinase during cell adhesion, we are assessing the effects of increasing Abl tyrosine kinase activity by characterizing the phenotypes of embryos expressing an oncogenic form of Abl, Bcr-Abl, which has elevated kinase activity and contributes to the pathogenesis of leukemia. In cell culture, Bcr-Abl expression results in increased cell motility and rearrangements of the actin cytoskeleton. We have found that Drosophila embryos ubiquitously expressing Bcr-Abl die with defects in morphogenetic processes that require cell shape changes and cell migration, including dorsal closure and germband retraction. Similar defects are observed in embryos over-expressing wild-type Abl, but not a mutant that lacks kinase activity, supporting the idea that regulated tyrosine kinase activity of Abl is critical for cell-cell adhesion in epithelial tissues. We hypothesize that Abl substrates play key roles at AJs and that Abl phosphorylation regulates their function. In support of this, Bcr-Abl localizes primarily to cell junctions; similarly, overall tyrosine phosphorylation levels are increased at cell junctions. Furthermore, we observe increased tyrosine phosphorylation levels of both Ena and Arm in the presence of Bcr-Abl. Studies to examine the effects of Bcr-Abl on other AJ components and the actin cytoskeleton are underway.