Many details of Ras pathway function, and of its associated dysfunction in cancer, have been elucidated in the last twenty years. However, effective therapies have been elusive. Recent work indicates that additional analysis of a key Ras effector pathway, the RalGEF/Ral GTPase pathway, is warranted. Specifically, studies have shown that RalGEF/Ral pathway activation is required for Ras induced transformation of diverse cancer cell lines. Therefore, understanding and targeting RalGEF/Ral is likely to also help target Ras. Like activating mutations in Ras and increased levels of active Ral, overexpression of the Aurora A kinase is particularly common in pancreatic cancer. A serine residue (S194) in the RalA GTPase is a target of Aurora A phosphorylation. Recently, we found that Aurora A-mediated phosphorylation of RalA changes its location within the cell and alters its downstream activities. Additionally, this phosphorylation step is required for optimal tumorigenicity of pancreatic cancer cells. These results suggest that Aurora A and RalA are important targets downstream of Ras, and that targeting Aurora can impair Ras-driven tumors. The goal of this proposal is to further understand the role of Aurora A regulation of RalGEF/Ral GTPase ? signaling in cancer. I will test whether RalA influences the sensitivity of human pancreatic cancer cell lines to an Aurora A-selective pharmacological inhibitor, whether the effectiveness of the inhibitor can be monitored by analyzing phosphorylation of RalA on S194, and whether a RalA mutant that mimics Aurora A phosphorylation can block the effects of the inhibitor. Additionally, I will determine whether Aurora A also phosphorylates RalGEFs, which are upstream activators of Ral GTPases, and if so, determine the functional consequences. Finally, I will determine the role of RalGEF/Ral signaling in radiation response of pancreatic cancer cell lines and analyze its regulation by activated Ras and Aurora A. Together, my studies have the potential to improve our understanding of the contribution of Ras, Ral and Aurora A to pancreatic cancer, to validate Aurora A as a target for pancreatic cancer treatment, to identify phosphorylated RalA(S194) as a biomarker for successful application of a pharmacological Aurora A inhibitor, to identify RalGEFs/Ral and/or Aurora A as targets for novel radiosensitizers, and to implicate the importance of targeting Aurora A and RalGEF/Ral as surrogates for targeting Ras in pancreatic cancer. ? ? ?
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|Kidd 3rd, Ambrose R; Snider, Jared L; Martin, Timothy D et al. (2010) Ras-related small GTPases RalA and RalB regulate cellular survival after ionizing radiation. Int J Radiat Oncol Biol Phys 78:205-12|