Research Projects |Overview
The superfamily of Ras-like G proteins comprises the Ras, Rho, Arf, Rab, and Ran families. Ras is the principle oncogene in human cancer and utilizes members of the Rho in particular to elicit oncogenic transformation. Ras-like G proteins generally cycle between an inactive, GDP-bound, and an active GTP-bound state. This is cycle is often referred to as a molecular switch, because Ras-like G proteins bind effector molecules and elicit downstream signaling only in the GTP-bound state. However, most Ras-like G proteins are ineffective enzymes and rely on guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), to promote exchange of GDP for GTP and hydrolysis of GTP, respectively. In addition to domains conferring catalytic activity, the GEFs and GAPs contain numerous protein-protein interaction domains that provide spatial and temporal control over where in the cells and when a given Ras-like G protein is active.
Our work focuses on p190A and p190B RhoGAP, encoded byARHGAP35andARHGAP5, respectively. p190A and p190B are both widely expressed and arguably the most important RhoGAPs in mammals.ARHGAP35moreover ranks among the most frequently mutated genes in human cancer, in particular in adenocarcinomas, which are derived from polarized epithelial cells. Past work from our lab has demonstrated that p190A and p190B represent nodes for crosstalk among Rho family G proteins. Ongoing efforts in the lab seek to define the roles of p190A and p190B in epithelial morphogenesis and oncogenic transformation, as well as to identify means to devise targeted therapies in cancers with ARHGAP35 mutation.
We are also interested in a protein complex consisting of GITs, bPIX, and PAKs. GITs are putative GAPs for Arf proteins. bPIX is a GEF for the Rho-family proteins Rac and Cdc42, and PAK kinases are effector molecules for Rac and Cdc42. It is established that the GIT-bPIX-PAK complex exerts control over motile capacities, but the underlying mechanisms remain enigmatic. We have moreover demonstrated that bPIX and PAK2 function at membranes engaged in intercellular contact to offset apoptotic signals emanating from cell-cell adhesion complexes. However, the signaling pathway downstream of bPIX and PAK2 remains to be defined. We are working to elucidate such functions of the GIT-bPIX-PAK complex, which is implicated in cancer and a wide range of other diseases.