research
current projects
Identification of and characterization of novel RhoGEFs.
We have used multiple approaches over the years to define novel roles for multiple RhoGEFs, including protein-protein interaction and proteomics studies, shRNA candidate screens, as well as fixed and live imaging. These studies, from my lab and several collaborative efforts, have resulted in multiple publications, including our recent collaborative effort identified three novel Rac-GEFs, ARHGEF39, Tiam2 and FARP1, involved in the regulation of cell motility in lung adenocarcinoma. We continue characterizing the molecular mechanisms controlling RhoGEF signaling in both normal and cancer cells.
Regulation of invadopodia formation by RhoGEFs and RhoGAPs.
During metastasis, cancer cells need to traverse the dense extracellular matrix (ECM), which acts as a physical barrier. When cancer cells shift to a more invasive phenotype, they form specialized membrane structures called invadopodia that mediate the degradation of the ECM. The loss of invadopodia correlates with decreased tumorigenicity and dissemination in vivo and makes them very attractive targets for cancer therapy.
Regulation of epithelial cell junctions and polarity by Rho GTPases.
The establishment of apicobasal identity is essential for epithelial cells’ function, and the loss of cell polarity is a hallmark of many diseases, including cancer. Therefore, it is fundamentally important to understand the molecular mechanisms that control epithelial polarization. In two recent studies, we demonstrated that SGEF forms a ternary complex with the Scribble polarity complex proteins Scribble and Dlg1, and regulates the formation and maintenance of adherens and tight junctions in epithelial cells. Notably, SGEF depletion (but not Scribble or Dlg1) reduces E-cadherin and ZO-1 levels, destabilizes apical junctions, and increases epithelial permeability. SGEF activity is required for E-cadherin stability, which is linked to β-catenin signaling, Slug-mediated transcriptional repression, and E-cadherin endocytosis. We are currently exploring the role of this ternary complex in regulating the targeting and activation of SGEF, as well as its role in E-cadherin recycling and lumen formation in 3D cysts.
Developing new tools to study Rho GTPase signaling dynamics of in live cells.
A key challenge in the Rho GTPase field is the development of tools that avoid overexpression or compensation artifacts and also function within the temporal and spatial scales relevant to Rho GTPase signaling processes. Continuing our long-standing history of designing tools to analyze Rho GTPases function, we are developing several new tools to study Rho signaling in live cells and under physiological conditions: 1) New Rho localization sensors to study the spatiotemporal dynamics of Rho GTPases. 2) Optogenetic control of Rho signaling. 3) Endogenous tagging of Rho regulators. We are using a CRISPR-Cas9 KI system to endogenously tag RhoGEFs and RhoGAPs with fluorescent proteins to study their dynamics at endogenous levels in live cells, avoiding overexpression artifacts.