Projects

Regulation of Rho-GEFs by scaffolding proteins 

 

    Sequence analysis shows that approximately half of the Rho-GEF family members contain putative binding motifs for PDZ domains in their C-terminus. PDZ domains are protein-protein interaction domains that act as scaffolds to concentrate signaling molecules at specialized regions in the cell. Our preliminary results show that these motifs in Rho-GEFs are functional and specifically bind to PDZ-containing proteins. We also found that some of these PDZ proteins were able to target the Rho-GEFs to different subcellular locations. In addition, we found that some PDZ proteins are able to modulate the activity of Rho-GEFs upon binding. My hypothesis is that the regulated binding to and release from PDZ domain-containing scaffolding proteins is a simple but versatile mechanism to control temporally and spatially the localized activation of Rho-GEFs. 

 

Role of Rho-GTPases in Podosomes/Invadopodia Formation

       Podosomes are highly dynamic, actin-rich adhesion structures that are found mainly in motile cells, and are thought to contribute to tissue invasion and matrix remodeling. Podosome formation induces a dramatic change in the actin cytoskeleton, promoting stress fiber disassembly and actin polymerization at the podosome ring. We are interested in characterizing the regulation of Rho GTPases activity during podosome formation in rat vascular smooth muscle cells and also identify the Rho-GEFs and Rho-GAPs responsible for their regulation.

Characterization of RhoA function in the cell nucleus

       We have recently described a RhoA signaling pathway in the nucleus dowsntream of DNA damage. We are now investigating the molecular mechanisms that regulate RhoA activation in the nucleus, as well as the downstream effectors involved in the response to ionizing radiation-induced DNA damage.