RhoGTPase signaling pathways in cell growth regulation and transformation

The RhoGTPases and the GEFs that activate them, regulate several aspects of oncogenic transformation like cell cycle progression or protection from apoptosis. This, along with their involvement in cell motility and cytoskeletal reorganization, strongly suggests that they may have a important role in the aberrant regulation of cell growth in tumor cells. In order to understand how the RhoGTPases regulate growth and transformation, it is important to determine which are the molecular pathways and the target proteins that mediate these processes. We have studied two different aspects of their transforming capacity.;We have explored the mechanism by which Dbl, a GEF for Rho, Rac, and Cdc42, and the GTPase activate the NF-kappaB pathway. We have looked at the components of the NF-kappaB pathway that are targeted and activated by the different GTPases. Interestingly, we have found that there are different molecular mechanism utilized by Rho, Rac and Cdc42 to induce NF-kappaB activation. In addition, we found that the signaling enzymes that mediate NF-kappaB activation by Dbl and the GTPases are also necessary for malignant transformation induced by Dbl.;We have also looked at Pak4, a target protein that may be mediating transformation induced by Cdc42. Pak4 is overexpressed in human tumor cell lines, and it is the only member of the Pak family that is highly transforming in immortalized fibroblasts. To explore the effects of Pak4 on cell growth in more detail, we have looked at its effects in primary cells. We found that, similar to strong oncogenes like Ras, Pak4 does not transform primary cells, but instead inhibits cell proliferation and induces premature cellular senescence.