Jeffrey R. Peterson, PhD
Office Phone: 215-728-3568
1. Specificity in Rho GTPase Signaling
Cancer can arise as a result of mutations of genes participating in cellular signaling networks. One of the genes most commonly mutated in cancer is Ras. Once turned on, Ras, in turn, activates other signaling proteins that lead to cancer. One important set of proteins turned on by Ras is the Rho family of proteins, which includes Rac and Cdc42. Like Ras, the Rho proteins are GTP-binding signaling proteins that control the activity of a variety of other proteins, called effectors. Because of their important roles in cancer, Rho proteins and their effectors could be attractive targets for anti-cancer therapeutics.
It has been assumed that when the Rho proteins are turned on, all of their effectors must also be turned on. We have discovered that there are not enough of the Rho proteins to turn on all of their effectors. This means that only a subset of effectors can be turned on by Rho proteins at a time. The question now is what controls which effectors are activated by Rho? In order to answer this question we have developed a new model system to study Rho protein signaling in the test tube. Using this system we have documented three principles governing effector activation: 1) there is competition between effectors for the limiting amounts of Rho proteins, 2) Some effectors can act as “scaffolds” to preferentially link Rho proteins to particular effectors, and 3) Some effectors directly modulate the activation of other effectors. Our ongoing studies are revealing the mechanistic details of how Rho effector proteins are controlled and may reveal new opportunities for therapeutic intervention for cancer and metastasis.
2. Biological Functions of Rho Family Effectors
Once a Rho GTP-binding protein becomes active (GTP-bound) it can bind to any of a host of cellular effector proteins. One of our goals is to understand the function of each effector. We utilize in vitro biochemical studies and cell-based assays to elucidate the biological function of individual effectors. Our recent studies on the p21-activated kinases (Paks 1-6) have investigated their substrate specificity, identified novel substrates, determined crystal structures and identified selective drug-like inhibitors. We are expanding this analysis to other effectors in order to develop a comprehensive view of signaling downstream of Rho GTP-binding proteins.Top
3. High Throughput Identification of Drug-Like Inhibitors
Drug-like chemical inhibitors are important research tools to elucidate protein function and may form the basis for new therapeutics. We seek to identify new chemical inhibitors through high throughput screening of large libraries of diverse chemical compounds. Though this approach is common in the pharmaceutical industry as the first step in drug development, it is rather new in the academic environment. Our goals are to illustrate novel approaches to drug discovery through the development of new screening assays and to develop inhibitors against targets that may have, as yet, been ignored by industry. Active compounds are characterized with regard to their mechanism of action, activity in cells, and, where appropriate, tested in cell or animal cancer model systems.Top