Research Information

Defining the mechanisms of regulation of actin polymerization during morphogenesis

The ability of cells to self-assemble into organs is extraordinary and requires tight coordination between the cell machinery modulating adhesion and the cytoskeleton. Defects in this coordination contribute to diseases ranging from developmental defects to cancer; thus it is critical to understand the mechanisms by which coordination of changes in cell adhesion and the actin cytoskeleton is achieved. One factor that regulates this is Abelson tyrosine kinase (Abl). Abl is both a key oncogene and developmental regulator, which functions to link receptors, small adaptor proteins, and cytoskeletal regulators. Three models for Abl function currently exist: 1) Abl phosphorylates protein targets, thus altering their function and influencing cell behavior, 2) Abl directly modulates cytoskeletal dynamics through its conserved C-terminal actin binding domain (FABD), and 3) Abl acts as a scaffold to assemble multi-protein signaling complexes. However, the importance of each role during morphogenesis remains untested.

Using Drosophila embryogenesis as a model, I am working to distinguish between these models by defining how specific functional domains (e.g., kinase activity, F-actin binding, or motifs involved in protein-protein interactions) contribute to Abl’s roles in embryonic morphogenesis. Recently, we have found that specific functional domains differentially affect distinct morphogenic events ranging from epithelial morphogenesis to central nervous system patterning, suggesting that Abl functions as a robust regulatory machine during morphogenesis, with different aspects of its mechanisms of action (e.g., kinase activity, FABD domain, binding partners, etc.) being differentially important for certain biological processes. The overall goal of my work is to define how Abl and its interacting partners regulate cell adhesion and actin dynamics in a normal developmental context. Insight gained from this work will provide new clues as to how Abl works to regulate dynamic cell behaviors during human development and diseases, including cancer.