UCRF 2012 Innovation Award: Molecular Characterization of Monoubiquitinated Ras and its Role in Cancer

Title: Molecular Characterization of Monoubiquitinated Ras and its Role in Cancer, PI: Sharon L Campbell

Normal Ras proteins bind guanine nucleotide ligands (GTP, GDP) with high affinity, and cycle between active GTPbound and inactive GDP-bound states to regulate cellular pathways involved in cell growth, differentiation and apoptosis.

Ras is mutated in 33% of human cancers, leading to a persistently GTP-bound and activated mutant Ras protein. However, because of the picomolar binding affinity of Ras for GTP, the development of GTP binding antagonists is not feasible. Hence, it has been widely conceded that Ras is not a “druggable” protein.

However, recent findings by Cantley and colleagues that covalent modification of Ras by monoubiquitination may be key for its ability to drive human oncogenesis, suggests one possible handle on developing direct Ras inhibitors. To rigorously assess this possibility, two key issues need to be addressed.

First, what are the direct consequences of monoubiquitination on intrinsic Ras function? Second, the previous study showed that preventing monoubiquitination impaired the ability of activated K-Ras to promote tumor xenograft growth when ectopically expressed in NIH 3T3 mouse fibroblasts. How important is this modification for endogenous mutant Ras in human tumor cells with validated addiction to mutant Ras? Is this modification important for all Ras isoforms?

We propose studies to address these issues, with the long-term goal of determining the usefulness and feasibility of targeting Ras monoubiquitination in anti-Ras inhibitor development. In addition to the translational importance, our studies may also define new basic science paradigms regarding novel mechanisms by which monoubiquitination can regulate protein function.

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