Elizabeth (Lizz) Grevengoed    1998-2003         
Curriculum in Genetics and Molecular Biology 

The roles of Abelson kinase and Enabled in cytoskeletal regulation
and cell adhesion during morphogenesis

Lizz's picture One research interest in our lab is the formation, morphogenesis, and maintenance of epithelial tissues. We focus on the role of specialized cell-cell junctions known as adherens junctions. Work from many labs has given us a static picture of how transmembrane cadherins mediate cell adhesion, and how they are linked to the underlying actin cytoskeleton by alpha- and ß-catenin. However, during development, epithelial cells are neither stationary nor rigid, but instead change shape and move in dramatic ways. In doing so, epithelial cells must coordinate their actions. Adherens junctions are a point of integration, holding adjacent cells together, and interacting with an underlying belt of actin that generates mechanical force. We hypothesized that signaling molecules were necessary to convey information between adherens junctions and the cytoskeleton to regulate adhesion and cytoskeletal connections and contractility, allowing cells to achieve the changes observed during morphogenesis. Previous data from our lab suggested that the non-receptor tyrosine kinase Abelson (Abl) was a candidate for this role. Abl is well known because mis-regulation of its kinase activity causes two types of human leukemia.

The first half of my work focused on testing the hypothesis that Abl plays a role in epithelial development. Previous work from other labs had suggested that Abl primarily functioned in the nervous system. However, this work was done in animals that were zygotically abl mutant. By generating embryos devoid of both maternal and zygotic Abl, we identified a novel role for Abl in epithelial morphogenesis. In this role, Abl regulates the stability of adherens junctions. We also observed that a known substrate of Abl, Enabled (Ena), which modulates the actin cytoskeleton, localizes to adherens junctions (Grevengoed et al., 2001). Thus Ena may be an Abl target in epithelial cells. We formulated two possible hypotheses for Abl function: 1) Abl directly phosphorylates adherens junction components or 2) Abl directly influences the actin cytoskeleton associated with adherens junctions, potentially via Ena.


In the second half of my work, I tested these two hypotheses, focusing on a novel role for Abl in early Drosophila development, where it regulates the site and type of actin structures produced. In Abl’s absence excess actin is polymerized in apical microvilli, while too little actin is assembled into pseudocleavage and cellularization furrows. These effects involve Ena mis-regulation. In abl mutants Ena accumulates ectopically at the apical cortex where excess actin is observed, suggesting that Abl regulates Ena’s subcellular localization. We also examined other actin regulators. Loss of Abl leads to changes in the localization of the Arp2/3 complex and the formin Diaphanous, and mutations in diaphanous or capping protein beta enhance abl phenotypes. These data led us to propose that Abl is a key regulator of the actin cytoskeleton and that it acts in part by regulating the localization of Ena (Grevengoed et al., 2003). Applying this to my earlier work, (Grevengoed et al., 2001), we propose that Abl plays a similar function during later morphogenesis, preventing inappropriate Ena accumulation along the leading edge during dorsal closure. Thus, Abl may stabilize components of adherens junctions by regulating actin polymerization at adherens junctions via Ena and possibly other partners. More generally, my work suggests that a cell must target different regulators of actin polymerization and depolymerization to different sites in the cell at different times, allowing it to build the diverse array of actin structures found during development.

Publications

Grevengoed E.E., Fox D., Gates J., Peifer, M. (2003). Balancing different types of actin polymerization at distinct sites: Roles for Abelson kinase and Enabled. Journal of Cell Biology 163:1267-79.

Grevengoed, E.E., and Peifer, M.  (2003).  Cytoskeletal connections: Building strong cells in new ways.  Current Biology 13: R568-R570.  

Akong, K., Grevengoed, E.E., Price, M.H., McCartney, B.M., Hayden, M.A., DeNofrio, J.C., and Peifer, M.  (2002).  Drosophila APC2 and APC1 play overlapping roles in Wingless signaling in the embryo and imaginal discs.  Developmental Biology 250, 91-100.

Grevengoed, E.E., Loureiro, J.J., Jesse, T.L., and Peifer, M.  (2001).  Abelson kinase regulates epithelial morphogenesis in Drosophila .  Journal of Cell Biology 155, 1185-1197.

McCartney, B.M., McEwen, D.G., Grevengoed,, E., Maddox, P., Bejsovec, A., Peifer, M.  (2001)  Drosophila APC2 and Armadillo participate in tethering mitotic spindles to cortical actin.  Nature Cell Biology 3, 933-938.