Regulation and function of Ral GTPases

Oncogenic Ras triggers several pathways that collaboratively promote cellular transformation, including the Raf/MAPK, PI3K/Akt and Ral GTPase signaling cascades. An effective therapy will consequently require inhibiting multiple targets. In the last decade Ral GTPase signaling has emerged as a critical arm in Ras-driven oncogenesis, but remains poorly characterized. This is highlighted by the fact that while about 40 inhibitors for the Ras-induced Raf/MAPK and PI3K/Akt pathways are currently undergoing clinical evaluation, strategies to target Ral signaling in oncogenesis do not exist, mainly due to a lack of information on the regulatory and downstream events. We therefore aim to define how the Ral pathway is regulated and differentially integrated in normal and cancer cells, as well as how deregulated Ral signaling drives cancer.
The Ral GTPases, RalA and RalB, transmit cellular signals through conformational transition between GDP- and GTP- bound states, a process regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs). We are currently focusing on gaining detailed insight into how these different Ral regulators, especially the newly identified Ral-GAP complexes, function to ensure proper control of Ral activity in cells. We are interested in how exactly Ral GTPases are activated in response to different stimuli and how this confers specificity to signal transmission through regulation of localization and timing via combinatorial control through different regulators. Another goal in the lab is to identify and characterize Ral-driven downstream pathways that affect gene profiles and proliferative characteristics of Ras-driven cancer cells for which we are employing different high throughput screening strategies.

We will also engage in additional projects that address epigenetic control mechanisms in Ras-dependent cancers and the interplay of chronic inflammation and cancer development.