Signaling behind bars: a role for bar domains

In this thesis we describe several novel components of growth factor receptor and RhoGTPase activation and signaling. We have demonstrated that the F-BAR protein PACSIN2 is an important regulator of Rac1 output and, as a consequence, cell spreading and migration. This study further established the importance of traffic in the regulation of RhoGTPase function. In addition, we identified HMHA1 as a novel hematopoietic cell-restricted RhoGAP that regulates the actin cytoskeleton as well as cell spreading. Because expression of the HMHA1 has been observed in epithelial tumor cells as well, future studies should define the mechanisms through which HMHA1 regulates the transformation and invasiveness of these tumor cells. Furthermore, owing to its role as a minor histocompatibility antigen, T cells are generated against epitopes of HMHA1. As the healthy epithelium does not express HMHA1, it might prove an excellent target for tumor therapy. In addition, we describe a novel mechanism through which Rac1 regulates epithelial junction stability independent of the actin cytoskeleton. Although many studies focused on the regulatory role of RhoGTPase in junction remodeling in the context of actin dynamics, our study revealed that additional mechanisms through which RhoGTPases affect cell-cell junctions exist, further underscoring the complexity of RhoGTPase signaling in junction remodeling. Finally, although many pathways that regulate growth factor receptor traffic have already been described, we demonstrate in this thesis a novel component, PACSIN2, that acts as an important regulator of growth factor receptor activation and signaling.