Role of RhoGTPases during Invadopodia formation

The migration of cancer cells away from the primary tumor and their subsequent metastasis to distant organs is the leading cause of mortality. Because the dense extracellular matrix (ECM) present acts as a physical barrier, cancer cells need to degrade the ECM during the metastatic processes. When cancer cells shift to a more invasive phenotype, they form specialized membrane structures called invadopodia that mediate the degradation of the ECM. Formation of invadopodia involves a dramatic rearrangement of the actin cytoskeleton, including the disassembly of focal adhesions and stress fibers, a process that is regulated by the Rho family of small GTPases. Our goal is to characterize the molecular mechanisms by which Rho GTPases regulate the formation of invadopodia in cancer cells.

Identification of novel RhoGEFs/GAPs

Activation of Rho proteins is mediated by RhoGEFs (guanine nucleotide exchange factors), whereas RhoGAPs (GTPase activating proteins) mediate their inactivation. There are more than 70 RhoGEFs, approximately 65 RhoGAPs and more than 100 effectors in humans, allowing cells to regulate the activity of Rho proteins through multiple pathways However, very little is known about the upstream and downstream components that regulate the Rho family of proteins, in particular the identity of the GEFs and GAPs and effectors that control each of the pathways where Rho GTPases are involved. Our long-term goal is to characterize novel mechanisms of regulation of Rho GTPases that contribute to cell adhesion, migration, and invasion. 

The role of Scribble/SGEF/Dlg1 complex in epithelial cell junctions

We have recently shown that SGEF, a RhoG-specific GEF, is a new component of the Scribble complex that acts as a scaffold to form a ternary complex by interacting directly with Scribble and Dlg1 (See Awadia et al., 2019 in Publications), and plays a role during junction formation, apical contractility, E-cadherin stability and lumen formation. We propose that SGEF plays a key role in coordinating junctional assembly and actomyosin contractility by bringing together Scribble and Dlg1 and targeting RhoG activation to cell-cell junctions. We are currently exploring the molecular mechanisms of regulation of the Scribble/SGEF/Dlg1 complex, its upstream and downstream regulation and its function in vivo.